WO2018199039A1 - Method for predicting development of metabolic syndrome using aim as index - Google Patents

Method for predicting development of metabolic syndrome using aim as index Download PDF

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WO2018199039A1
WO2018199039A1 PCT/JP2018/016492 JP2018016492W WO2018199039A1 WO 2018199039 A1 WO2018199039 A1 WO 2018199039A1 JP 2018016492 W JP2018016492 W JP 2018016492W WO 2018199039 A1 WO2018199039 A1 WO 2018199039A1
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mets
concentration
serum
aim
risk
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Japanese (ja)
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明子 秦
真理 船木
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明子 秦
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

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  • the present invention relates to a method for predicting the onset of metabolic syndrome (MetS), and in particular, to a method for predicting the risk of MetS onset using AIM (Apoptosis Inhibitor of Macrophage).
  • MetS metabolic syndrome
  • AIM Apoptosis Inhibitor of Macrophage
  • Metabolic syndrome is a condition in which lifestyle-related diseases such as diabetes, dyslipidemia, hypertension, and obesity occur in one person, and the risk of arteriosclerosis is extremely high. It is used as a disease name representing the above.
  • the treatment of MetS is not aimed at alleviating the symptoms, but is aimed at preventing the onset of the various diseases that can develop in a chained manner. Since it is difficult to restore the pathological condition once advanced, it is necessary to start prevention at an early stage. Therefore, a prediction method capable of evaluating the risk of developing MetS at an early stage is required. At present, there are diagnostic criteria for MetS, and the risk of onset of MetS is predicted based on how close the criteria are.
  • Non-Patent Document 1 AIM secreted from macrophages plays a role of promoting these processes in a series of processes of generation of chronic inflammation in hypertrophic adipocytes and thereby induction of insulin resistance.
  • AIM also has an anti-obesity effect that breaks down fat and contributes to MetS-related diseases such as diabetes and arteriosclerosis, and has an important contribution to the autoimmune process associated with obesity. It is also reported that it plays a decisive role (Non-Patent Document 2). In this way, it has been suggested that AIM is directly involved in the origin of MetS as research on AIM progresses (Patent Document 1).
  • the cause of macrophage migration to adipose tissue is that the blood concentration of AIM increases with obesity. That is, it is considered that macrophages infiltrate adipose tissue to cause chronic inflammation in the adipose tissue and the whole body, induce insulin resistance, and cause a series of MetS disease chains.
  • An object of the present invention is to provide a method capable of accurately predicting the actual onset of MetS. Furthermore, it aims at providing the method of avoiding MetS onset using this prediction method.
  • the present inventors examined the relationship between the serum AIM concentration and the onset of MetS based on the results of follow-up studies on the onset of MetS in Tokushima Prefecture. When the cumulative incidence of MetS after 8 years was evaluated based on the serum AIM concentration at the start of follow-up, the following findings were obtained. a) As shown in FIG.
  • the cumulative incidence of MetS after age adjustment is the quantile of serum AIM concentration (less than 3.071 ⁇ g / ml, 3.071 ⁇ g / ml-3.980 ⁇ g / ml, 3 .981 ⁇ g / ml-5.247 ⁇ g / ml, 5.247 ⁇ g / ml)) increased statistically significantly from the third quantile. In addition, a significant linear trend was also observed.
  • FIG. 1 (right) the serum AIM concentrations in the multivariate adjustment model (models excluding the influence of age, BMI, smoking, drinking, and exercise habit risk factors) The hazard ratio for the onset of MetS was determined.
  • the hazard ratio of the first quantile is 1.00
  • the second quantile is 1.63
  • the third quantile is 2.79
  • the fourth quantile is 2.41.
  • the hazard ratio increased significantly in the quantile and the fourth quantile.
  • the risk of developing MetS increased significantly.
  • the serum AIM concentration is classified into a low value group and a high value group with a median value (3.98 ⁇ g / ml).
  • the median age (40 years) was also used to classify the age group into the older group and the younger group, and the hazard ratio for the onset of MetS was determined.
  • the hazard ratio (risk of developing MetS) is the first time that both the older age and the high blood AIM value are available. It has been clarified by the present invention that the rise is.
  • the AIM concentration in the blood is taken as one index, and the following index group (age, lifestyle index (smoking, drinking, exercise, obesity, nutrients, food group, etc.), metabolic index (blood pressure, lipid) Metabolic marker, serum adiponectin concentration, serum FABP4 (Fatty acid-binding protein 4) concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after glucose tolerance test (OGTT), 1 hour after meal or 2 hours.
  • MetS risk ratio
  • the gist of the present invention is as follows. (1) A method for predicting the onset of metabolic syndrome (MetS), From AIM concentration in test subject's blood, age, lifestyle index, metabolic index, In combination with serum AIM concentration and one or more other indicators, The prediction method characterized by determining that the subject has a high risk of developing or suffering from MetS or a related disease. (2) From the subject's blood AIM concentration, age, lifestyle index, and metabolic index, combining the serum AIM concentration and one or more other indicators, the subject may have MetS or related diseases.
  • MetS metabolic syndrome
  • Determining a high risk of developing or being affected Measuring the AIM concentration in the blood of the subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and if each index meets a reference or reference value, the subject The method according to (1) above, further comprising determining that the risk of developing or suffering from MetS or a related disease is high.
  • the above metabolic indicators are blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 hour or 2 hours after meal.
  • the prediction method as described in said (7) that the AIM density
  • the AIM concentration in blood is 3.98 ⁇ g / ml or more (in particular, 3.98-5.25 ⁇ g) / Ml)
  • the method for predicting the onset of MetS includes the AIM concentration in blood as one index, and further, age, lifestyle index (smoking, drinking, exercise, obesity, nutrients, food group, etc.), metabolic index (blood pressure). , Lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 or 2 hours after meal, blood HbA1c concentration, inflammatory marker, etc. ) As an index, and a combination of multiple evaluation methods.
  • the multidimensional prediction method using the serum AIM concentration of the present invention as an index has been found to be quite effective and highly accurate for the future prediction of the onset risk of MetS.
  • Cumulative incidence and hazard ratio of MetS in 369 subjects (male, 20-60 years old) by serum AIM concentration level in 2008 (less than 3.071 ⁇ g / ml, 3.071 ⁇ g / ml-3.980 ⁇ g / ml, (3. 981 ⁇ g / ml-5.247 ⁇ g / ml, 5.247 ⁇ g / ml excess).
  • serum AIM concentration increased, the cumulative incidence of MetS increased statistically significantly.
  • the cumulative incidence of MetS increased significantly when the serum AIM concentration exceeded 3.98 ⁇ g / ml.
  • the risk of developing MetS increased significantly as the serum AIM concentration increased.
  • the “metabolic syndrome (MetS) onset prediction method” of the present invention is a method for predicting the risk of onset of MetS by taking AIM concentration in blood as one index and combining it with other indices in combination with other indices.
  • Other indicators include, for example, age considered to be an indicator affecting MetS, lifestyle indicators (one or more of smoking, drinking, exercise, obesity, nutrients, food groups, etc.), and metabolic indicators (blood pressure, lipid metabolism) Marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 hour or 2 hours after meal, blood HbA1c concentration, inflammatory marker concentration, etc. 1 or more) can be used.
  • ⁇ g / ml is set as a determination reference value for the AIM concentration in blood, and the test subjects are classified into subjects having higher values and subjects having lower values.
  • BMI value degree of obesity
  • FIG. 1 The relationship between the serum AIM concentration and the cumulative incidence of MetS or the risk of developing MetS is shown in FIG. 1, and it is shown that the cumulative incidence of MetS and the risk of developing MetS increase as the serum AIM concentration increases.
  • FIG. 1 confirms the known relevance that the risk of developing MetS increases as the serum AIM concentration increases, indicating that there is no significant bias in the subject population of the present invention.
  • FIG. 2 shows an overview of evaluation of the risk of developing binary MetS based on serum AIM concentration and age.
  • Combining serum AIM concentration and age index has a synergistic effect on the onset of MetS by combining both older age and high AIM concentration, rather than aging or increasing serum AIM concentration alone It was shown that. From this, it was found that a person having a high risk of developing MetS can be screened with high accuracy using a combination of serum AIM concentration and an index related to MetS.
  • the method for predicting the onset of metabolic syndrome (MetS) according to the present invention includes serum AIM concentration and other one or more of AIM concentration, age, lifestyle index, and metabolic index in a subject's blood. It is a prediction method that determines that the subject has a high risk of developing or suffering from MetS or a related disease by combining indices.
  • the prediction method of the present invention can also be regarded as a screening method for subjects having a high risk of developing or suffering from MetS or related diseases.
  • each index is a reference or This is a method for predicting the onset of MetS when it is determined that the subject has a high risk of developing or suffering from MetS or a related disease when the reference value is met.
  • the method of the present invention comprises the steps of measuring AIM concentration in the blood of a subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and each index is a reference or reference
  • a method for predicting the onset of MetS including a step of determining that the subject has a high risk of developing or suffering from MetS or a related disease when the subject falls under the value. “High risk” can be regarded as “risk”.
  • the present invention provides a combination of serum AIM concentration and one or more other indicators among the AIM concentration in blood of the subject, age, lifestyle indicators, and metabolic indicators, and MetS in the subject or its This is a method for predicting the possibility of progression of MetS or a related disease, which is judged to have a high possibility that the disease state of the related disease will progress (particularly, the progression of the disease state is accelerated).
  • the prediction method of the present invention can also be regarded as a screening method for a subject who is highly likely to progress in the pathological condition of MetS or a related disease (particularly, the progress of the pathological condition is accelerated).
  • the methods of the present invention among the AIM concentration in the blood of the subject, age, lifestyle index, metabolic index, the serum AIM concentration and one or more other indices are combined, and each index is a reference or When the reference value is met, MetS or the related disease in the subject is considered to have a high probability of progression (especially, the progression of the disease is accelerated). There is a prediction method.
  • the method of the present invention comprises the steps of measuring AIM concentration in the blood of a subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and MetS in the subject or its A method for predicting the possibility of progression of MetS or a related disease, comprising a step of determining that there is a high possibility that the disease state of the related disease progresses (in particular, the progression of the disease state is accelerated). “High possibility” can be regarded as “possibility”. Other conditions or configurations are the same as the method for predicting the onset of metabolic syndrome (MetS) of the present invention.
  • the “AIM concentration in blood” of the present invention refers to the concentration of protein AIM present in blood.
  • blood examples include whole blood, serum, plasma and the like. Among them, serum is preferable because it can be predicted with high accuracy.
  • AIM not only suppresses apoptosis of macrophages, but also plays a very important role in the progression of obesity and various pathological conditions associated with obesity. It is thought to receive. It has been reported that as obesity progresses, the AIM concentration in blood increases (Non-patent Document 1). In addition, it is known that the AIM concentration in human blood varies among individuals and varies depending on sex and age.
  • AIM increases its blood concentration under obesity, acts directly on adipocytes, and causes degradation of triglycerides via AIM-dependent lipolysis, free fatty acids and glycerol Occurs. Free fatty acids stimulate TLR4 expressed in adipocytes and promote the production of chemokines, and as a result, induce macrophage infiltration into hypertrophic adipocytes. Due to such a mechanism of action, it has been reported that obesity causes chronic inflammation in adipose tissue. Thus, AIM acts directly on adipose tissue to promote the release of free fatty acids through AIM-dependent lipolysis and induces macrophage infiltration, which leads to chronic inflammation of visceral fat and subsequent insulin resistance.
  • the “judgment standard value of AIM concentration in blood” of the present invention means a numerical value exceeding about 3.5 ⁇ g / ml, and depending on the combination with other indicators, it is about 4 (particularly about 4.0).
  • a numerical value exceeding ⁇ g / ml can be mentioned.
  • preferable numerical values include numerical values exceeding about 4.5 ⁇ g / ml or about 5 (particularly 5.0) ⁇ g / ml. More preferable numerical values include values exceeding 5.5 ⁇ g / ml or about 6 (particularly about 6.0) ⁇ g / ml. Most preferred values include values that exceed about 6.5 ⁇ g / ml or about 7 (particularly about 7.0) ⁇ g / ml. That is, when the AIM concentration in the blood exceeds the above value, it is determined that the reference value is met.
  • the “indicator of lifestyle habit” of the present invention refers to, for example, smoking, drinking, exercise, obesity, nutrients, food group, and the like.
  • One or more lifestyle indicators can be used.
  • smoking is used as an index, subjects are classified based on whether or not there has been a current smoking habit or a past smoking habit.
  • the criteria for higher risk of onset is to classify subjects based on whether or not they currently have a smoking habit. That is, it is determined that the current condition or the past, particularly, if there is a smoking habit at present, falls under the standard.
  • When using drinking classify subjects based on whether or not they have drinking habits.
  • subjects are classified based on a drinking habit of 20 g / day in terms of pure alcohol. That is, when there is a drinking habit, especially when there is a drinking habit of 20 g / day or more in terms of pure alcohol, it is determined that the standard or the reference value is met.
  • When using exercise classify subjects based on whether or not they have exercise habits.
  • subjects are classified on the basis of 23 mets ⁇ hour / week. That is, when there is no exercise habit, especially when the amount of exercise is 23 Mets ⁇ hour / week or less, it is determined that it corresponds to the reference or the reference value.
  • subjects are classified based on the BMI value of 23.
  • a BMI value of 25 As a criterion with a higher risk of onset, subjects are classified based on a BMI value of 25. That is, when the BMI value is 23 or more, particularly when the BMI value is 25 or more, it is determined that the reference value is satisfied.
  • the target daily intake or recommended dose For example, the subjects are classified into subjects such as excessive energy intake, excessive lipid intake, excessive carbohydrate intake, excessive sodium intake, or insufficient dietary fiber intake, and other subjects.
  • Daily target intake or recommended amount is described in “Japanese dietary intake standards” (2015, Ministry of Health, Labor and Welfare).
  • lipid intake, carbohydrate intake, and sodium intake if the daily intake target amount or recommended amount is exceeded, it is determined that it falls within the reference value. Moreover, about dietary fiber intake, when less than the daily intake target amount, it determines that it corresponds to a reference value. Even when food is used as an indicator, subjects are classified based on the daily intake standard. For example, excessive intake of meat, excessive intake of confectionery, excessive intake of alcohol / preference drinks, insufficient intake of seafood, insufficient intake of vegetables, insufficient intake of seaweed, excessive intake of sugar, excessive intake of fats and oils, etc. Divide the subject into other subjects.
  • the daily intake standard is calculated based on the description of “Meal Balance Guide” (2005, Ministry of Health, Labor and Welfare, Ministry of Agriculture, Forestry and Fisheries). Meat intake, confectionery intake, alcohol / preference drink intake, sugar intake, and fat intake are judged to meet the standard values when exceeding the daily intake standard. Regarding seafood intake, vegetable intake, and seaweed intake, if the intake is below the daily intake standard, it is determined that it falls under the standard value.
  • the “indicator of metabolism” of the present invention includes, for example, blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level after 2 hours of OGTT, 1 hour or 2 hours after meal Blood glucose level, blood HbA1c concentration, inflammatory marker concentration, and the like.
  • One or more metabolic indicators can be used.
  • blood pressure is used as an index, subjects are classified based on systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg.
  • systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg subjects are classified based on systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg. That is, when the systolic blood pressure is 130 mmHg or more or the diastolic blood pressure is 85 mmHg or more, particularly when the systolic blood pressure is 140 mmHg or more or the diastolic blood pressure is 90 mmHg or more, it is determined that the reference value is satisfied.
  • lipid metabolism markers include LDL cholesterol, HDL cholesterol, neutral fat, and total cholesterol. When LDL cholesterol is used as an index, subjects are classified based on 120 mg / dl.
  • subjects are classified based on 140 mg / dl. That is, when the serum LDL cholesterol concentration is 120 mg / dl or higher, particularly when the serum LDL cholesterol concentration is 140 mg / dl or higher, it is determined that it corresponds to the reference value.
  • HDL cholesterol is used as an index
  • subjects are classified based on 40 mg / dl. That is, when the serum HDL cholesterol concentration is less than 40 mg / dl, it is determined that the reference value is met.
  • subjects are classified based on 150 mg / dl.
  • the serum triglyceride concentration is 150 mg / dl or more, it is determined that the reference value is satisfied.
  • total cholesterol is used as an index
  • subjects are classified based on 220 mg / dl. That is, when the serum total cholesterol concentration is 220 mg / dl or more, it is determined that it corresponds to the reference value.
  • serum adiponectin concentration as an index, subjects are classified based on 9.9 ⁇ g / ml for males and 9.1 ⁇ g / ml for females. As a criterion with a higher risk of onset, male subjects are classified based on 6.2 ⁇ g / ml.
  • serum adiponectin concentration is less than 9.9 ⁇ g / ml for men and less than 9.1 ⁇ g / ml for women, particularly when it is less than 6.2 ⁇ g / ml, it is determined that the reference value is met.
  • serum FABP4 concentration is used as an index, subjects are classified based on 9.0 ng / ml. As a criterion with a higher risk of onset, subjects are classified based on 11.0 ng / ml. That is, when the serum FABP4 concentration is 9.0 ng / ml or higher, particularly when it is 11.0 ng / ml or higher, it is determined that the serum FABP4 concentration falls within the reference value.
  • liver function marker When the liver function marker is used as an index, subjects are classified based on the serum ALT concentration of 30 U / L, the serum AST concentration of 30 U / L, the serum ⁇ GTP concentration of male 45 U / L, and female 25 U / L. That is, when the serum ALT concentration is 30 U / L or more, when the serum AST concentration is 30 U / L or more, and / or when the serum ⁇ GTP concentration is 45 U / L or more for men and 25 U / L or more for women, It is judged that it corresponds to.
  • serum IgM concentration When serum IgM concentration is used as an index, subjects are classified based on 77.0 mg / dl.
  • subjects are classified based on whether or not the fasting blood glucose level satisfies the criteria of 100 mg / dl, 110 mg / dl, or prediabetes.
  • the criteria 100 mg / dl, 110 mg / dl, or prediabetes.
  • subjects are classified based on a fasting blood glucose level of 126 mg / dl. That is, when the fasting blood glucose level satisfies 100 mg / dl or more, 110 mg / dl or more, or the prediabetes standard (Diabetes Care 2017; Volume 40 Issue Supplemet 1), particularly when it is 126 mg / dl or more, it falls under the standard value to decide.
  • a test subject is classified on the basis of whether the reference
  • postprandial blood glucose as an index, subjects are classified based on 160 mg / dl as the blood glucose level for 1 hour after meal and 140 mg / dl as the blood glucose level for 2 hours.
  • subjects are classified based on a postprandial blood glucose level of 200 mg / dl. That is, when the blood glucose level for 1 hour after a meal is 160 mg / dl or more, or the blood glucose level for 2 hours is 140 mg / dl or more, and especially the postprandial blood glucose level is 200 mg / dl or more, it is determined that the reference value is met.
  • the blood HbA1c concentration is used as an index
  • subjects are classified based on whether the criteria of 5.6% or prediabetes are satisfied.
  • the criterion for higher risk of onset is to classify subjects on the basis of 6.5%.
  • serum IL-6 concentration subjects are classified based on 4.0 pg / ml. That is, when the serum IL-6 concentration is 4.0 pg / ml or more, it is determined that the reference value is met. Subjects are classified based on the serum TNF- ⁇ concentration of 2.9 pg / ml and the serum MCP-1 concentration of 150 pg / ml. That is, when the serum TNF- ⁇ concentration is 2.9 pg / ml or more, it is determined to be a reference value, and when the serum MCP-1 concentration is 150 pg / ml or more, it is determined to be a reference value.
  • age When using age as an index, classify subjects based on 40 years old. That is, when the age is 40 years or older, it is determined that the reference value is met.
  • the “metabolic syndrome onset” of the present invention is, for example, a diagnostic criterion of MetS (A joint statement of IDF, NHLBI, AHA, World Heart Federation, International Athleto Society Society, International Society of Science, It is determined that it is MetS based on the MetS diagnostic criteria. In addition, in the current diagnostic criteria in Japan, MetS is diagnosed if it falls into two of the following three items in addition to abdominal circumference (male 85 cm or more, female 90 cm or more).
  • Item 1 Neutral fat 150 mg / dl or more and / or (2) HDL-C less than 40 mg / dl
  • Item 2 Systolic blood pressure 130 mmHg or more and / or diastolic blood pressure 85 mmHg or more
  • Item 3 Fasting blood glucose level 110 mg / dl or more Item 1 (1) is treated with drug treatment for hypertriglyceridemia, Item 1 (2) is treated with drug treatment for low HDL cholesterolemia, Item 2 is treated for hypertension When receiving medical treatment, item 3 is also included in each item when receiving medical treatment for diabetes.
  • the “MetS or related disease” of the present invention refers to a disease caused by MetS and caused thereby, such as MetS, obesity, insulin resistance, diabetes, dyslipidemia, hypertension, arteriosclerotic disease, Examples thereof include cerebrovascular disorder, ischemic heart disease, heart failure, dementia, stroke, neuropathy, renal disease, abnormal secretion of adipocytokines and abnormal free fatty acid in blood.
  • the “risk of developing or suffering from MetS or a related disease” refers to the risk that a subject develops MetS or a related disease. Among other things, it may be a risk of developing MetS or its related diseases in 8 years. For example, as shown in FIG. 1 (right figure) and FIG. 2, this risk can be expressed as “hazard ratio” in the present invention.
  • the hazard ratio is a numerical value representing the relative risk by evaluating the risk of developing MetS at the blood AIM concentration using a multivariate adjustment model (for example, the Cox proportional hazard model). For example, as shown in FIG.
  • the risk of developing or suffering from MetS or a related disease is high” compared to the case where the AIM concentration in blood is less than 3 (particularly less than 3.07). Can be expensive.
  • the AIM concentration in the blood is 3.98 ⁇ g / ml or more
  • MetS or a related disease is developed or compared with a subject whose AIM concentration in the blood is less than 3 (particularly less than 3.07). It can be determined that the risk of suffering is significantly or 2.4 times higher.
  • the risk of developing or suffering from MetS or a related disease is high means that the AIM concentration in blood is 4 ⁇ g / ml or less (in particular, 3.98 ⁇ g / ml or less) and higher than that when the age is less than 40 years.
  • the AIM concentration in the blood exceeds 4 ⁇ g / ml (particularly exceeds 3.98 ⁇ g / ml) and the age is 40 years or older, the AIM concentration in the blood is 4 ⁇ g / ml or less (particularly 3. 98 ⁇ g / ml or less) and a risk of developing or suffering from MetS or a related disease can be determined to be significantly or 2.3 times higher than that of a subject who is less than 40 years old.
  • Example 1 Verification of the relationship between serum AIM concentration and the onset of MetS (1) About subjects a) Following-up target: 463 Tokushima male workers in 2008, 20-60 years old (exclusion criteria) Postprandial examinee, not yet Blood sample, measurement deficient, person with MetS b) Analysis target: 369 persons who could follow MetS onset or not c) Follow-up period: 8 years (2008-2016) d) Diagnostic criteria: MetS criteria were based on the following diagnostic criteria. A joint statement of IDF, NHLBI, AHA, World Heart Federation, International Aeroclerosity Society, International Association of the Study of Obesity e) Implementing organization: National University Corporation Tokushima University Hospital
  • the applicable person was determined to be MetS in the case of 3 or more of the 5 items listed in Table 1.
  • Serum AIM concentration at the start of follow-up to quartile (less than 3.071 ⁇ g / ml, 3.071 ⁇ g / ml-3.980 ⁇ g / ml, 3.981 ⁇ g / ml-5.247 ⁇ g / ml, 5.247 ⁇ g / ml)
  • the hazard ratio for the onset of MetS by quartile of serum AIM concentration in a multivariate adjustment model is 1 for the first quantile.
  • the serum AIM concentration is classified into a low value group and a high value group with a median value (3.98 ⁇ g / ml). Similarly, the age was also divided into two groups using the median (40 years).
  • the hazard ratio significantly increases 2.34 times when the age of 40 years or older and the serum AIM concentration is high. Therefore, a significant interaction is observed between age and serum AIM concentration, and the combination of increased age and increased serum AIM concentration can provide a synergistic effect on the onset of MetS and significantly increase the risk of developing MetS. I was able to clarify. From this finding, it has become clear that unlike the previous reports, the risk of developing MetS can be accurately predicted only by evaluating it with other indicators such as age rather than serum AIM concentration alone.
  • the method for predicting the onset of multidimensional MetS using the serum AIM concentration of the present invention as one index particularly by evaluating the risk of developing MetS based on age and serum AIM concentration as binary. It was possible to predict the onset of MetS in subjects. Furthermore, it has become possible to review lifestyle habits such as dietary habits and daily exercise using the method for predicting the risk of developing MetS according to the present invention, and it has become possible to control MetS prevention and treatment. Furthermore, it became easy to confirm the therapeutic effect of the onset MetS, and the disease state control of MetS became possible. It is also industrially useful in that it has been found that social resources for avoiding the onset of MetS should be allocated to people who are older and have a high AIM concentration in the blood.

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Abstract

From a cohort study conducted in Tokushima prefecture, Japan, a method for predicting a multidimensional risk of MetS (Metabolic Syndrome) development using the serum AIM (Apoptosis Inhibitor of Macrophage) level as an index was found using an epidemiological approach. Through the evaluation of the risk of MetS development using two indexes of age and serum AIM level, it was found that the risk of MetS development is 2.3 times higher for test subjects of at least 40 years old and having a serum AIM level exceeding 3.98 μg/ml. Using the method for predicting multidimensional MetS development of the present invention, where serum AIM level plays a key role, a chance to review one's daily health management, dietary habits, and lifestyle habits such as daily exercise is provided, making it possible to manage the prevention and treatment of MetS.

Description

ＡＩＭを指標とするメタボリック・シンドロームの発症予測方法Metabolic syndrome onset prediction method using AIM as an index
　本発明は、メタボリック・シンドローム（ＭｅｔＳ）の発症予測方法に関するものであり、特に、ＡＩＭ（Ａｐｏｐｔｏｓｉｓ　Ｉｎｈｉｂｉｔｏｒ　ｏｆ　Ｍａｃｒｏｐｈａｒｇｅ）を用いたＭｅｔＳ発症のリスクの予測方法に関するものである。 The present invention relates to a method for predicting the onset of metabolic syndrome (MetS), and in particular, to a method for predicting the risk of MetS onset using AIM (Apoptosis Inhibitor of Macrophage).
　メタボリック・シンドローム（ＭｅｔＳ）とは、糖尿病、脂質異常症、高血圧、肥満症といった生活習慣病が、一個人に重積して生じた状態のことをいい、動脈硬化症などのリスクが非常に高くなることを表す疾患名として用いられている。
　ＭｅｔＳの治療は、症状の緩和を目的とするのではなく、連鎖的に発症しうる上記の様々な疾患の発症予防が目標となっている。一度進行した病態を元通りに戻すのは難しいため、早い段階で予防を開始する必要があり、そのため早期にＭｅｔＳの発症リスクを評価できる予測方法が必要とされている。
　現状ではＭｅｔＳの診断基準があり、その基準にどれだけ近づいて来たかということで、ＭｅｔＳの発症リスクの予測がなされている。そこでＭｅｔＳの診断基準についてもこれまでに様々な診断基準が提唱されている。例えば、腹囲、中性脂肪、ＨＤＬコレステロール、血圧、空腹時血糖値等が診断項目として挙げられ、このうちいくつかの項目に該当する場合にＭｅｔＳと診断する実務がとられている。
　しかし、現行のＭｅｔＳの診断基準については種々の議論があり、ＭｅｔＳの病態の多様性に対応し難いことや、各診断項目の基準値を超過することがＭｅｔＳの発症及び病態の進行を必ずしも反映しないことが指摘されている。 Metabolic syndrome (MetS) is a condition in which lifestyle-related diseases such as diabetes, dyslipidemia, hypertension, and obesity occur in one person, and the risk of arteriosclerosis is extremely high. It is used as a disease name representing the above.
The treatment of MetS is not aimed at alleviating the symptoms, but is aimed at preventing the onset of the various diseases that can develop in a chained manner. Since it is difficult to restore the pathological condition once advanced, it is necessary to start prevention at an early stage. Therefore, a prediction method capable of evaluating the risk of developing MetS at an early stage is required.
At present, there are diagnostic criteria for MetS, and the risk of onset of MetS is predicted based on how close the criteria are. Therefore, various diagnostic criteria have been proposed for the diagnostic criteria of MetS. For example, abdominal circumference, neutral fat, HDL cholesterol, blood pressure, fasting blood glucose level, and the like are listed as diagnostic items, and practice of diagnosing MetS is taken when some of these items are met.
However, there are various discussions about the current diagnostic criteria for MetS, and it is difficult to cope with the diversity of MetS pathologies, and exceeding the standard values of each diagnostic item does not necessarily reflect the onset of MetS and the progression of the pathological conditions. It has been pointed out not to.
　近年、マクロファージから分泌されているＡＩＭが、肥大化した脂肪細胞における慢性炎症の発生、及びそれによるインスリン抵抗性の惹起という一連の過程においてこれらの過程を促進する役割を担っていることが明らかになってきた（非特許文献１）。
　また、ＡＩＭは脂肪を分解する抗肥満作用を始め、糖尿病や動脈硬化のようなＭｅｔＳと関連もしく連鎖的に発症する疾患にも重要な寄与をしており、肥満に伴う自己免疫のプロセスに対しても決定的な役割を果たしていると報告されている（非特許文献２）。
　このようにＡＩＭに関する研究が進展する中で、ＡＩＭがＭｅｔＳの成因に直接関与していることが示唆されている（特許文献１）。例えば、マクロファージが脂肪組織へ遊走する原因として、肥満に伴ってＡＩＭの血中濃度が上昇することが挙げられている。即ち、マクロファージが脂肪組織に浸潤することによって、脂肪組織及び全身に慢性の炎症を生じ、インスリン抵抗性が惹起され、ＭｅｔＳの一連の疾患連鎖が引き起こされると考えられている。 In recent years, it has been clarified that AIM secreted from macrophages plays a role of promoting these processes in a series of processes of generation of chronic inflammation in hypertrophic adipocytes and thereby induction of insulin resistance. (Non-Patent Document 1).
AIM also has an anti-obesity effect that breaks down fat and contributes to MetS-related diseases such as diabetes and arteriosclerosis, and has an important contribution to the autoimmune process associated with obesity. It is also reported that it plays a decisive role (Non-Patent Document 2).
In this way, it has been suggested that AIM is directly involved in the origin of MetS as research on AIM progresses (Patent Document 1). For example, the cause of macrophage migration to adipose tissue is that the blood concentration of AIM increases with obesity. That is, it is considered that macrophages infiltrate adipose tissue to cause chronic inflammation in the adipose tissue and the whole body, induce insulin resistance, and cause a series of MetS disease chains.
　そこで、ＡＩＭの血中濃度の上昇を検出すれば、ＭｅｔＳにおける一連の疾患連鎖のリスクを、そのもっとも上流の段階で早期に診断できると考えられた（特許文献１）。
　しかし、現実のＭｅｔＳ発症に対するＡＩＭの影響に関しては未だ不明な点も多く、更にＡＩＭとＭｅｔＳとの関連を見た追跡研究も少ない。また、ＡＩＭの血中の数値を用いたＭｅｔＳ危険度の予測方法は、まだ検討されていない状況であった。 Therefore, it was considered that the risk of a series of disease chains in MetS can be diagnosed early in the most upstream stage by detecting an increase in the blood concentration of AIM (Patent Document 1).
However, there are still many unclear points regarding the impact of AIM on the actual occurrence of MetS, and there are also few follow-up studies that looked at the relationship between AIM and MetS. In addition, a method for predicting the MetS risk using AIM blood values has not yet been studied.
再公表２０１１－１４５７２５号公報Republished 2011-145725
　本発明は、実際のＭｅｔＳ発症を精度よく予測できる方法を提供することを目的とする。更には、この予測方法を用いてＭｅｔＳ発症を回避する方法を提供することを目的とする。 An object of the present invention is to provide a method capable of accurately predicting the actual onset of MetS. Furthermore, it aims at providing the method of avoiding MetS onset using this prediction method.
　本発明者らは、徳島県のＭｅｔＳ発症に関する追跡調査の成績を基にして、血清ＡＩＭ濃度とＭｅｔＳ発症との関連性を検討した。追跡開始時の血清ＡＩＭ濃度に基づき、８年後のＭｅｔＳ累積発症率を評価すると、以下の知見が得られた。
ａ）　図１（左図）に示すように、年齢調整後のＭｅｔＳ累積発症率は、血清ＡＩＭ濃度の分位（３．０７１μｇ／ｍｌ未満、３．０７１μｇ／ｍｌ－３．９８０μｇ／ｍｌ、３．９８１μｇ／ｍｌ－５．２４７μｇ／ｍｌ、５．２４７μｇ／ｍｌ超過）が上昇するにつれ、第３分位から統計学的有意に増加した。加えて、有意な線形のトレンドも認めた。
ｂ）　図１（右図）に示すように、多変量調整モデル（年齢、ＢＭＩ、喫煙、飲酒、及び運動習慣の危険因子の影響を除いたモデル）における血清ＡＩＭ濃度の上記４分位別のＭｅｔＳ発症のハザード比を求めた。第１分位のハザード比を１．００とすると、第２分位１．６３、第３分位２．７９、第４分位２．４１であり、第１分位に比較し、第３分位と第４分位で有意にハザード比が上昇した。加えて、血清ＡＩＭ濃度が上昇するにしたがって、ＭｅｔＳ発症リスクは有意に上昇した。
ｃ）　多変量調整モデル（ＢＭＩ、喫煙、飲酒、及び運動習慣の危険因子の影響を除いたモデル）において、血清ＡＩＭ濃度を中央値（３．９８μｇ／ｍｌ）で低値群と高値群に分類し、同様に、年齢も中央値（４０歳）を用いて高年齢群と低年齢群に分類し、ＭｅｔＳ発症のハザード比を求めた。図２に示すように、血清ＡＩＭ濃度低値かつ４０歳未満の群と比べると、４０歳未満かつ血清ＡＩＭ濃度高値群、及び４０歳以上かつ血清ＡＩＭ濃度低値群ではハザード比に有意な変化は見られなかった。しかし、４０歳以上かつ血清ＡＩＭ濃度高値群では、４０歳未満かつ血清ＡＩＭ濃度低値群と比較すると、多変量調整後のＭｅｔＳ発症ハザード比は２．３４倍となり、ＭｅｔＳ発症リスクの有意な上昇を認めた。
　本発明の知見により、血液中のＡＩＭ濃度と年齢の指標を組み合わせることで、発症リスクの高い者を極めて高い精度でスクリーニングできることが見出された。即ち、これまで予想されていたように、血液中のＡＩＭ濃度の上昇がハザード比の上昇につながっているものの、高年齢と高血液ＡＩＭ値の両者が揃うことで初めてハザード比（ＭｅｔＳ発症リスク）が上昇する、ということが本発明により明らかになった。 The present inventors examined the relationship between the serum AIM concentration and the onset of MetS based on the results of follow-up studies on the onset of MetS in Tokushima Prefecture. When the cumulative incidence of MetS after 8 years was evaluated based on the serum AIM concentration at the start of follow-up, the following findings were obtained.
a) As shown in FIG. 1 (left figure), the cumulative incidence of MetS after age adjustment is the quantile of serum AIM concentration (less than 3.071 μg / ml, 3.071 μg / ml-3.980 μg / ml, 3 .981 μg / ml-5.247 μg / ml, 5.247 μg / ml)) increased statistically significantly from the third quantile. In addition, a significant linear trend was also observed.
b) As shown in FIG. 1 (right), the serum AIM concentrations in the multivariate adjustment model (models excluding the influence of age, BMI, smoking, drinking, and exercise habit risk factors) The hazard ratio for the onset of MetS was determined. Assuming that the hazard ratio of the first quantile is 1.00, the second quantile is 1.63, the third quantile is 2.79, and the fourth quantile is 2.41. The hazard ratio increased significantly in the quantile and the fourth quantile. In addition, as the serum AIM concentration increased, the risk of developing MetS increased significantly.
c) In the multivariate adjustment model (excluding the effects of risk factors for BMI, smoking, drinking, and exercise habits), the serum AIM concentration is classified into a low value group and a high value group with a median value (3.98 μg / ml). Similarly, the median age (40 years) was also used to classify the age group into the older group and the younger group, and the hazard ratio for the onset of MetS was determined. As shown in FIG. 2, compared with the group with low serum AIM concentration and under 40 years of age, there is a significant change in the hazard ratio in the group under 40 years of age and high serum AIM concentration, and in the group of 40 years of age and above and low serum AIM concentration Was not seen. However, in the group over 40 years of age and the high serum AIM concentration group, the MetS onset hazard ratio after multivariate adjustment was 2.34 times as compared with the group under the age of 40 and low serum AIM concentration, and the MetS onset risk was significantly increased. Admitted.
Based on the findings of the present invention, it has been found that by combining the AIM concentration in blood and an index of age, it is possible to screen a person with a high risk of onset with extremely high accuracy. That is, as expected, an increase in the AIM concentration in the blood leads to an increase in the hazard ratio, but the hazard ratio (risk of developing MetS) is the first time that both the older age and the high blood AIM value are available. It has been clarified by the present invention that the rise is.
　本発明の結果、血液中のＡＩＭ濃度を１つの指標とし、次の指標群（年齢、生活習慣の指標（喫煙、飲酒、運動、肥満、栄養素、食品群等）、代謝の指標（血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４（Ｆａｔｔｙ　ａｃｉｄ－ｂｉｎｄｉｎｇ　ｐｒｏｔｅｉｎ ４）濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ブドウ糖負荷試験（ＯＧＴＴ）２時間後の血糖値、食後1時間後または２時間後の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカー等））の中から選択される１つ或いはそれ以上の組み合わせで多元的に評価することにより、ＭｅｔＳ発症リスク（ハザード比）の上昇を的確に評価することができるようになった。
　これまでのＭｅｔＳの発症リスクの評価指標は、単独では充分な妥当性を担保し難いものであったが、本発明により、血液中のＡＩＭ濃度を中心にして、他の指標と組み合わせる多元的な評価が、より適切であることが明らかとなった。また、血液中のＡＩＭ濃度の中央値（３．９８μｇ／ｍｌ）を定め、それを基準にすることが、より将来的なＭｅｔＳの発症リスクの評価として有効であることが見出された。
　本発明により、ＭｅｔＳ発症リスク（ハザード比）を軽減するために、壮年期・中年期での血清ＡＩＭ濃度測定の重要性が明らかになった。
　本発明者らは、上記の知見に基づいて、本発明を完成した。 As a result of the present invention, the AIM concentration in the blood is taken as one index, and the following index group (age, lifestyle index (smoking, drinking, exercise, obesity, nutrients, food group, etc.), metabolic index (blood pressure, lipid) Metabolic marker, serum adiponectin concentration, serum FABP4 (Fatty acid-binding protein 4) concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after glucose tolerance test (OGTT), 1 hour after meal or 2 hours The subsequent increase in the risk of developing MetS (hazard ratio) can be accurately assessed by multiple evaluation with one or more combinations selected from later blood glucose levels, blood HbA1c concentrations, inflammatory markers, etc.) It became possible to evaluate.
Until now, the evaluation index of the risk of onset of MetS has been difficult to ensure sufficient validity by itself. However, according to the present invention, a multidimensional combination with other indices centering on the AIM concentration in blood is possible. It became clear that the evaluation was more appropriate. In addition, it was found that setting a median value (3.98 μg / ml) of AIM concentration in blood and using it as a reference is effective as a future risk assessment of MetS.
According to the present invention, in order to reduce the risk of developing MetS (hazard ratio), the importance of measuring serum AIM concentration in middle and middle age has been clarified.
Based on the above findings, the present inventors have completed the present invention.
　本発明の要旨は以下の通りである。
（１）　メタボリック・シンドローム（ＭｅｔＳ）発症の予測方法であって、
被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、
血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、
当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断することを特徴とする、予測方法。
（２）　被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断することが、
　被験者の血液中のＡＩＭ濃度を測定し、かつ年齢、生活習慣の指標、及び代謝の指標の一つ以上を判定又は測定する工程と、各指標が基準又は基準値に該当する場合に、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断する工程とを含むことである、上記（１）に記載の、予測方法。
（３）　上記生活習慣の指標が、喫煙、飲酒、運動、肥満、栄養素、食品群の中から選択されることを特徴とする、上記(１)又は（２）に記載の予測方法。
（４）　上記代謝の指標が、血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ＯＧＴＴ２時間後の血糖値、食後1時間または２時間の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカーの中から選択されることを特徴とする、上記（１）～（３）のいずれかに記載の予測方法。
（５）　被験者の血清ＡＩＭ濃度の判断基準値が３．５μｇ／ｍｌを超過する数値である、上記（１）～（４）のいずれかに記載の予測方法
（６）　血液中のＡＩＭ濃度の判断基準値が３．９８μｇ／ｍｌを超過する数値である、上記（１）～（４）のいずれかに記載の予測方法
（７）　年齢を指標として用い、年齢の判断基準値が４０歳以上である、上記（１）～（６）のいずれかに記載の予測方法
（８）　上記リスクが高いことが、血液中のＡＩＭ濃度として３．９８μｇ／ｍｌ以下で、４０歳未満の被験者と対比して、血液中のＡＩＭ濃度が３．９８μｇ／ｍｌを超え、かつ４０歳以上の被験者のＭｅｔＳ発症リスクが２．３倍以上であることである、上記（７）に記載の予測方法。
（９）　上記リスクが高いことが、血液中のＡＩＭ濃度として３．０７μｇ／ｍｌ未満の被験者と比較し、血液中のＡＩＭ濃度が３．９８μｇ／ｍｌ以上（中でも、３．９８～５．２５μｇ／ｍｌ）である被験者のＭｅｔＳ発症リスクが２．４倍以上（中でも、２．８倍以上）であることである、上記（１）に記載の予測方法。 The gist of the present invention is as follows.
(1) A method for predicting the onset of metabolic syndrome (MetS),
From AIM concentration in test subject's blood, age, lifestyle index, metabolic index,
In combination with serum AIM concentration and one or more other indicators,
The prediction method characterized by determining that the subject has a high risk of developing or suffering from MetS or a related disease.
(2) From the subject's blood AIM concentration, age, lifestyle index, and metabolic index, combining the serum AIM concentration and one or more other indicators, the subject may have MetS or related diseases. Determining a high risk of developing or being affected
Measuring the AIM concentration in the blood of the subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and if each index meets a reference or reference value, the subject The method according to (1) above, further comprising determining that the risk of developing or suffering from MetS or a related disease is high.
(3) The prediction method according to (1) or (2), wherein the lifestyle index is selected from smoking, drinking, exercise, obesity, nutrients, and a food group.
(4) The above metabolic indicators are blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 hour or 2 hours after meal The method according to any one of (1) to (3) above, wherein the method is selected from blood HbA1c concentration and inflammatory marker.
(5) The prediction method according to any one of (1) to (4) above, wherein the determination standard value of the serum AIM concentration of the subject exceeds 3.5 μg / ml (6) AIM concentration in blood The prediction method according to any one of the above (1) to (4), wherein the criterion value is a numerical value exceeding 3.98 μg / ml (7) Age is used as an index, and the criterion value of age is 40 years or older (8) The prediction method according to any one of (1) to (6) above, wherein the high risk indicates that the AIM concentration in the blood is 3.98 μg / ml or less and is compared with subjects under 40 years of age. And the prediction method as described in said (7) that the AIM density | concentration in the blood exceeds 3.98 microgram / ml, and is MetS onset risk of the test subject 40 years or older 2.3 times or more.
(9) Compared with a subject whose blood AIM concentration is less than 3.07 μg / ml, the AIM concentration in blood is 3.98 μg / ml or more (in particular, 3.98-5.25 μg) / Ml) The prediction method according to (1) above, wherein the subject's risk of developing MetS is 2.4 times or more (in particular, 2.8 times or more).
　本発明のＭｅｔＳ発症の予測方法は、血液中のＡＩＭ濃度を一つの指標として、更に、年齢、生活習慣の指標（喫煙、飲酒、運動、肥満、栄養素、食品群等）、代謝の指標（血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ＯＧＴＴ２時間後の血糖値、食後1時間または２時間の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカー等）をそれぞれ指標にして多元的に組み合わせて評価する予測方法である。本発明の血清ＡＩＭ濃度を指標とする多元的予測方法は、ＭｅｔＳの発症リスクの将来予測には、かなり有効で精度の高いものであることが明らかになった。
　更に本発明では、疫学的な検討の結果、ＭｅｔＳ発症予測の基準値として、血液中のＡＩＭ濃度の中央値３．９８μｇ／ｍｌを決定した。この中央値を基準として高値群、低値群に分けると、高値群の被験者は、他の指標と組わせることによりＭｅｔＳ発症のリスクが高いことを疫学的に見出した。
　これまでの報告によれば、血液中のＡＩＭ濃度の上昇、あるいは加齢がＭｅｔＳ発症に関係するとされている。しかし本発明の知見では、加齢を伴わない血液中のＡＩＭ濃度上昇、あるいは血液中のＡＩＭ濃度上昇を伴わない加齢では、ＭｅｔＳ発症リスクが上昇しないことが見出された。一方、血液中のＡＩＭ濃度の上昇と加齢が伴った場合には、特に顕著にＭｅｔＳ発症リスクが上昇することが見出された。本発明の知見に基づけば、例えば、年齢などで規定される集団に属する個人に対し、本発明の血中ＡＩＭ濃度の基準値を使用し、生活習慣に留意すれば、将来のＭｅｔＳの発症を回避できることが見出された。更に、ＭｅｔＳを発症した患者であっても、本発明を指標として使用して、生活改善や治療を継続することによって、発症したＭｅｔＳからの回復や軽減を期待できることが見出された。 The method for predicting the onset of MetS according to the present invention includes the AIM concentration in blood as one index, and further, age, lifestyle index (smoking, drinking, exercise, obesity, nutrients, food group, etc.), metabolic index (blood pressure). , Lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 or 2 hours after meal, blood HbA1c concentration, inflammatory marker, etc. ) As an index, and a combination of multiple evaluation methods. The multidimensional prediction method using the serum AIM concentration of the present invention as an index has been found to be quite effective and highly accurate for the future prediction of the onset risk of MetS.
Furthermore, in the present invention, as a result of epidemiological studies, a median value of 3.98 μg / ml of AIM concentration in blood was determined as a reference value for predicting the onset of MetS. It was found epidemiologically that subjects in the high value group had a high risk of developing MetS when combined with other indicators when divided into the high value group and the low value group based on this median value.
According to previous reports, the increase in AIM concentration in blood or aging is related to the onset of MetS. However, according to the knowledge of the present invention, it has been found that the risk of developing MetS does not increase with an increase in AIM concentration in blood without aging, or with aging without an increase in AIM concentration in blood. On the other hand, it was found that the risk of onset of MetS increases particularly remarkably when the AIM concentration in the blood is increased and aging is accompanied. Based on the knowledge of the present invention, for example, for individuals belonging to a group defined by age or the like, if the reference value of the blood AIM concentration of the present invention is used and attention is given to lifestyle, future MetS development may be prevented. It has been found that it can be avoided. Furthermore, it has been found that even patients who develop MetS can be expected to recover from or reduce the onset of MetS by using the present invention as an index and continuing life improvement and treatment.
被験者３６９名（男性、２０～６０歳）における、ＭｅｔＳの累積発症率とハザード比を２００８年の血清ＡＩＭ濃度レベル別（３．０７１μｇ／ｍｌ未満、３．０７１μｇ／ｍｌ－３．９８０μｇ／ｍｌ、３．９８１μｇ／ｍｌ－５．２４７μｇ／ｍｌ、５．２４７μｇ／ｍｌ超過）に整理した図である。血清ＡＩＭ濃度が上昇するにしたがって、ＭｅｔＳ累積発症率は統計学的有意に上昇した。更に、血清ＡＩＭ濃度が一番低い群と比べると、血清ＡＩＭ濃度が３．９８μｇ／ｍｌを超過すると、ＭｅｔＳ累積発症率は有意に上昇した。同様に、ＭｅｔＳ発症リスクも血清ＡＩＭ濃度が上昇するにつれ、ＭｅｔＳ発症リスクは有意に上昇した。更に、ＡＩＭ濃度が一番低い群と比べると、血清ＡＩＭ濃度が３．９８μｇ／ｍｌを超過すると、２倍以上に上昇し、この上昇は統計学的に有意であった。Cumulative incidence and hazard ratio of MetS in 369 subjects (male, 20-60 years old) by serum AIM concentration level in 2008 (less than 3.071 μg / ml, 3.071 μg / ml-3.980 μg / ml, (3. 981 μg / ml-5.247 μg / ml, 5.247 μg / ml excess). As serum AIM concentration increased, the cumulative incidence of MetS increased statistically significantly. Furthermore, compared to the group with the lowest serum AIM concentration, the cumulative incidence of MetS increased significantly when the serum AIM concentration exceeded 3.98 μg / ml. Similarly, the risk of developing MetS increased significantly as the serum AIM concentration increased. Furthermore, compared to the group with the lowest AIM concentration, when the serum AIM concentration exceeded 3.98 μg / ml, it increased more than twice, and this increase was statistically significant. ＭｅｔＳ発症のハザード比を年齢別（４０歳以上と４０歳未満）かつ血清ＡＩＭ濃度レベル別（３．９８μｇ／ｍｌ以下と３．９８μｇ／ｍｌ超過）に整理した図である。ＭｅｔＳ発症のハザード比は、血清ＡＩＭ濃度低値かつ４０歳未満の群と比べると、ＡＩＭ高値かつ４０歳以上群では２．３４と有意にＭｅｔＳ発症リスクが上昇した。It is the figure which arranged the hazard ratio of MetS onset according to age (over 40 years old and under 40 years old) and serum AIM concentration level (less than 3.98 μg / ml and over 3.98 μg / ml). The hazard ratio for the onset of MetS was 2.34 in the group with a high AIM and 40 years or older, and the risk of onset of MetS was significantly increased compared to the group with a low serum AIM concentration and under 40 years of age.
　本発明の「メタボリック・シンドローム（ＭｅｔＳ）発症の予測方法」とは、血液中のＡＩＭ濃度を一つの指標として、それと共に多元的に他の指標と組み合わせてＭｅｔＳの発症リスクを予測する方法である。他の指標としては、例えば、ＭｅｔＳに影響する指標と考えられる年齢、生活習慣の指標（喫煙、飲酒、運動、肥満、栄養素、食品群等の１以上）、及び代謝の指標（血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ＯＧＴＴ２時間後の血糖値、食後1時間後または２時間の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカー濃度等の１以上）の１以上を用いることができる。 The “metabolic syndrome (MetS) onset prediction method” of the present invention is a method for predicting the risk of onset of MetS by taking AIM concentration in blood as one index and combining it with other indices in combination with other indices. . Other indicators include, for example, age considered to be an indicator affecting MetS, lifestyle indicators (one or more of smoking, drinking, exercise, obesity, nutrients, food groups, etc.), and metabolic indicators (blood pressure, lipid metabolism) Marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after OGTT, blood glucose level 1 hour or 2 hours after meal, blood HbA1c concentration, inflammatory marker concentration, etc. 1 or more) can be used.
　例えば、血液中のＡＩＭ濃度の判断基準値として３．９８μｇ／ｍｌを設定し、それより高値の被験者、低値の被験者に区分する。加えて、年齢、肥満の程度（ＢＭＩ値）等でも被験者を区分し、２元又は多元的な解析を行うことにより、血清ＡＩＭ濃度が低値の被験者であって更に他の指標が正常な被験者と比較して、ＭｅｔＳの発症リスク（ハザード比）を評価する予測方法である。
　血清ＡＩＭ濃度と、ＭｅｔＳ累積発症率あるいはＭｅｔＳ発症リスクとの関連が図１に示されており、血清ＡＩＭ濃度の上昇により、ＭｅｔＳ累積発症率とＭｅｔＳ発症リスクが増大することを示している。この図１の評価では、ＭｅｔＳ発症の危険因子と考えられる要因（加齢、肥満、喫煙習慣、飲酒習慣、運動習慣）の影響を限りなく除外して、ＭｅｔＳ発症に対する血清ＡＩＭ濃度の影響を検討している。従って、図１により、血清ＡＩＭ濃度の上昇に伴い、ＭｅｔＳ発症リスクが上昇する既知の関連性が確認でき、本発明の被験者集団に大きな偏りがないことが示された。 For example, 3.98 μg / ml is set as a determination reference value for the AIM concentration in blood, and the test subjects are classified into subjects having higher values and subjects having lower values. In addition, by classifying subjects by age, degree of obesity (BMI value), etc., and conducting a binary or multi-dimensional analysis, subjects whose serum AIM concentration is low and whose other indicators are normal It is the prediction method which evaluates the onset risk (hazard ratio) of MetS compared with.
The relationship between the serum AIM concentration and the cumulative incidence of MetS or the risk of developing MetS is shown in FIG. 1, and it is shown that the cumulative incidence of MetS and the risk of developing MetS increase as the serum AIM concentration increases. In the evaluation of FIG. 1, the influence of serum AIM concentration on the onset of MetS is examined by excluding the influence of factors (aging, obesity, smoking habits, drinking habits, exercise habits) considered as risk factors for the onset of MetS. is doing. Therefore, FIG. 1 confirms the known relevance that the risk of developing MetS increases as the serum AIM concentration increases, indicating that there is no significant bias in the subject population of the present invention.
　次に、血清ＡＩＭ濃度と年齢との２元ＭｅｔＳ発症リスクの評価概要が図２に示されている。血清ＡＩＭ濃度と年齢の指標を組み合わせることで、加齢もしくは血清ＡＩＭ濃度の単独での上昇ではなく、高年齢と高ＡＩＭ濃度の両者が揃うことでＭｅｔＳの発症に対して相乗的な影響を与えることが示された。これより、血清ＡＩＭ濃度とＭｅｔＳに係る指標の組み合わせを用いて、ＭｅｔＳの発症リスクの高い者を高い精度でスクリーニングできることが見出された。 Next, FIG. 2 shows an overview of evaluation of the risk of developing binary MetS based on serum AIM concentration and age. Combining serum AIM concentration and age index has a synergistic effect on the onset of MetS by combining both older age and high AIM concentration, rather than aging or increasing serum AIM concentration alone It was shown that. From this, it was found that a person having a high risk of developing MetS can be screened with high accuracy using a combination of serum AIM concentration and an index related to MetS.
　即ち、本発明のメタボリック・シンドローム（ＭｅｔＳ）発症の予測方法は、被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断する予測方法である。本発明の予測方法は、ＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高い被験者のスクリーニング方法と捉えることもできる。
　本発明方法は、中でも、被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、各指標が基準又は基準値に該当する場合に、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断するＭｅｔＳ発症の予測方法である。
　換言すれば、本発明方法は、被験者の血液中のＡＩＭ濃度を測定し、かつ年齢、生活習慣の指標、及び代謝の指標の一つ以上を判定又は測定する工程と、各指標が基準又は基準値に該当する場合に、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断する工程とを含む、ＭｅｔＳ発症の予測方法である。
　「リスクが高い」ことは「リスクがある」ことと捉えることもできる。 That is, the method for predicting the onset of metabolic syndrome (MetS) according to the present invention includes serum AIM concentration and other one or more of AIM concentration, age, lifestyle index, and metabolic index in a subject's blood. It is a prediction method that determines that the subject has a high risk of developing or suffering from MetS or a related disease by combining indices. The prediction method of the present invention can also be regarded as a screening method for subjects having a high risk of developing or suffering from MetS or related diseases.
Among the methods of the present invention, among the AIM concentration in the blood of the subject, age, lifestyle index, metabolic index, the serum AIM concentration and one or more other indices are combined, and each index is a reference or This is a method for predicting the onset of MetS when it is determined that the subject has a high risk of developing or suffering from MetS or a related disease when the reference value is met.
In other words, the method of the present invention comprises the steps of measuring AIM concentration in the blood of a subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and each index is a reference or reference A method for predicting the onset of MetS, including a step of determining that the subject has a high risk of developing or suffering from MetS or a related disease when the subject falls under the value.
“High risk” can be regarded as “risk”.
　また、図１、２の結果から、被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せることで、当該被験者におけるＭｅｔＳ又はその関連疾患の病態が進行する(特に、病態の進行が加速する)可能性がある又は高いと判断できることが見出された。
　従って、本発明は、被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、当該被験者におけるＭｅｔＳ又はその関連疾患の病態が進行する(特に、病態の進行が加速する)可能性が高いと判断する、ＭｅｔＳ又はその関連疾患の進行の可能性の予測方法である。本発明の予測方法は、ＭｅｔＳ又はその関連疾患の病態が進行する(特に、病態の進行が加速する)可能性が高い被験者のスクリーニング方法と捉えることもできる。
　本発明方法は、中でも、被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、各指標が基準又は基準値に該当する場合に、当該被験者におけるＭｅｔＳ又はその関連疾患の病態が進行する(特に、病態の進行が加速する)可能性が高いと判断する、ＭｅｔＳ又はその関連疾患の進行の可能性の予測方法ある。
　換言すれば、本発明方法は、被験者の血液中のＡＩＭ濃度を測定し、かつ年齢、生活習慣の指標、及び代謝の指標の一つ以上を判定又は測定する工程と、当該被験者におけるＭｅｔＳ又はその関連疾患の病態が進行する(特に、病態の進行が加速する)可能性が高いと判断する工程とを含む、ＭｅｔＳ又はその関連疾患の進行の可能性の予測方法である。
　「可能性が高い」ことは、「可能性があること」と捉えることもできる。
　その他の条件又は構成は、本発明のメタボリック・シンドローム（ＭｅｔＳ）発症の予測方法と同じである。 In addition, from the results of FIGS. 1 and 2, by combining the serum AIM concentration and one or more other indicators from the AIM concentration in the blood of the subject, age, lifestyle indicators, metabolic indicators, It has been found that the condition of MetS or a related disease in the subject can be judged to be likely or high (particularly, the progression of the condition is accelerated).
Accordingly, the present invention provides a combination of serum AIM concentration and one or more other indicators among the AIM concentration in blood of the subject, age, lifestyle indicators, and metabolic indicators, and MetS in the subject or its This is a method for predicting the possibility of progression of MetS or a related disease, which is judged to have a high possibility that the disease state of the related disease will progress (particularly, the progression of the disease state is accelerated). The prediction method of the present invention can also be regarded as a screening method for a subject who is highly likely to progress in the pathological condition of MetS or a related disease (particularly, the progress of the pathological condition is accelerated).
Among the methods of the present invention, among the AIM concentration in the blood of the subject, age, lifestyle index, metabolic index, the serum AIM concentration and one or more other indices are combined, and each index is a reference or When the reference value is met, MetS or the related disease in the subject is considered to have a high probability of progression (especially, the progression of the disease is accelerated). There is a prediction method.
In other words, the method of the present invention comprises the steps of measuring AIM concentration in the blood of a subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and MetS in the subject or its A method for predicting the possibility of progression of MetS or a related disease, comprising a step of determining that there is a high possibility that the disease state of the related disease progresses (in particular, the progression of the disease state is accelerated).
“High possibility” can be regarded as “possibility”.
Other conditions or configurations are the same as the method for predicting the onset of metabolic syndrome (MetS) of the present invention.
　本発明の「血液中のＡＩＭ濃度」とは、血液中に存在するタンパク質ＡＩＭの濃度のことを言う。血液としては、全血、血清、血漿などが挙げられ、中でも、精度良く予測できる点で、血清が好ましい。
　ＡＩＭは、マクロファージのアポトーシスを抑制するだけでなく、肥満や肥満に伴う種々の病態の進行に非常に重要な役割を果たしており、その血中濃度も遺伝的な背景以外に生活習慣の影響も大きく受けると考えられている。肥満が進行すると血中のＡＩＭ濃度が上昇すると報告されている（非特許文献１）。なお、ヒトの血中のＡＩＭ濃度には個人差があり、性別、年齢によっても異なることが知られている。これまでの報告によれば、ＡＩＭは肥満状況下でその血中濃度が増加し、脂肪細胞に直接作用して、ＡＩＭ依存的なｌｉｐｏｌｙｓｉｓを介して中性脂肪の分解が起こり、遊離脂肪酸とグリセロールの放出が起きる。遊離脂肪酸は脂肪細胞が発現しているＴＬＲ４を刺激し、ケモカイン類の産生を促し、その結果、肥大化脂肪細胞に対するマクロファージの浸潤を誘導する。このような作用機序によって、肥満すると脂肪組織に慢性炎症が起きると報告されている。このように、ＡＩＭは、脂肪組織に直接作用してＡＩＭ依存的なｌｉｐｏｌｙｓｉｓを介して遊離脂肪酸の放出を促し、マクロファージの浸潤を誘導することから、内臓脂肪の慢性炎症と、それに続くインスリン抵抗性の惹起に関するＦｉｒｓｔ　Ｓｔｅｐとなる重要な分子であるとされている。しかし、これまでのＡＩＭ研究では、ＡＩＭの作用機序とＡＩＭを用いた治療に関する報告が中心であり、ＭｅｔＳ対策に実践的に使用可能な、血中ＡＩＭ濃度の基準値に関する疫学的な研究報告はなく、ＭｅｔＳの発症予測に関して血中ＡＩＭ濃度を基準値として使用する試みもなされていない。 The “AIM concentration in blood” of the present invention refers to the concentration of protein AIM present in blood. Examples of blood include whole blood, serum, plasma and the like. Among them, serum is preferable because it can be predicted with high accuracy.
AIM not only suppresses apoptosis of macrophages, but also plays a very important role in the progression of obesity and various pathological conditions associated with obesity. It is thought to receive. It has been reported that as obesity progresses, the AIM concentration in blood increases (Non-patent Document 1). In addition, it is known that the AIM concentration in human blood varies among individuals and varies depending on sex and age. According to previous reports, AIM increases its blood concentration under obesity, acts directly on adipocytes, and causes degradation of triglycerides via AIM-dependent lipolysis, free fatty acids and glycerol Occurs. Free fatty acids stimulate TLR4 expressed in adipocytes and promote the production of chemokines, and as a result, induce macrophage infiltration into hypertrophic adipocytes. Due to such a mechanism of action, it has been reported that obesity causes chronic inflammation in adipose tissue. Thus, AIM acts directly on adipose tissue to promote the release of free fatty acids through AIM-dependent lipolysis and induces macrophage infiltration, which leads to chronic inflammation of visceral fat and subsequent insulin resistance. It is said that it is an important molecule that serves as the First Step for the induction of. However, the previous AIM research centered on reports on the mechanism of action of AIM and treatment using AIM, and epidemiological reports on the reference value of blood AIM concentration that can be used practically for MetS countermeasures. No attempt has been made to use blood AIM concentration as a reference value for predicting the onset of MetS.
　本発明の「血液中のＡＩＭ濃度の判断基準値」とは、約３．５μｇ／ｍｌを超過する数値のことを言い、他の指標との組み合わせによっては、約４（特に約４．０）μｇ／ｍｌを超過する数値を挙げることができる。更に組み合わせる指標に従い、好ましい数値として、約４．５μｇ／ｍｌ又は約５（特に５．０）μｇ／ｍｌを超過する数値を挙げることができる。より好ましい数値としては、５．５μｇ／ｍｌ又は約６（特に約６．０）μｇ／ｍｌを超過する数値を挙げることができる。最も好ましい数値としては、約６．５μｇ／ｍｌ又は約７（特に、約７．０)μｇ／ｍｌを超過する数値を挙げることができる。即ち、血液中のＡＩＭ濃度が上記値を超過する場合に、基準値に該当すると判断する。 The “judgment standard value of AIM concentration in blood” of the present invention means a numerical value exceeding about 3.5 μg / ml, and depending on the combination with other indicators, it is about 4 (particularly about 4.0). A numerical value exceeding μg / ml can be mentioned. Further, according to the combined index, preferable numerical values include numerical values exceeding about 4.5 μg / ml or about 5 (particularly 5.0) μg / ml. More preferable numerical values include values exceeding 5.5 μg / ml or about 6 (particularly about 6.0) μg / ml. Most preferred values include values that exceed about 6.5 μg / ml or about 7 (particularly about 7.0) μg / ml. That is, when the AIM concentration in the blood exceeds the above value, it is determined that the reference value is met.
　本発明の「生活習慣の指標」とは、例えば喫煙、飲酒、運動、肥満、栄養素、食品群等のことをいう。生活習慣の指標は、１以上を用いることができる。
　指標として喫煙を使用する場合には、現在の喫煙習慣或いは過去に喫煙習慣があったか否かを基準にして被験者を区分する。より発症リスクの高い基準としては、現在喫煙習慣があるか否かを基準にして被験者を区分する。即ち、現在又は過去、中でも、現在において喫煙習慣がある場合に、基準に該当すると判断する。
　飲酒を使用する場合には、飲酒習慣があるか否かを基準にして被験者を区分する。より発症リスクが高い基準としては、純アルコール換算で２０ｇ／日の飲酒習慣を基準として被験者を区分する。即ち、飲酒習慣がある場合、中でも、純アルコール換算で２０ｇ／日以上の飲酒習慣がある場合に、基準又は基準値に該当すると判断する。
　運動を使用する場合には、運動習慣があるか否かを基準にして被験者を区分する。より発症リスクの高い基準としては、２３メッツ・時／週を基準として被験者を区分する。即ち、運動習慣がない場合、中でも、運動量が２３メッツ・時／週以下である場合に、基準又は基準値に該当すると判断する。
　肥満を使用する場合には、ＢＭＩ値で２３を基準として被験者を区分する。より発症リスクの高い基準としては、ＢＭＩ値で２５を基準として被験者を区分する。即ち、ＢＭＩ値が２３以上の場合、中でも、２５以上である場合に、基準値に該当すると判断する。
　栄養素を指標として使用する場合には、一日の摂取目標量又は推奨量を基準にして被験者を区分する。例えばエネルギー摂取量過多、脂質摂取量過多、糖質摂取量過多、ナトリウム摂取量過多、あるいは食物繊維摂取量不足などの被験者とそれ以外の被験者にそれぞれ区分する。一日の摂取目標量又は推奨量は、「日本人の食事摂取基準」（2015年、厚生労働省）に記載されている。エネルギー摂取量、脂質摂取量、糖質摂取量、ナトリウム摂取量については、一日の摂取目標量又は推奨量を超える場合に基準値に該当すると判断する。また、食物繊維摂取量については、一日の摂取目標量を下回る場合に、基準値に該当すると判断する。
　食品を指標として使用する場合にも、一日の摂取目安を基準にして被験者を区分する。例えば肉類摂取量過多、菓子類摂取量過多、アルコール・嗜好飲料摂取量過多、魚介類摂取量不足、野菜摂取量不足、海藻類摂取量不足、砂糖摂取量過多、油脂類摂取量過多等の各被験者と、それ以外の被験者に区分する。一日の摂取目安は、「食事バランスガイド」（2005年、厚生労働省・農林水産省）の記載に基づき算出される。肉類摂取量、菓子類摂取量、アルコール・嗜好飲料摂取量、砂糖摂取量、油脂類摂取量については、一日の摂取目安を超える場合に、基準値に該当すると判断する。魚介類摂取量、野菜摂取量、海藻類摂取量については、一日の摂取目安を下回る場合に、基準値に該当すると判断する。 The “indicator of lifestyle habit” of the present invention refers to, for example, smoking, drinking, exercise, obesity, nutrients, food group, and the like. One or more lifestyle indicators can be used.
When smoking is used as an index, subjects are classified based on whether or not there has been a current smoking habit or a past smoking habit. The criteria for higher risk of onset is to classify subjects based on whether or not they currently have a smoking habit. That is, it is determined that the current condition or the past, particularly, if there is a smoking habit at present, falls under the standard.
When using drinking, classify subjects based on whether or not they have drinking habits. As a criterion with a higher risk of onset, subjects are classified based on a drinking habit of 20 g / day in terms of pure alcohol. That is, when there is a drinking habit, especially when there is a drinking habit of 20 g / day or more in terms of pure alcohol, it is determined that the standard or the reference value is met.
When using exercise, classify subjects based on whether or not they have exercise habits. As a criterion with a higher risk of onset, subjects are classified on the basis of 23 mets · hour / week. That is, when there is no exercise habit, especially when the amount of exercise is 23 Mets · hour / week or less, it is determined that it corresponds to the reference or the reference value.
When obesity is used, subjects are classified based on the BMI value of 23. As a criterion with a higher risk of onset, subjects are classified based on a BMI value of 25. That is, when the BMI value is 23 or more, particularly when the BMI value is 25 or more, it is determined that the reference value is satisfied.
When using nutrients as an indicator, classify subjects based on the target daily intake or recommended dose. For example, the subjects are classified into subjects such as excessive energy intake, excessive lipid intake, excessive carbohydrate intake, excessive sodium intake, or insufficient dietary fiber intake, and other subjects. Daily target intake or recommended amount is described in “Japanese dietary intake standards” (2015, Ministry of Health, Labor and Welfare). Regarding energy intake, lipid intake, carbohydrate intake, and sodium intake, if the daily intake target amount or recommended amount is exceeded, it is determined that it falls within the reference value. Moreover, about dietary fiber intake, when less than the daily intake target amount, it determines that it corresponds to a reference value.
Even when food is used as an indicator, subjects are classified based on the daily intake standard. For example, excessive intake of meat, excessive intake of confectionery, excessive intake of alcohol / preference drinks, insufficient intake of seafood, insufficient intake of vegetables, insufficient intake of seaweed, excessive intake of sugar, excessive intake of fats and oils, etc. Divide the subject into other subjects. The daily intake standard is calculated based on the description of “Meal Balance Guide” (2005, Ministry of Health, Labor and Welfare, Ministry of Agriculture, Forestry and Fisheries). Meat intake, confectionery intake, alcohol / preference drink intake, sugar intake, and fat intake are judged to meet the standard values when exceeding the daily intake standard. Regarding seafood intake, vegetable intake, and seaweed intake, if the intake is below the daily intake standard, it is determined that it falls under the standard value.
　本発明の「代謝の指標」とは、例えば血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ＯＧＴＴ２時間後の血糖値、食後1時間または２時間の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカー濃度等のことをいう。代謝の指標は、１以上を用いることができる。
　指標として血圧を使用する場合には、収縮期血圧１３０ｍｍＨｇ又は拡張期血圧８５ｍｍＨｇを基準として被験者を区分する。より発症リスクの高い基準としては、収縮期血圧１４０ｍｍＨｇ又は拡張期血圧９０ｍｍＨｇを基準として被験者を区分する。即ち、収縮期血圧１３０ｍｍＨｇ以上又は拡張期血圧８５ｍｍＨｇ以上の場合、中でも、収縮期血圧１４０ｍｍＨｇ以上又は拡張期血圧９０ｍｍＨｇ以上である場合に、基準値に該当すると判断する。
　脂質代謝マーカーとしては、ＬＤＬコレステロール、ＨＤＬコレステロール、中性脂肪、総コレステロールを挙げることができる。ＬＤＬコレステロールを指標として使用する場合、１２０ｍｇ／ｄｌを基準として被験者を区分する。より発症リスクの高い基準としては１４０ｍｇ／ｄｌを基準として被験者を区分する。即ち、血清ＬＤＬコレステロール濃度が１２０ｍｇ／ｄｌ以上の場合、中でも、１４０ｍｇ／ｄｌ以上である場合に、基準値に該当すると判断する。ＨＤＬコレステロールを指標として使用する場合、４０ｍｇ／ｄｌを基準として被験者を区分する。即ち、血清ＨＤＬコレステロール濃度が４０ｍｇ／ｄｌ未満の場合に、基準値に該当すると判断する。中性脂肪を指標として使用する場合、１５０ｍｇ／ｄｌを基準として被験者を区分する。即ち、血清中性脂肪濃度が１５０ｍｇ／ｄｌ以上の場合に、基準値に該当すると判断する。総コレステロールを指標として使用する場合、２２０ｍｇ／ｄｌを基準として被験者を区分する。即ち、血清総コレステロール濃度が２２０ｍｇ／ｄｌ以上の場合に、基準値に該当すると判断する。
　血清アディポネクチン濃度を指標として使用する場合、男性で９．９μｇ／ｍｌ、女性で９．１μｇ／ｍｌを基準として被験者を区分する。より発症リスクの高い基準としては、６．２μｇ／ｍｌを基準として男性の被験者を区分する。即ち、血清アディポネクチン濃度が男性で９．９μｇ／ｍｌ未満、女性で９．１μｇ／ｍｌ未満の場合、中でも、６．２μｇ／ｍｌ未満である場合に、基準値に該当すると判断する。
　血清ＦＡＢＰ４濃度を指標として使用する場合には、９．０ｎｇ／ｍｌを基準として被験者を区分する。より発症リスクの高い基準としては、１１．０ｎｇ／ｍｌを基準として被験者を区分する。即ち、血清ＦＡＢＰ４濃度が９．０ｎｇ／ｍｌ以上の場合、中でも、１１．０ｎｇ／ｍｌ以上である場合に、基準値に該当すると判断する。
　肝機能マーカーを指標として使用する場合には、血清ＡＬＴ濃度として３０Ｕ／Ｌ、血清ＡＳＴ濃度として３０Ｕ／Ｌ、血清γＧＴＰ濃度として男性４５Ｕ／Ｌ、女性２５Ｕ／Ｌを基準として被験者を区分する。即ち、血清ＡＬＴ濃度が３０Ｕ／Ｌ以上である場合、血清ＡＳＴ濃度が３０Ｕ／Ｌ以上である場合、及び／又は血清γＧＴＰ濃度が男性４５Ｕ／Ｌ以上、女性２５Ｕ／Ｌ以上の場合に、基準値に該当すると判断する。
　血清ＩｇＭ濃度を指標として使用する場合には、７７．０ｍｇ／ｄｌを基準として被験者を区分する。
　血糖値を指標として使用する場合には、空腹時血糖値として１００ｍｇ／ｄｌ又は１１０ｍｇ／ｄｌ又はprediabetesの基準を満たすか否かを基準に被験者を区分する。より発症リスクが高い基準としては空腹時血糖値１２６ｍｇ／ｄｌを基準として被験者を区分する。即ち、空腹時血糖値が１００ｍｇ／ｄｌ以上又は１１０ｍｇ／ｄｌ以上又はprediabetesの基準（Diabetes Care 2017; Volume 40 Issue Supplemet 1）を満たす場合、中でも１２６ｍｇ／ｄｌ以上である場合に、基準値に該当すると判断する。また、ブドウ糖負荷試験（ＯＧＴＴ）２時間後の血糖値を指標として使用する場合には、１４０ｍｇ／ｄｌ又はprediabetesの基準を満たすか否かを基準として被験者を区分する。即ち、ＯＧＴＴ２時間後の血糖値が１４０ｍｇ／ｄｌ以上又はprediabetesの基準（Diabetes Care 2017; Volume 40 Issue Supplemet 1）を満たす場合に、基準値に該当すると判断する。また、食後血糖値を指標として使用する場合には、食後1時間の血糖値として１６０ｍｇ／ｄｌ、２時間の血糖値として１４０ｍｇ／ｄｌを基準に被験者を区分する。より発症リスクが高い基準としては食後血糖値２００ｍｇ／ｄｌを基準として被験者を区分する。即ち、食後1時間の血糖値が１６０ｍｇ／ｄｌ以上または２時間の血糖値が１４０ｍｇ／ｄｌ以上、中でも食後血糖値が２００ｍｇ／ｄｌ以上である場合に、基準値に該当すると判断する。
　血中ＨｂＡ１ｃ濃度を指標として使用する場合には、５．６％又はprediabetesの基準を満たすか否かを基準として被験者を区分する。より発症リスクが高い基準としては６．５％を基準として被験者を区分する。即ち、血中ＨｂＡ１ｃ濃度が５．６％以上又はprediabetesの基準（Diabetes Care 2017; Volume 40 Issue Supplemet 1）を満たす場合、中でも６．５％以上である場合に、基準値に該当すると判断する。
　炎症性マーカーを指標として使用する場合には、血清ｈｓＣＲＰ濃度が０．３ｍｇ／ｄｌを基準として被験者を区分する。より発症リスクが高い基準としては１．０ｍｇ／ｄｌを基準として被験者を区分する。即ち、血清ｈｓＣＲＰ濃度が０．３ｍｇ／ｄｌ以上、中でも１．０ｍｇ／ｄｌ以上である場合に、基準値に該当すると判断する。血清ＩＬ－６濃度では４．０ｐｇ／ｍｌを基準として被験者を区分する。即ち、血清ＩＬ－６濃度が４．０ｐｇ／ｍｌ以上である場合に、基準値に該当すると判断する。血清ＴＮＦ－α濃度では２．９ｐｇ／ｍｌ、血清ＭＣＰ－１濃度では１５０ｐｇ／ｍｌを基準として被験者を区分する。即ち、血清ＴＮＦ－α濃度が２．９ｐｇ／ｍｌ以上である場合に、基準値に該当すると判断し、血清ＭＣＰ－１濃度が１５０ｐｇ／ｍｌ以上である場合に、基準値に該当すると判断する。 The “indicator of metabolism” of the present invention includes, for example, blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level after 2 hours of OGTT, 1 hour or 2 hours after meal Blood glucose level, blood HbA1c concentration, inflammatory marker concentration, and the like. One or more metabolic indicators can be used.
When blood pressure is used as an index, subjects are classified based on systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg. As a criterion with a higher risk of onset, subjects are classified based on systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg. That is, when the systolic blood pressure is 130 mmHg or more or the diastolic blood pressure is 85 mmHg or more, particularly when the systolic blood pressure is 140 mmHg or more or the diastolic blood pressure is 90 mmHg or more, it is determined that the reference value is satisfied.
Examples of lipid metabolism markers include LDL cholesterol, HDL cholesterol, neutral fat, and total cholesterol. When LDL cholesterol is used as an index, subjects are classified based on 120 mg / dl. As a criterion with a higher risk of onset, subjects are classified based on 140 mg / dl. That is, when the serum LDL cholesterol concentration is 120 mg / dl or higher, particularly when the serum LDL cholesterol concentration is 140 mg / dl or higher, it is determined that it corresponds to the reference value. When HDL cholesterol is used as an index, subjects are classified based on 40 mg / dl. That is, when the serum HDL cholesterol concentration is less than 40 mg / dl, it is determined that the reference value is met. When using neutral fat as an index, subjects are classified based on 150 mg / dl. That is, when the serum triglyceride concentration is 150 mg / dl or more, it is determined that the reference value is satisfied. When total cholesterol is used as an index, subjects are classified based on 220 mg / dl. That is, when the serum total cholesterol concentration is 220 mg / dl or more, it is determined that it corresponds to the reference value.
When using serum adiponectin concentration as an index, subjects are classified based on 9.9 μg / ml for males and 9.1 μg / ml for females. As a criterion with a higher risk of onset, male subjects are classified based on 6.2 μg / ml. That is, when the serum adiponectin concentration is less than 9.9 μg / ml for men and less than 9.1 μg / ml for women, particularly when it is less than 6.2 μg / ml, it is determined that the reference value is met.
When serum FABP4 concentration is used as an index, subjects are classified based on 9.0 ng / ml. As a criterion with a higher risk of onset, subjects are classified based on 11.0 ng / ml. That is, when the serum FABP4 concentration is 9.0 ng / ml or higher, particularly when it is 11.0 ng / ml or higher, it is determined that the serum FABP4 concentration falls within the reference value.
When the liver function marker is used as an index, subjects are classified based on the serum ALT concentration of 30 U / L, the serum AST concentration of 30 U / L, the serum γGTP concentration of male 45 U / L, and female 25 U / L. That is, when the serum ALT concentration is 30 U / L or more, when the serum AST concentration is 30 U / L or more, and / or when the serum γGTP concentration is 45 U / L or more for men and 25 U / L or more for women, It is judged that it corresponds to.
When serum IgM concentration is used as an index, subjects are classified based on 77.0 mg / dl.
When using a blood glucose level as an index, subjects are classified based on whether or not the fasting blood glucose level satisfies the criteria of 100 mg / dl, 110 mg / dl, or prediabetes. As a criterion with a higher risk of onset, subjects are classified based on a fasting blood glucose level of 126 mg / dl. That is, when the fasting blood glucose level satisfies 100 mg / dl or more, 110 mg / dl or more, or the prediabetes standard (Diabetes Care 2017; Volume 40 Issue Supplemet 1), particularly when it is 126 mg / dl or more, it falls under the standard value to decide. Moreover, when using the blood glucose level 2 hours after a glucose tolerance test (OGTT) as a parameter | index, a test subject is classified on the basis of whether the reference | standard of 140 mg / dl or prediabetes is satisfy | filled. That is, when the blood glucose level after 2 hours of OGTT is 140 mg / dl or more or satisfies the prediabetes standard (Diabetes Care 2017; Volume 40 Issue Supplemet 1), it is determined that it falls under the standard value. When using postprandial blood glucose as an index, subjects are classified based on 160 mg / dl as the blood glucose level for 1 hour after meal and 140 mg / dl as the blood glucose level for 2 hours. As a criterion with a higher risk of onset, subjects are classified based on a postprandial blood glucose level of 200 mg / dl. That is, when the blood glucose level for 1 hour after a meal is 160 mg / dl or more, or the blood glucose level for 2 hours is 140 mg / dl or more, and especially the postprandial blood glucose level is 200 mg / dl or more, it is determined that the reference value is met.
When the blood HbA1c concentration is used as an index, subjects are classified based on whether the criteria of 5.6% or prediabetes are satisfied. The criterion for higher risk of onset is to classify subjects on the basis of 6.5%. That is, when the blood HbA1c concentration satisfies 5.6% or higher or the prediabetes standard (Diabetes Care 2017; Volume 40 Issue Supplemet 1), particularly when it is 6.5% or higher, it is determined that the standard value is met.
When using an inflammatory marker as an index, subjects are classified based on a serum hsCRP concentration of 0.3 mg / dl. As a criterion with a higher risk of onset, subjects are classified based on 1.0 mg / dl. That is, when the serum hsCRP concentration is 0.3 mg / dl or higher, particularly 1.0 mg / dl or higher, it is determined that it falls under the reference value. For serum IL-6 concentration, subjects are classified based on 4.0 pg / ml. That is, when the serum IL-6 concentration is 4.0 pg / ml or more, it is determined that the reference value is met. Subjects are classified based on the serum TNF-α concentration of 2.9 pg / ml and the serum MCP-1 concentration of 150 pg / ml. That is, when the serum TNF-α concentration is 2.9 pg / ml or more, it is determined to be a reference value, and when the serum MCP-1 concentration is 150 pg / ml or more, it is determined to be a reference value.
　年齢を指標として使用する場合には、４０歳を基準にして被験者を区分する。即ち、年齢が４０歳以上である場合に、基準値に該当すると判断する。 When using age as an index, classify subjects based on 40 years old. That is, when the age is 40 years or older, it is determined that the reference value is met.
　本発明の「メタボリック・シンドローム発症」は、例えば、ＭｅｔＳの診断基準（Ａ　ｊｏｉｎｔ　ｓｔａｔｅｍｅｎｔ　ｏｆ　ＩＤＦ，ＮＨＬＢＩ，ＡＨＡ，Ｗｏｒｌｄ　Ｈｅａｒｔ　Ｆｅｄｅｒａｔｉｏｎ，Ｉｎｔｅｒｎａｔｉｏｎａｌ　Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ　Ｓｏｃｉｅｔｙ，Ｉｎｔｅｒｎａｔｉｏｎａｌ　Ａｓｓｏｃｉａｔｉｏｎ　ｆｏｒ　ｔｈｅ　Ｓｔｕｄｙ　ｏｆ　Ｏｂｅｓｉｔｙ）、及び／又は日本のＭｅｔＳ診断基準に基づいて、ＭｅｔＳであると判断されることを言う。
　なお日本における現行の診断基準においては、腹囲（男性８５ｃｍ以上、女性９０ｃｍ以上）に加え、下記の３項目のうち２項目に該当するとＭｅｔＳと診断する。
項目１　(1)中性脂肪１５０ｍｇ／ｄｌ以上かつ／または(2)ＨＤＬ－Ｃ４０ｍｇ／ｄｌ未満
項目２　収縮期血圧１３０ｍｍＨｇ以上かつ／または拡張期血圧８５ｍｍＨｇ以上
項目３　空腹時血糖値１１０ｍｇ／ｄｌ以上
　また、項目１の(1)については高トリグリセライド血症に対する薬剤治療を受けている場合、項目１の(2)については低ＨＤＬコレステロール血症に対する薬剤治療を受けている場合、項目２については高血圧に対する薬剤治療を受けている場合、項目３については糖尿病に対する薬剤治療を受けている場合も、各項目に含める。 The “metabolic syndrome onset” of the present invention is, for example, a diagnostic criterion of MetS (A joint statement of IDF, NHLBI, AHA, World Heart Federation, International Athleto Society Society, International Society of Science, It is determined that it is MetS based on the MetS diagnostic criteria.
In addition, in the current diagnostic criteria in Japan, MetS is diagnosed if it falls into two of the following three items in addition to abdominal circumference (male 85 cm or more, female 90 cm or more).
Item 1 (1) Neutral fat 150 mg / dl or more and / or (2) HDL-C less than 40 mg / dl Item 2 Systolic blood pressure 130 mmHg or more and / or diastolic blood pressure 85 mmHg or more Item 3 Fasting blood glucose level 110 mg / dl or more Item 1 (1) is treated with drug treatment for hypertriglyceridemia, Item 1 (2) is treated with drug treatment for low HDL cholesterolemia, Item 2 is treated for hypertension When receiving medical treatment, item 3 is also included in each item when receiving medical treatment for diabetes.
　本発明の「ＭｅｔＳ又はその関連疾患」とは、ＭｅｔＳと共にそれに起因して惹起される疾患のことを言い、例えばＭｅｔＳ、肥満、インスリン抵抗性、糖尿病、脂質異常症、高血圧、動脈硬化性疾患、脳血管障害、虚血性心疾患、心不全、認知症、脳卒中、神経障害、腎疾患、アディポサイトカインの分泌異常及び血中遊離脂肪酸量の異常等のことを挙げることができる。 The “MetS or related disease” of the present invention refers to a disease caused by MetS and caused thereby, such as MetS, obesity, insulin resistance, diabetes, dyslipidemia, hypertension, arteriosclerotic disease, Examples thereof include cerebrovascular disorder, ischemic heart disease, heart failure, dementia, stroke, neuropathy, renal disease, abnormal secretion of adipocytokines and abnormal free fatty acid in blood.
　本発明の「ＭｅｔＳ又はその関連疾患を発症または罹患しているリスク」とは、被験者がＭｅｔＳ又はその関連疾患を発症するリスクのことをいう。中でも、８年間にＭｅｔＳ又はその関連疾患を発症するリスクであり得る。例えば、図１（右図）、図２に示すように、このリスクを、本発明では「ハザード比」として表すことができる。ハザード比は、多変量調整モデル（例えばＣｏｘ比例ハザードモデル）を用いて、血中ＡＩＭ濃度のＭｅｔＳ発症の危険性を評価し、その相対的な危険性を表した数値である。例えば、図１に示すように、血中ＡＩＭ濃度に応じて４群に分け、血中ＡＩＭ濃度の第１分位を１．００とすると、第２分位１．６３（９５％信頼区間０．７６～３．５０、ｐ＝０．２１）、第３分位２．７９（９５％信頼区間１．３５～５．７６、ｐ＜０．０１）、第４分位２．４１（９５％信頼区間１．１４～５．１１、ｐ＝０．０２）と表される、ＭｅｔＳ発症への相対的な危険性を表す指標となっている。また、図２に示すように、ＭｅｔＳ発症のハザード比を年齢別（４０歳以上と４０歳未満）かつ血清ＡＩＭ濃度レベル別（３．９８μｇ／ｍｌ以下と３．９８μｇ／ｍｌ超過）に整理すると、ＡＩＭ高値かつ４０歳以上群のＭｅｔＳ発症のハザード比は、血清ＡＩＭ濃度低値かつ４０歳未満の群を１とすると、２．３４になっている。この結果から、ＡＩＭ高値かつ４０歳以上の被験者がＭｅｔＳを発症する危険性は、血清ＡＩＭ濃度低値かつ４０歳未満の被験者がＭｅｔＳを発症する危険性よりも２．３４倍高いということが示された。
　これらのことから、本発明のリスク予測方法を用いて、４０歳以上の壮年及び中年の被験者におけるＭｅｔＳの発症予測を行い、食事習慣や日常の運動等の生活習慣を見直すことが重要になったと考えられる。 The “risk of developing or suffering from MetS or a related disease” according to the present invention refers to the risk that a subject develops MetS or a related disease. Among other things, it may be a risk of developing MetS or its related diseases in 8 years. For example, as shown in FIG. 1 (right figure) and FIG. 2, this risk can be expressed as “hazard ratio” in the present invention. The hazard ratio is a numerical value representing the relative risk by evaluating the risk of developing MetS at the blood AIM concentration using a multivariate adjustment model (for example, the Cox proportional hazard model). For example, as shown in FIG. 1, when divided into 4 groups according to the blood AIM concentration and the first quantile of the blood AIM concentration is 1.00, the second quantile 1.63 (95% confidence interval 0) .76 to 3.50, p = 0.21), third quantile 2.79 (95% confidence interval 1.35 to 5.76, p <0.01), fourth quantile 2.41 (95 % Confidence interval 1.14 to 5.11, p = 0.02), which is an index representing the relative risk of developing MetS. In addition, as shown in FIG. 2, when the hazard ratio of MetS onset is arranged by age (over 40 and under 40) and by serum AIM concentration level (under 3.98 μg / ml and over 3.98 μg / ml) The hazard ratio for the onset of MetS in the group with a high AIM value and 40 years or older is 2.34 when the group with a low serum AIM concentration and a age under 40 years is 1. The results show that subjects with a high AIM and 40 years of age or older have a MetS risk that is 2.34 times higher than those with a low serum AIM concentration and a subject under 40 years of age to develop MetS. It was done.
For these reasons, it is important to use the risk prediction method of the present invention to predict the onset of MetS in middle-aged and middle-aged subjects over 40 years of age and review lifestyle habits such as dietary habits and daily exercise. It is thought.
　上記結果から、本発明において、「ＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高い」ことは、血液中のＡＩＭ濃度が３未満（特に、３．０７未満）である場合に比べて高いこととすることができる。中でも、血液中のＡＩＭ濃度が３．９８μｇ／ｍｌ以上である場合に、血液中のＡＩＭ濃度が３未満（特に、３．０７未満）である被験者に比べて、ＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが有意に又は２．４倍以上高いと判定できる。
　また、血液中のＡＩＭ濃度と組み合わせる指標として年齢を用いる場合は、「ＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高い」ことは、血液中のＡＩＭ濃度が４μｇ／ｍｌ以下（特に、３．９８μｇ／ｍｌ以下）で、かつ年齢４０歳未満である場合に比べて高いこととすることができる。中でも、血液中のＡＩＭ濃度が４μｇ／ｍｌを超え（特に、３．９８μｇ／ｍｌを超え）、かつ年齢４０歳以上である場合に、血液中のＡＩＭ濃度が４μｇ／ｍｌ以下（特に、３．９８μｇ／ｍｌ以下）で、かつ年齢４０歳未満である被験者に比べて、ＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが有意に又は２．３倍以上高いと判定できる。 From the above results, in the present invention, “the risk of developing or suffering from MetS or a related disease is high” compared to the case where the AIM concentration in blood is less than 3 (particularly less than 3.07). Can be expensive. In particular, when the AIM concentration in the blood is 3.98 μg / ml or more, MetS or a related disease is developed or compared with a subject whose AIM concentration in the blood is less than 3 (particularly less than 3.07). It can be determined that the risk of suffering is significantly or 2.4 times higher.
Moreover, when using age as an index combined with the AIM concentration in blood, “the risk of developing or suffering from MetS or a related disease is high” means that the AIM concentration in blood is 4 μg / ml or less (in particular, 3.98 μg / ml or less) and higher than that when the age is less than 40 years. In particular, when the AIM concentration in the blood exceeds 4 μg / ml (particularly exceeds 3.98 μg / ml) and the age is 40 years or older, the AIM concentration in the blood is 4 μg / ml or less (particularly 3. 98 μg / ml or less) and a risk of developing or suffering from MetS or a related disease can be determined to be significantly or 2.3 times higher than that of a subject who is less than 40 years old.
　次に実施例を挙げて本発明を更に説明するが、本発明はこれらに限定されるものではない。 Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
（実施例１）血清ＡＩＭ濃度とＭｅｔＳ発症の関連性の検証
（１）被験者について
ａ）追跡対象：２００８年の徳島県男性労働者　４６３名，２０－６０歳
     (除外基準)  食後受診者, 未採血者, 測定値欠損者, ＭｅｔＳである者
ｂ）解析対象：ＭｅｔＳ発症の有無を追跡できた３６９名
ｃ）追跡期間：８年間（２００８年―２０１６年）
ｄ）診断基準：ＭｅｔＳの基準は、以下の診断基準に基づくものとした。
Ａ　ｊｏｉｎｔ　ｓｔａｔｅｍｅｎｔ　ｏｆ　ＩＤＦ，ＮＨＬＢＩ，ＡＨＡ，Ｗｏｒｌｄ　Ｈｅａｒｔ　Ｆｅｄｅｒａｔｉｏｎ，Ｉｎｔｅｒｎａｔｉｏｎａｌ　Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ　Ｓｏｃｉｅｔｙ，Ｉｎｔｅｒｎａｔｉｏｎａｌ　Ａｓｓｏｃｉａｔｉｏｎ　ｆｏｒ　ｔｈｅ　Ｓｔｕｄｙ　ｏｆ　Ｏｂｅｓｉｔｙ
ｅ）実施機関：国立大学法人徳島大学病院 (Example 1) Verification of the relationship between serum AIM concentration and the onset of MetS (1) About subjects a) Follow-up target: 463 Tokushima male workers in 2008, 20-60 years old (exclusion criteria) Postprandial examinee, not yet Blood sample, measurement deficient, person with MetS b) Analysis target: 369 persons who could follow MetS onset or not c) Follow-up period: 8 years (2008-2016)
d) Diagnostic criteria: MetS criteria were based on the following diagnostic criteria.
A joint statement of IDF, NHLBI, AHA, World Heart Federation, International Aeroclerosity Society, International Association of the Study of Obesity
e) Implementing organization: National University Corporation Tokushima University Hospital
Figure JPOXMLDOC01-appb-T000001
 　表１に記載の５項目中３項目以上の該当で該当者をＭｅｔＳと判定した。
Figure JPOXMLDOC01-appb-T000001
 The applicable person was determined to be MetS in the case of 3 or more of the 5 items listed in Table 1.
（２）解析方法とその結果：
　２００８年～２０１６年間の徳島県男性労働者（４６３名）のＭｅｔＳ発症に関して、Ｃｏｘ比例ハザードモデルを用いて血清ＡＩＭ濃度との関連を評価した。ＡＩＭ濃度の測定は、Ｈｕｍａｎ　ＡＩＭ測定用ＥＬＩＳＡキット（ＴｒａｎｓＧｅｎｉｃ　Ｉｎｃ．）を用いて行った。このキットに含まれる抗ＡＩＭ抗体は、ＡＩＭ濃度の測定に、最も一般的に用いられているものである。
　まず、開始時にＭｅｔＳではない男性４６３名を８年間追跡し、ＭｅｔＳの有無を判定できた３６９名を解析対象者とした。その内、７１名がＭｅｔＳを発症した。追跡開始時の血清ＡＩＭ濃度を４分位（３．０７１μｇ／ｍｌ未満、３．０７１μｇ／ｍｌ－３．９８０μｇ／ｍｌ、３．９８１μｇ／ｍｌ－５．２４７μｇ／ｍｌ、５．２４７μｇ／ｍｌ超過）すると、年齢調整後のＭｅｔＳの累積発症率は、血清ＡＩＭ濃度の分位が増加するごとに有意に上昇した（傾向性検定ｐ＝０．０１）。
　また、多変量調整モデル（年齢、ＢＭＩ、喫煙、飲酒、及び運動習慣の危険因子の影響を除いたモデル）における血清ＡＩＭ濃度４分位別のＭｅｔＳ発症のハザード比は、第１分位を１．００とすると、第２分位１．６３（９５％信頼区間０．７６～３．５０、ｐ＝０．２１）、第３分位２．７９（９５％信頼区間１．３５～５．７６、ｐ＜０．０１）、第４分位２．４１（９５％信頼区間１．１４～５．１１、ｐ＝０．０２）と分位が増加するごとにハザード比が有意に上昇した（傾向性検定ｐ＜０．０１）。
　更に、多変量調整モデル（ＢＭＩ、喫煙、飲酒、及び運動習慣の危険因子の影響を除いたモデル）において、血清ＡＩＭ濃度を中央値（３．９８μｇ／ｍｌ）で低値群と高値群に分類し、同様に、年齢も中央値（４０歳）を用いて二群に分類した。血清ＡＩＭ濃度低値かつ４０歳未満の群と比べると、血清ＡＩＭ濃度高値かつ４０歳以上の群では、ＭｅｔＳ発症のハザード比が、２．３４（９５％信頼区間１．１９～４．６１、ｐ＝０．０１）と有意に上昇した。（Ｐ　ｆｏｒ　ｉｎｔｅｒａｃｔｉｏｎ　＜０．０５）。 (2) Analysis method and results:
Regarding the onset of MetS in Tokushima Prefecture male workers (463) from 2008 to 2016, the relationship with serum AIM concentration was evaluated using the Cox proportional hazard model. The AIM concentration was measured using an ELISA kit for human AIM measurement (TransGenic Inc.). The anti-AIM antibody contained in this kit is the one most commonly used for measuring AIM concentration.
First, 463 men who were not MetS were tracked for 8 years at the start, and 369 who could determine the presence or absence of MetS were analyzed. Of those, 71 developed MetS. Serum AIM concentration at the start of follow-up to quartile (less than 3.071 μg / ml, 3.071 μg / ml-3.980 μg / ml, 3.981 μg / ml-5.247 μg / ml, 5.247 μg / ml) Then, the cumulative incidence of MetS after age adjustment increased significantly each time the quantile of serum AIM concentration increased (propensity test p = 0.01).
In addition, the hazard ratio for the onset of MetS by quartile of serum AIM concentration in a multivariate adjustment model (a model that excludes the effects of risk factors of age, BMI, smoking, drinking, and exercise habits) is 1 for the first quantile. .00, the second quantile 1.63 (95% confidence interval 0.76 to 3.50, p = 0.21) and the third quantile 2.79 (95% confidence interval 1.35 to 5. 76, p <0.01), 4th quantile 2.41 (95% confidence interval 1.14-5.11, p = 0.02) and the hazard ratio increased significantly as the quantile increased. (Tendency test p <0.01).
Furthermore, in a multivariate adjustment model (a model that excludes the effects of risk factors for BMI, smoking, drinking, and exercise habits), the serum AIM concentration is classified into a low value group and a high value group with a median value (3.98 μg / ml). Similarly, the age was also divided into two groups using the median (40 years). Compared to the group with low serum AIM concentration and under 40 years old, the group with high serum AIM concentration and over 40 years old had a hazard ratio of developing MetS of 2.34 (95% confidence interval 1.19 to 4.61, p = 0.01). (P for interaction <0.05).
　徳島県の追跡調査結果によれば、血清ＡＩＭ濃度の上昇はＭｅｔＳ発症リスク（ハザード比）の上昇と有意に関連することが明らかとなった。特に、４０歳以上の男性労働者では、血清ＡＩＭ濃度が上昇するとＭｅｔＳ発症リスク（ハザード比）が高くなることから、壮年期・中年期での血清ＡＩＭ濃度測定の重要性が明らかになった。
　その結果を整理すると以下のようになる。
ａ）ＭｅｔＳ累積発症率とハザード比：
　図１に示されるように、ＭｅｔＳの累積発症率とハザード比は、２００８年度の血清ＡＩＭ濃度を４分位（３．０７１μｇ／ｍｌ未満、３．０７１μｇ／ｍｌ－３．９８０μｇ／ｍｌ、３．９８１μｇ／ｍｌ－５．２４７μｇ／ｍｌ、５．２４７μｇ／ｍｌ超過）し、血清ＡＩＭ濃度が一番低い群と比べると、血清ＡＩＭ濃度が３．９８μｇ／ｍｌを超過すると、８年間でのＭｅｔＳ累積発症率は、約２．１～２．３倍であり、及びハザード比（ＭｅｔＳ発症の危険性）は約２．４～２．８倍であった。
ｂ）ＭｅｔＳ発症のハザード比に対する年齢の影響：
　図２に示されるように、ＭｅｔＳ発症のハザード比（ＭｅｔＳ発症の危険性）は、血清ＡＩＭ濃度低値かつ４０歳未満の群と比べると、４０歳未満の若い人で血清ＡＩＭ濃度が高い人、及び４０歳以上で血清ＡＩＭ濃度が低い人ではハザード比に有意な変化は見られなかった。しかし、４０歳以上かつ血清ＡＩＭ濃度が高値の場合、ハザード比は２．３４倍に有意に上昇することが明らかとなった。したがって、年齢と血清ＡＩＭ濃度の間に有意な交互作用が認められ、年齢の上昇と血清ＡＩＭ濃度上昇を組み合わせることで、ＭｅｔＳ発症に対する相乗効果が得られ、ＭｅｔＳ発症の危険性が著しく高まることが明らかにできた。この知見から、これまでの報告とは異なり、血清ＡＩＭ濃度単独ではなく、年齢などの他の指標と共に評価することによりはじめてＭｅｔＳ発症リスクを精度よく予測できることが明らかとなった。 According to the follow-up results of Tokushima Prefecture, it was revealed that an increase in serum AIM concentration is significantly associated with an increase in the risk of developing MetS (hazard ratio). In particular, male workers over 40 years of age have a higher risk of developing MetS (hazard ratio) when serum AIM concentration increases, and the importance of measuring serum AIM concentration in middle and middle age has become clear .
The results are summarized as follows.
a) Cumulative incidence of MetS and hazard ratio:
As shown in FIG. 1, the cumulative incidence of MetS and the hazard ratio are based on the serum AIM concentration in the fourth quarter (less than 3.071 μg / ml, 3.071 μg / ml-3.980 μg / ml, 3. 981 μg / ml-5.247 μg / ml and 5.247 μg / ml), and when the serum AIM concentration exceeds 3.98 μg / ml, the MetS accumulation over 8 years The incidence was about 2.1 to 2.3 times, and the hazard ratio (risk of developing MetS) was about 2.4 to 2.8 times.
b) Effect of age on hazard ratio for MetS development:
As shown in FIG. 2, the hazard ratio for developing MetS (risk of developing MetS) is lower in the serum AIM concentration and younger than 40 years and higher in serum AIM compared to the group younger than 40 years No significant change in the hazard ratio was observed in people over 40 years of age with low serum AIM concentrations. However, it has been clarified that the hazard ratio significantly increases 2.34 times when the age of 40 years or older and the serum AIM concentration is high. Therefore, a significant interaction is observed between age and serum AIM concentration, and the combination of increased age and increased serum AIM concentration can provide a synergistic effect on the onset of MetS and significantly increase the risk of developing MetS. I was able to clarify. From this finding, it has become clear that unlike the previous reports, the risk of developing MetS can be accurately predicted only by evaluating it with other indicators such as age rather than serum AIM concentration alone.
　本発明の血清ＡＩＭ濃度を一つの指標とする多元的ＭｅｔＳ発症の予測方法により、特に年齢と血清ＡＩＭ濃度を２元とするＭｅｔＳ発症リスクを評価することにより、４０歳以上の壮年及び中年の被験者におけるＭｅｔＳの発症予測が可能となった。更に本発明の多元的ＭｅｔＳ発症リスクの予測方法を用いて、食事習慣や日常の運動等の生活習慣を見直すことが可能となり、ＭｅｔＳの予防と治療のコントロールが可能になった。更には発症したＭｅｔＳの治療効果の確認が容易になり、ＭｅｔＳの病勢コントロールが可能になった。また、高年齢かつ血液中のＡＩＭ濃度が高い人に、ＭｅｔＳ発症回避のための社会資源を配分すればよいことが見出された点でも、産業上有用である。 According to the method for predicting the onset of multidimensional MetS using the serum AIM concentration of the present invention as one index, particularly by evaluating the risk of developing MetS based on age and serum AIM concentration as binary, It was possible to predict the onset of MetS in subjects. Furthermore, it has become possible to review lifestyle habits such as dietary habits and daily exercise using the method for predicting the risk of developing MetS according to the present invention, and it has become possible to control MetS prevention and treatment. Furthermore, it became easy to confirm the therapeutic effect of the onset MetS, and the disease state control of MetS became possible. It is also industrially useful in that it has been found that social resources for avoiding the onset of MetS should be allocated to people who are older and have a high AIM concentration in the blood.

Claims (9)

  1. 　メタボリック・シンドローム（ＭｅｔＳ）発症の予測方法であって、
    被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、
    血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、
    当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断することを特徴とする、予測方法。     A method for predicting the onset of metabolic syndrome (MetS),
    From AIM concentration in test subject's blood, age, lifestyle index, metabolic index,
    In combination with serum AIM concentration and one or more other indicators,
    The prediction method characterized by determining that the subject has a high risk of developing or suffering from MetS or a related disease.
  2. 　被験者の血液中のＡＩＭ濃度、年齢、生活習慣の指標、代謝の指標の中から、血清ＡＩＭ濃度と、その他の一つ以上の指標を組み合せて、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断することが、
    　被験者の血液中のＡＩＭ濃度を測定し、かつ年齢、生活習慣の指標、及び代謝の指標の一つ以上を判定又は測定する工程と、各指標が基準又は基準値に該当する場合に、当該被験者がＭｅｔＳ又はその関連疾患を発症または罹患しているリスクが高いと判断する工程とを含むことである、請求項１に記載の、予測方法。     The subject develops or suffers from MetS or a related disease by combining serum AIM concentration with one or more other indicators from among AIM concentrations in blood, age, lifestyle indicators, and metabolic indicators To judge that the risk is high
    Measuring the AIM concentration in the blood of the subject and determining or measuring one or more of age, lifestyle index, and metabolic index, and if each index meets a reference or reference value, the subject The method according to claim 1, further comprising: determining that the risk of developing or suffering from MetS or a related disease is high.
  3. 　上記生活習慣の指標が、喫煙、飲酒、運動、肥満、栄養素、食品群の中から選択されることを特徴とする、請求項１又は２に記載の予測方法。 The prediction method according to claim 1 or 2, wherein the lifestyle index is selected from smoking, drinking, exercise, obesity, nutrients, and a food group.
  4. 　上記代謝の指標が、血圧、脂質代謝マーカー、血清アディポネクチン濃度、血清ＦＡＢＰ４濃度、肝機能マーカー、血清ＩｇＭ濃度、血糖値、ブドウ糖負荷試験（ＯＧＴＴ）２時間後の血糖値、食後1時間または２時間の血糖値、血中ＨｂＡ１ｃ濃度、炎症性マーカー濃度の中から選択されることを特徴とする、請求項１～３のいずれかに記載の予測方法。 The above metabolic indicators are blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, blood glucose level 2 hours after glucose tolerance test (OGTT), 1 hour or 2 hours after meal The prediction method according to any one of claims 1 to 3, wherein the blood glucose level, HbA1c concentration in blood, and inflammatory marker concentration are selected.
  5. 　被験者の血液中のＡＩＭ濃度の判断基準値が３．５μｇ／ｍｌを超過する数値である、請求項１～４のいずれかに記載の予測方法 The prediction method according to any one of claims 1 to 4, wherein the criterion value of the AIM concentration in the blood of the subject is a numerical value exceeding 3.5 µg / ml.
  6. 　血清ＡＩＭ濃度の判断基準値が３．９８μｇ／ｍｌを超過する数値である、請求項１～４のいずれかに記載の予測方法 The prediction method according to any one of claims 1 to 4, wherein the criterion value of the serum AIM concentration exceeds 3.98 µg / ml.
  7. 　年齢を指標として用い、年齢の判断基準値が４０歳以上である、請求項１～６のいずれかに記載の予測方法。 The prediction method according to any one of claims 1 to 6, wherein the age is used as an index, and the age criterion value is 40 years or older.
  8. 　上記リスクが高いことが、血清ＡＩＭ濃度として３．９８μｇ／ｍｌ以下で、４０歳未満の被験者と対比して、血清ＡＩＭ濃度が３．９８μｇ／ｍｌを超え、かつ４０歳以上の被験者のＭｅｔＳ発症リスクが２．３倍以上であることである、請求項７に記載の予測方法。 The above-mentioned high risk is that the serum AIM concentration is 3.98 μg / ml or less, the serum AIM concentration is higher than 3.98 μg / ml, and the onset of MetS is 40 years or older in comparison with subjects under 40 years old. The prediction method according to claim 7, wherein the risk is 2.3 times or more.
  9. 　上記リスクが高いことが、血清ＡＩＭ濃度として３．０７μｇ／ｍｌ未満の被験者と比較し、血清ＡＩＭ濃度が３．９８μｇ／ｍｌ以上である被験者のＭｅｔＳ発症リスクが２．４倍以上であることである、請求項１に記載の予測方法。 The above-mentioned risk is high because the risk of developing MetS is 2.4 times or more in subjects whose serum AIM concentration is 3.98 μg / ml or more compared to subjects whose serum AIM concentration is less than 3.07 μg / ml. The prediction method according to claim 1.
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