JP2020109355A - Onset prediction method of metabolic syndrome using aim as index - Google Patents

Onset prediction method of metabolic syndrome using aim as index Download PDF

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JP2020109355A
JP2020109355A JP2017096799A JP2017096799A JP2020109355A JP 2020109355 A JP2020109355 A JP 2020109355A JP 2017096799 A JP2017096799 A JP 2017096799A JP 2017096799 A JP2017096799 A JP 2017096799A JP 2020109355 A JP2020109355 A JP 2020109355A
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明子 秦
Akiko Hata
明子 秦
真理 船木
Mari Funaki
真理 船木
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Abstract

To provide an onset prediction method of a metabolic syndrome using AIM concentration in blood.SOLUTION: A prediction method of a pluralistic MetS onset risk using serum AIM concentration as an index has been found, by an epidemiological approach, from a cohort study in Tokushima Prefecture. It has been found that the MetS onset risk is increased by 2.3 times, in a subject who is 40 or older and whose serum AIM concentration exceeds 3.98 μg/ml, when evaluating the MetS onset risk by using an age and the serum AIM concentration as two indexes. Review of life style such as daily health management, diet habit and daily exercise can be promoted, by using the prediction method of the pluralistic MetS onset with the serum AIM concentration as a center, and prevention of the MetS and control of medical treatment becomes possible.SELECTED DRAWING: None

Description

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 more particularly to a method for predicting the risk of developing MetS 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 are accumulated in one individual, and the risk of arteriosclerosis is extremely high. It is used as the name of a disease that means that.
The purpose of treating MetS is not to alleviate symptoms, but to prevent the development of the various diseases described above that may develop in a linked manner. Since it is difficult to restore a disease state once advanced to its original state, it is necessary to start prevention at an early stage. Therefore, a predictive method that can evaluate the risk of developing MetS at an early stage is required.
At present, there are diagnostic criteria for MetS, and the risk of developing MetS is predicted based on how close the criteria are. Therefore, various diagnostic criteria for MetS have been proposed so far. For example, abdominal girth, triglyceride, HDL cholesterol, blood pressure, fasting blood glucose level, etc. are listed as diagnostic items, and it is practiced to diagnose MetS when some of these items are met.
However, there are various discussions regarding the current diagnostic criteria for MetS, and it is difficult to deal with the diversity of MetS pathological conditions, and exceeding the standard values for each diagnostic item does not necessarily reflect the onset and progression of MetS. It is pointed out that it does not.

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。Recently, it has been clarified that AIM secreted by macrophages plays a role in promoting these processes in a series of processes in which chronic inflammation occurs in hypertrophic adipocytes and the resulting induction of insulin resistance. (Non-patent document 1).
In addition, AIM plays an important role not only in anti-obesity action that decomposes fat but also in diseases such as diabetes and arteriosclerosis that are linked to MetS and linked to each other, and contribute to the process of autoimmunity associated with obesity. It is also reported that it plays a decisive role (Non-Patent Document 2).
While research on AIM has progressed in this way, it has been suggested that AIM is directly involved in the origin of MetS (Patent Document 1). For example, as a cause of migration of macrophages into adipose tissue, an increase in blood concentration of AIM with obesity is mentioned. That is, it is considered that infiltration of macrophages into adipose tissue causes chronic inflammation in the adipose tissue and the whole body, insulin resistance is induced, and a series of disease chains of MetS is caused.

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、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 could be diagnosed early at the most upstream stage by detecting an increase in blood concentration of AIM (Patent Document 1).
However, there are still many unclear points regarding the effect of AIM on the onset of MetS, and there are few follow-up studies that have examined the relationship between AIM and MetS. In addition, the method of predicting the MetS risk using the numerical value in blood of AIM has not yet been studied.

再公表２０１１−１４５７２５号公報Republication 2011-145725

新井郷子、アステラス病態代謝研究会平成２２年度第４２回助成研究報告集「脂肪融解タンパク質ＡＩＭによるメタボリックシンドローム制御の研究」Satoko Arai, Astellas Metabolism Study Group 2010 42nd Grant-in-Aid for Scientific Research "A study on metabolic syndrome control by fat-melting protein AIM" Ｃｅｌｌ Ｒｅｐｏｒｔｓ，２０１３，Ａｐｒ ２５，３（４）１１８７−９８Cell Reports, 2013, Apr 25, 3(4) 1187-98.

本発明の課題は、ＡＩＭを用いたＭｅｔＳ発症の予測方法を目的とする。更には、この予測方法を用いてＭｅｔＳ発症の回避方法を目的とする。 The subject of this invention is aimed at the prediction method of MetS onset using AIM. Furthermore, it aims at the avoidance method of 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の累積発症率を評価すると、図１に示す以下の知見が得られた。
ａ）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）多変量調整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）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、血清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、血清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、高年齢と高血清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 a follow-up study 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 shown in FIG. 1 were obtained.
a) 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, Statistically significant increase from the third quartile as increasing (> 5.247 μg/ml). In addition, there was a significant linear trend.
b) The hazard ratio of the onset of MetS was calculated for each quartile of the serum AIM concentration in the multivariate adjustment model. 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 quartile and the 4th quantile. In addition, the risk of developing MetS increased significantly as the serum AIM concentration increased.
c) Serum AIM concentration is classified into a low value group and a high value group with a median value (3.98 μg/ml), and similarly, age is also classified into a high age group and a low age group using the median value (40 years old). , MetS onset hazard ratio was determined. As shown in FIG. 2, as compared with the group with low serum AIM concentration and under 40 years old, there was no significant change in the hazard ratio in the group under 40 years old and high serum AIM concentration group, and the group over 40 years old and low serum AIM concentration group. I couldn't see it. However, the MetS-onset hazard ratio after multivariate adjustment was 2.34 times in the group aged 40 years or older and the serum AIM concentration high group was less than 40 years old and the serum AIM concentration low group was 2.34 times, which significantly increased the risk of MetS development. Admitted.
It was found from the knowledge of the present invention that by combining the serum AIM concentration and the index of age, it is possible to screen a person with a high risk of onset with extremely high accuracy. That is, as expected so far, the increase in serum AIM concentration leads to an increase in hazard ratio, but the hazard ratio (risk of developing MetS) increases only when both old age and high serum AIM value are met. The present invention has made it clear.

本発明の結果、血清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、血清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では、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、血清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、血清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, serum AIM concentration is used as one index, and the following index groups (age, lifestyle-related indexes (smoking, drinking, exercise, obesity, nutrients, food groups, etc.), metabolic indexes (blood pressure, lipid metabolism markers) , Serum adiponectin concentration, serum FABP4 (Fatty acid-binding protein 4) concentration, liver function marker, serum IgM concentration, blood glucose level, serum HbA1c concentration, inflammatory marker, etc.)) By conducting multidimensional evaluation with a combination, it has become possible to accurately evaluate an increase in the risk of developing MetS (hazard ratio).
Although it has been difficult to ensure sufficient validity by itself with regard to the evaluation index of the risk of developing MetS, the present invention provides a multidimensional evaluation that combines serum AIM concentration with other indexes. , It was found to be more appropriate. Further, it was found that determining the median serum AIM concentration (3.98 μg/ml) and using it as a reference is effective as an assessment of the future risk of developing MetS.
The present invention has revealed the importance of measuring serum AIM concentration in the middle-aged and middle-aged periods in order to reduce the risk of MetS development (hazard ratio).
The present inventors have completed the present invention based on the above findings.

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、
被験者の血清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）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）に記載の予測方法。
（３）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、血清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）又は（２）に記載の予測方法。
（４）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）〜（３）のいずれかに記載の予測方法
（５）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、上記（１）〜（３）のいずれかに記載の予測方法
（６）年齢の判断基準値が４０歳以上である、上記（１）〜（５）のいずれかに記載の予測方法
（７）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、当該被験者のＭｅｔＳ発症リスクが２．３倍以上である、上記（６）に記載の予測方法。
（８）上記リスクが高いことが、血清ＡＩＭ濃度として３．０７μｇ／ｍｌ以下の場合と比較し、血清ＡＩＭ濃度が３．９８〜５．２５である当該被験者のＭｅｔＳ発症リスクが２．８倍以上である、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), comprising:
From the subject's serum AIM concentration, age, lifestyle index, metabolic index,
Combining serum AIM concentration with one or more other indicators,
A predictive method, which comprises determining that the subject has a high risk of developing or suffering from MetS or a related disease thereof.
(2) The prediction method according to (1) above, wherein the lifestyle habit index is selected from smoking, drinking, exercise, obesity, nutrients, and food groups.
(3) The above-mentioned metabolic index is selected from blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, serum HbA1c concentration, and inflammatory marker The prediction method according to (1) or (2) above.
(4) The prediction method according to any one of (1) to (3) above, wherein the criterion value for the serum AIM concentration of the subject is a value exceeding 3.5 μg/ml. (5) The criterion for determining the serum AIM concentration The prediction method according to any one of (1) to (3) above, wherein the value is a numerical value exceeding 3.98 μg/ml (6) The judgment criterion value for age is 40 years or older, above (1) to Prediction method according to any one of (5) (7) The high risk, the serum AIM concentration is 3.98μg / ml or less, compared with subjects under 40 years of age, MetS onset risk of the subject The prediction method according to (6) above, which is 2.3 times or more.
(8) Compared with the case where the serum AIM concentration is 3.07 μg/ml or less, the high risk is 2.8 times the MetS onset risk of the subject whose serum AIM concentration is 3.98 to 5.25. The prediction method according to (1) above is the above.

本発明のＭｅｔＳ発症の予測方法は、血清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、血清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、血清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、血清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、加齢を伴わない血清ＡＩＭ濃度上昇、あるいは血清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、血清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 of the present invention uses the serum AIM concentration as one index, and further, age, lifestyle index (smoking, drinking, exercise, obesity, nutrients, food groups, etc.), metabolic index (blood pressure, lipids). Metabolic markers, serum adiponectin levels, serum FABP4 levels, liver function markers, serum IgM levels, blood glucose levels, serum HbA1c levels, inflammatory markers, etc.) are used as indicators and are predicted in a multidimensional combination. It has been revealed that the multidimensional prediction method using the serum AIM concentration of the present invention as an index is considerably effective and highly accurate in predicting the future risk of developing MetS.
Further, in the present invention, as a result of epidemiological studies, a median serum AIM concentration of 3.98 μg/ml was determined as a reference value for predicting the onset of MetS. When the median value was used as a reference to divide into a high value group and a low value group, it was found epidemiologically that the subjects in the high value group had a high risk of developing MetS when combined with other indicators.
According to the reports so far, it is considered that the increase of serum AIM concentration or aging is associated with the onset of MetS. However, according to the findings of the present invention, it was found that the risk of developing MetS does not increase in the serum AIM concentration increase without aging or in the aging without serum AIM concentration increase. On the other hand, it was found that the risk of developing MetS was remarkably increased when the serum AIM concentration was increased and aging was accompanied. Based on the findings of the present invention, for example, for individuals belonging to a group defined by age and the like, if the reference value of the blood AIM concentration of the present invention is used and the lifestyle is taken into consideration, the onset of future MetS may be It has been found that it can be avoided. Further, it has been found that even a patient who has developed MetS can expect recovery or alleviation from the onset 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。The cumulative incidence and hazard ratio of MetS in 369 subjects (male, 20 to 60 years old) were classified according to the 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, more than 5.247 μg/ml). The cumulative incidence of MetS increased statistically significantly as the serum AIM concentration increased. Furthermore, as compared with the group with the lowest serum AIM concentration, when the serum AIM concentration exceeded 3.98 μg/ml, the cumulative incidence of MetS was significantly increased. Similarly, the risk of developing MetS increased significantly as the serum AIM concentration increased. Furthermore, compared with the group with the lowest AIM concentration, when the serum AIM concentration exceeded 3.98 μg/ml, it increased more than 2-fold, 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 (40 years old or more and under 40 years old) and according to serum AIM concentration level (3.98 microgram/ml or less and 3.98 microgram/ml excess). The hazard ratio for the onset of MetS was 2.34 in the group with a high AIM level and 40 years or older, which was significantly higher than that in 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、血清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、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）、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、血清ＨｂＡ１ｃ濃度、炎症性マーカー濃度等）を挙げることができる。例えば、血清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。
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。The “method of predicting the onset of metabolic syndrome (MetS)” of the present invention is a method of predicting the risk of developing MetS by using the serum AIM concentration as one index and combining it with other indexes multidimensionally. Other indexes include age, lifestyle-related indexes (smoking, drinking, exercise, obesity, nutrients, food groups, etc.), which are considered to be indexes that affect MetS, metabolic indexes (blood pressure, lipid metabolism markers, serum adiponectin concentration, Serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, serum HbA1c concentration, inflammatory marker concentration and the like). For example, 3.98 μg/ml is set as a criterion value for the serum AIM concentration, and the test subject is classified into a subject having a higher value and a subject having a lower value. In addition, by dividing the subjects by age, degree of obesity (BMI value), etc., and performing a two-dimensional or multi-dimensional analysis, subjects with low serum AIM concentration and other normal subjects It is a prediction method for evaluating the risk of developing MetS (hazard ratio) as compared with.
The relationship between the serum AIM concentration and the MetS cumulative onset rate or MetS onset risk is shown in FIG. 1, and it is shown that the increase in the serum AIM concentration increases the MetS cumulative onset rate and MetS onset risk. In the evaluation of FIG. 1, influences of serum AIM concentration on the onset of MetS are examined by excluding the influences of factors (age, obesity, smoking habits, drinking habits, exercise habits) that are considered to be risk factors for the onset of MetS. doing. Therefore, FIG. 1 confirms the known association that the risk of developing MetS increases as the serum AIM concentration increases, and that the subject population of the present invention is not significantly biased.
Next, FIG. 2 shows an outline of evaluation of the risk of developing two-dimensional MetS with serum AIM concentration and age. The combination of serum AIM concentration and age index has a synergistic effect on the onset of MetS by having both old age and high AIM concentration, rather than aging or an increase in serum AIM concentration alone. Was shown. From this, it was found that a combination of the serum AIM concentration and the index related to MetS can be used to screen a person with a high risk of developing MetS with high accuracy.

本発明の「血清ＡＩＭ濃度」とは、血清中に存在するタンパク質ＡＩＭの濃度のことを言う。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。
本発明の「血清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４．０μｇ／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５．０μｇ／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６．０μｇ／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７．０μｇ／ｍｌを超過する数値を挙げることができる。The “serum AIM concentration” of the present invention refers to the concentration of protein AIM present in serum. AIM not only suppresses macrophage apoptosis but also plays a very important role in the progression of obesity and various pathological conditions associated with obesity, and its blood concentration and genetic background greatly influence lifestyle habits. Is believed to receive. It is reported that the AIM concentration in blood rises as obesity progresses (Non-Patent Document 1). It is known that there are individual differences in the AIM concentration in human blood, and that it also varies depending on sex and age. According to previous reports, AIM increases its blood concentration in obese conditions and directly acts on adipocytes to cause the degradation of neutral fat through AIM-dependent lipolysis, resulting in free fatty acids and glycerol. Release occurs. Free fatty acids stimulate TLR4 expressed in adipocytes, promote the production of chemokines, and as a result, induce macrophage infiltration into enlarged adipocytes. It is reported that obesity causes chronic inflammation in adipose tissue by such a mechanism of action. Thus, AIM directly acts on adipose tissue, promotes release of free fatty acid through AIM-dependent lipolysis, and induces infiltration of macrophages, which results in chronic inflammation of visceral fat and subsequent insulin resistance. It is said to be an important molecule that becomes the First Step in the induction of However, previous AIM studies have focused on reports on the mechanism of action of AIM and treatment using AIM, and epidemiological research reports on the practical reference value of blood AIM concentration that can be practically used for MetS countermeasures. Moreover, no attempt has been made to use the blood AIM concentration as a reference value for predicting the onset of MetS.
The “judgment standard value of serum AIM concentration” of the present invention means a numerical value exceeding about 3.5 μg/ml, and a numerical value exceeding about 4.0 μg/ml depending on the combination with other indexes. Can be mentioned. According to the index to be further combined, preferable numerical values include a numerical value exceeding about 4.5 μg/ml or 5.0 μg/ml. More preferred values include values above 5.5 μg/ml or about 6.0 μg/ml. Most preferred values may include values above about 6.5 μg/ml or about 7.0 μg/ml.

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。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。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。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。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。栄養素を指標として使用する場合には、一日の摂取必要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。食品を指標として使用する場合にも、一日の摂取必要量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。 The “lifestyle index” of the present invention means, for example, smoking, drinking, exercising, obesity, nutrients, food groups and the like. When smoking is used as an index, subjects are classified based on whether they have a smoking habit or a smoking habit in the past. As a criterion with a higher risk of onset, subjects are classified based on whether or not they currently have a smoking habit. When using alcohol, the subjects are classified based on whether or not they have a drinking habit. As a standard with a higher onset risk, subjects are classified based on a drinking habit of 20 g/day in pure alcohol. When exercising, subjects are classified based on whether or not they have exercise habits. As a standard with a higher risk of onset, subjects are classified based on 23 mets/hour/week. When obesity is used, subjects are classified based on a BMI value of 23. As a standard with a higher onset risk, subjects are classified based on a BMI value of 25. When nutrients are used as an index, subjects are classified based on the daily intake requirement. For example, subjects having excessive energy intake, excessive lipid intake, excessive sugar intake, excessive sodium intake, or insufficient intake of dietary fiber are classified into test subjects and other test subjects. Even when food is used as an index, the subjects are classified based on the daily intake requirement. For example, excessive intake of meat, excessive intake of sweets, excessive intake of alcohol/favorite beverages, insufficient intake of seafood, insufficient intake of vegetables, insufficient intake of seaweed, excessive intake of sugar, excessive intake of fats and oils, etc. It is divided into subjects and other subjects.

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、血清ＨｂＡ１ｃ濃度、炎症性マーカー濃度等のことをいう。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。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。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。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。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。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。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。肝機能マーカーを指標として使用する場合には、ＡＬＴとして３０Ｕ／Ｌ、ＡＳＴとして３０Ｕ／Ｌ、γＧＴＰ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。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。血清ＨｂＡ１ｃ濃度を指標として使用する場合には、５．６％もしくはｐｒｅｄｉａｂｅｔｅｓの基準値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。炎症性マーカーを指標として使用する場合には、ｈｓＣＲＰ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。ＩＬ−６では４．０ｐｇ／ｍｌを基準として被験者を区分する。ＴＮＦ−αでは２．９ｐｇ／ｍｌ、ＭＣＰ−１では１５０ｐｇ／ｍｌを基準として被験者を区分する。なお、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。 The “metabolic index” of the present invention refers to, for example, blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, serum HbA1c concentration, inflammatory marker concentration and the like. .. When blood pressure is used as an index, subjects are classified based on systolic blood pressure of 130 mmHg or diastolic blood pressure of 85 mmHg. As a standard with a higher onset risk, subjects are classified based on a systolic blood pressure of 140 mmHg or a diastolic blood pressure of 90 mmHg. Examples of lipid metabolism markers include LDL cholesterol, HDL cholesterol, neutral fat, and total cholesterol. When LDL cholesterol is used as an index, the subjects are classified based on 120 mg/dl. As a standard with a higher risk of onset, subjects are classified based on 140 mg/dl. When HDL cholesterol is used as an index, subjects are classified based on 40 mg/dl. When using neutral fat as an index, subjects are classified based on 150 mg/dl. When total cholesterol is used as an index, subjects are classified based on 220 mg/dl. When the serum adiponectin concentration is used as an index, the subjects are classified based on 9.9 μg/ml for men and 9.1 μg/ml for women. As a criterion with a higher risk of onset, male subjects are classified based on 6.2 μg/ml. When the serum FABP4 concentration is used as an index, the subjects are classified based on 9.0 ng/ml. As a standard with a higher onset risk, subjects are classified based on 11.0 ng/ml. When the liver function marker is used as an index, subjects are classified based on 30 U/L as ALT, 30 U/L as AST, 45 U/L for males and 25 U/L for females as γGTP. When using serum IgM concentration as an index, subjects are classified based on 77.0 mg/dl. When using the blood glucose level as an index, subjects are classified based on a fasting blood glucose level of 100 mg/dl. As a standard with a higher onset risk, subjects are classified based on a fasting blood glucose level of 126 mg/dl. When the serum HbA1c concentration is used as an index, the subjects are classified based on the standard value of 5.6% or prediabetes. As a standard with a higher onset risk, subjects are classified based on 6.5%. When using an inflammatory marker as an index, subjects are classified based on hsCRP of 0.3 mg/dl. As a standard with a higher risk of development, subjects are classified based on 1.0 mg/dl. In IL-6, subjects are classified based on 4.0 pg/ml. Subjects are classified based on 2.9 pg/ml for TNF-α and 150 pg/ml for MCP-1. When using age as an index, subjects are classified based on the age of 40.

本発明の「メタボリック・シンドローム発症」とは、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）に基づいて、ＭｅｔＳであると判断されることを言うと共に、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。
・中性脂肪１５０ｍｇ／ｄｌ以上かつ／またはＨＤＬ−Ｃ４０ｍｇ／ｄｌ未満
・収縮期血圧１３０ｍｍＨｇ以上かつ／または拡張期血圧８５ｍｍＨｇ以上
・空腹時血糖値１１０ｍｇ／ｄｌ以上。
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。
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。このリスクを、本発明では「ハザード比」として表している。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 “metabolic syndrome onset” of the present invention is, for example, based on the diagnostic criteria of MetS (A joint state of IDF, NHLBI, AHA, World Heart Federation of International Society of Sociology, International Association of International Sociology, International Association of Society, International Association of Severity, International Association of Society, International Association of Society, International Association of International Sociology, International Association of Scholarship (AH). In addition to saying that it is determined to be MetS, based on the Japanese MetS diagnostic criteria. In addition, according to the current diagnostic criteria in Japan, MetS is diagnosed when two of the following three items are applicable in addition to the abdominal circumference (85 cm or more for men, 90 cm or more for women).
-Triglyceride 150 mg/dl or more and/or HDL-C 40 mg/dl or less-systolic blood pressure 130 mmHg or more and/or diastolic blood pressure 85 mmHg or more-fasting blood glucose level 110 mg/dl or more.
The "MetS or a disease related thereto" of the present invention refers to a disease caused by MetS together therewith, and includes, for example, MetS, obesity, insulin resistance, diabetes, dyslipidemia, hypertension, arteriosclerotic disease, Examples thereof include cerebrovascular disorder, ischemic heart disease, heart failure, dementia, stroke, neuropathy, renal disease, adipocytokine secretion abnormality, and blood free fatty acid amount abnormality.
The “risk of developing or suffering from MetS or a related disease thereof” in the present invention refers to a risk of a subject developing MetS or a related disease thereof. In the present invention, this risk is expressed as "hazard ratio". The hazard ratio is a numerical value that indicates the relative risk by evaluating the risk of developing MetS at the blood AIM concentration using a multivariate adjustment model (eg, Cox proportional hazard model). For example, as shown in FIG. 1, if the first quantile of the blood AIM concentration is divided into four groups according to the blood AIM concentration and the first quantile is 1.00, the second quantile is 1.63 (95% confidence interval 0. .76-3.50, p=0.21), third quantile 2.79 (95% confidence interval 1.35-5.76, p<0.01), fourth quantile 2.41 (95) % Confidence interval 1.14 to 5.11, p=0.02), which is an index showing the relative risk of developing MetS. In addition, as shown in FIG. 2, when the hazard ratio of MetS onset is sorted by age (40 years or older and under 40 years) and serum AIM concentration level (3.98 μg/ml or less and 3.98 μg/ml or more), , The hazard ratio for the onset of MetS in the group with a high AIM and 40 years or older is 2.34 when the group with a low serum AIM concentration and a group under 40 years of age is 1. The results show that the risk of developing MetS in subjects with high AIM and 40 years or older is 2.34 times higher than the risk of developing MetS in subjects with low serum AIM concentration and under 40 years of age. Was done.
From these things, it is important to predict the onset of MetS in subjects aged 40 and older and for middle-aged and middle-aged subjects by using the risk prediction method of the present invention, and to review lifestyle habits such as eating habits and daily exercise. It is believed that

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.

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 ＯｂｅｓｉｔｙVerification of Relationship between Serum AIM Concentration and MetS Onset (1) About Subjects a) Follow-up Target: 463 Tokushima Male Workers, 20-60 Years Old (Exclusion Criteria) Postprandial Consultants, Uncollected Blood, Measurements Deficient person, person with MetS b) Analysis target: 369 people who were able to follow the presence or absence of MetS onset c) Follow-up period: 8 years (2008-2016)
d) Diagnostic criteria: The MetS criteria were based on the following diagnostic criteria.
A joint statement of IDF, NHLBI, AHA, World Heart Federation, International Atherosclerosis Society, International Association of the Study of Obesity

（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。
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、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 its result:
The Cox proportional hazard model was used to evaluate the association of MetS incidence in Tokushima male workers (463) between 2008 and 2016 with serum AIM concentration.
First, 463 males who were not MetS were followed for 8 years at the start, and 369 persons who were able to determine the presence or absence of MetS were analyzed. 71 of them developed MetS. Serum AIM concentration at the start of follow-up is 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 with increasing quantiles of serum AIM concentration (propensity test p=0.01).
In addition, the hazard ratio of the onset of MetS for each quartile of serum AIM concentration in the multivariate adjusted model is 1.63 for the second quantile (95% confidence interval 0.76 to 3 when the first quantile is 1.00). .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) .14-5.11, p=0.02) and the hazard ratio increased significantly with each increase of the quantile (propensity test p<0.01).
Further, the serum AIM concentration was classified into a low value group and a high value group based on the median value (3.98 μg/ml), and similarly, age was also classified into two groups using the median value (40 years old). Compared with the group with a low serum AIM concentration and under 40 years of age, the hazard ratio of the onset of MetS was 2.34 (95% confidence interval 1.19 to 4.61) in the group with a high serum AIM concentration and 40 years or older. (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累積発症率及びハザード比（ＭｅｔＳ発症の危険性）は約２倍であった。
ｂ）ＭｅｔＳ累積発症率と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 results of a follow-up survey in Tokushima Prefecture, it was revealed that an increase in serum AIM concentration was significantly associated with an increase in the risk of developing MetS (hazard ratio). In particular, in the case of male workers aged 40 years or older, the risk of developing MetS (hazard ratio) increases as the serum AIM concentration increases, so the importance of measuring serum AIM concentration during the middle-aged and middle-aged years became clear. ..
The results are summarized below.
a) MetS cumulative incidence and hazard ratio:
As shown in FIG. 1, the cumulative incidence of MetS and the hazard ratio were as follows. The serum AIM concentration in 2008 was quartile (less than 3.071 μg/ml, 3.071 μg/ml-3.980 μg/ml, 3. 981 μg/ml-5.247 μg/ml, exceeding 5.247 μg/ml), and when the serum AIM concentration exceeds 3.98 μg/ml compared to the group with the lowest serum AIM concentration, MetS accumulation for 8 years The incidence and hazard ratio (risk of developing MetS) were approximately doubled.
b) Effect of age on cumulative MetS incidence and hazard ratio:
As shown in FIG. 2, the hazard ratio of developing MetS (risk of developing MetS) was lower in serum AIM concentration and in those younger than 40 years old and higher in serum AIM concentration than in the group under 40 years old. , And those with age 40 and older who had low serum AIM levels did not show any significant change in the hazard ratio. However, it was revealed that the hazard ratio was significantly increased to 2.34 times when the serum AIM concentration was high at the age of 40 or older. Therefore, there is a significant interaction between age and serum AIM concentration, and by combining the increase in age and the increase in serum AIM concentration, a synergistic effect on the onset of MetS is obtained, and the risk of onset of MetS is significantly increased. I was able to make it clear. From this finding, it has been clarified that, unlike the previous reports, the risk of developing MetS can be accurately predicted only by evaluating the serum AIM concentration together with other indicators such as age.

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。 By the method for predicting the onset of multiple MetS using the serum AIM concentration as one index according to the present invention, particularly by evaluating the risk of developing MetS with two sources of age and serum AIM concentration, the ages of 40 years or older and middle-aged and middle-aged people It has become possible to predict the onset of MetS in subjects. Furthermore, by using the method for predicting the risk of developing multiple MetS according to the present invention, it becomes possible to review lifestyle habits such as eating habits and daily exercise, and it becomes possible to prevent and control MetS. Furthermore, it became easier to confirm the therapeutic effect of the onset MetS, and it became possible to control the disease state of MetS.

Claims (8)

メタボリック・シンドローム（ＭｅｔＳ）発症の予測方法であって、
被験者の血清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), comprising:
From the subject's serum AIM concentration, age, lifestyle index, metabolic index,
Combining serum AIM concentration with one or more other indicators,
A predictive method, which comprises determining that the subject has a high risk of developing or suffering from MetS or a related disease thereof. 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に記載の予測方法。 The prediction method according to claim 1, wherein the lifestyle index is selected from smoking, drinking, exercising, obesity, nutrients, and food groups. 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、血清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又は２に記載の予測方法。 The above-mentioned metabolic index is selected from blood pressure, lipid metabolism marker, serum adiponectin concentration, serum FABP4 concentration, liver function marker, serum IgM concentration, blood glucose level, serum HbA1c concentration, and inflammatory marker concentration. The prediction method according to claim 1 or 2. 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、請求項１〜３のいずれかに記載の予測方法 The prediction method according to any one of claims 1 to 3, wherein the criterion value of the serum AIM concentration of the subject is a numerical value exceeding 3.5 µg/ml. 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１〜３のいずれかに記載の予測方法 The prediction method according to any one of claims 1 to 3, wherein the criterion value for the serum AIM concentration is a numerical value exceeding 3.98 µg/ml. 年齢の判断基準値が４０歳以上である、請求項１〜５のいずれかに記載の予測方法。 The prediction method according to claim 1, wherein the criterion value for age is 40 years or older. 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、当該被験者のＭｅｔＳ発症リスクが２．３倍以上である、請求項６に記載の予測方法。 7. The high risk is that the serum AIM concentration is 3.98 μg/ml or less, and the risk of developing MetS of the subject is 2.3 times or more as compared with the subject under 40 years of age. Prediction method. 上記リスクが高いことが、血清ＡＩＭ濃度として３．０７μｇ／ｍｌ以下の場合と比較し、血清ＡＩＭ濃度が３．９８〜である当該被験者のＭｅｔＳ発症リスクが２．４倍以上である、請求項１に記載の予測方法。 The high risk is that the MetS development risk of the subject having a serum AIM concentration of 3.98 to is 2.4 times or more as compared with the case where the serum AIM concentration is 3.07 μg/ml or less. The prediction method described in 1.
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