CN104830963A - Method of in-vitro measuring obesity-causing risk - Google Patents
Method of in-vitro measuring obesity-causing risk Download PDFInfo
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Abstract
The invention provides a method of in-vitro measuring obesity-causing risk, which comprises following steps: (1) preparing a sample containing nucleic acid; (2) detecting the genotypes of an estrogen receptor 1 (ESR1) allele and a syndecan3 (SDC3) allele; and (3) identifying the genotypes of the ESR1 allele and the SDC3 allele to obtain an identifying result, wherein if the ESR1 allele and the SDC3 allele are mutated at the same time, the sample is sourced from an individual having increasing obesity-causing risk. The method is used for determining the obesity-causing risk with the genotypes of the ESR1 gene and the SDC3 gene. Compared with a method in which the genotype of single gene is employed, the method is increased in the accuracy of prediction, so that possibility of mistake generated by determining the obesity-causing risk just by the same specific single gene in different individuals is reduced. The method also can be used as a basis for providing corresponding health-caring strategy.
Description
Technical field
The present invention relates to a kind of method that detection causes risk of obesity, espespecially utilize the single Nucleotide polytypism of multiple specific gene in the method in vitro measuring obesogenous risk.
Background technology
Estrogen receptor (estrogen receptor, ESR) mainly contains ESR1 and ESR2 two kinds of forms, all can express in human body most tissues, but expression amount can be different according to tissue, biological age and women physiological period difference.ESR Main Function can divide into two large classes, and one as cytolemma receptor, can with oestrogenic hormon in conjunction with startup second information (second massager) system fading margin human physiological reaction; Another function can be used as transcription factor in nucleus, regulates and controls downstream gene expression by the mode directly or indirectly combined.
In experimentation on animals, find the male and female mice that estrogen receptor alpha (ER α, with ESR1 gene) lacks, its white adipose tissue can obviously increase.In addition, the estrogen receptor alpha mouse of rejecting than wild-type mice look more fat (Proc Natl Acad Sci U S A.2000Nov7; 97 (23): 12729-34); infer that its reason is that estrogen receptor on fatty precursor cell (pre-adipocyte) cannot combine with 17b estradiol (17b-estradiol) (it is estrogenic one); make fatty precursor cell towards lipogenetic path, cause adipocyte hypertrophy and hyperplasia (ExpBiol Med (Maywood) .2004Dec; 229 (11): 1127-35.Review).
Although researchist quite makes earnest efforts for ESR1 gene and fat research, it is not still determine very much with fat cognation at present; Such as; PvuII (T → C) XbaI (A → G) variation of the research and inquirement ESR gene of Japan and associating of fat distribution; found that with the genotypic middle-aged women of XbaIG/G, its UBSO ratio is (Int J Obes RelatMetab Disord.2003Sep quite significantly; 27 (9): 1020-7).Also find in the research in Taiwan; ESR1rs712221 can make severe simple obesity risk increase by five times in conjunction with PPARG rs1801282 variation; and the combination of ESR1rs712221 and FTO and UCP2 variation; severe simple obesity patient is carried out to loss of weight and the glycemic control effect of stomach bypass surgery, there is good assessment function (Am J Clin Nutr.2009Aug; 90 (2): 255-62.doi:10.3945/ajcn.2009.25914.Epub2009Jun2; Obes Surg.2011Nov; 21 (11): 1758-65.doi:10.1007/s11695-011-0457-3).Contrary, in research detecting ESR1 gene 23 mark SNP (taq SNP) variations of Sweden, but all do not find and obesity, steatogenesis and relevant (the BMC Med Genet.2007Dec4 of fat nutriment in a fertilizer solution; 8:73), using ESR1 genovariation, as detecting the technology causing risk of obesity, still to have many problems to be solved.
Syndecan (syndecan, SDC) be a kind of heparin sulfate proteoglycans (heparansulfate proteoglycan, HSPG), formed primarily of core protein (core protein) and heparin sulfate polysaccharide chains (heparin sulfate chain) two part.SDC gene family is mainly present on cytolemma, and by 4 member compositions (SDC1 ~ SDC4), wherein syndecan 3 (syndecan3, SDC3) is mainly expressed in neural system, comprises the hypothalamus of appetite control.In normal mouse fasting experiment, under finding fasting state, brain hypothalamus neurocyte SDC3 gene table has remarkable rising, infer that now SDC3 may be Agouti related peptides (Agouti-relatedpeptide, AGRP) coreceptor, and increased the signal of appetite in conjunction with melatonin receptors (melanocortinreceptor) transmission by AGRP, promote feeding behavior.When giving feeding, SDC3 film outer structure (ectodomain) can depart from cytolemma makes α melanochrome stimulate hormone (α-MSH) can be combined the signal transmitting depress appetite with melatonin receptors.The proterties of observing SDC3 gene knockout mice (SDC3null mice) also finds that its fat quantity is lower than normal mouse, and food ration declines, and energy expenditure rises, and inference SDC3 gene can regulate the balance of body weight and body energy.But, find that the variation of SDC3 occurs without significant correlation with fat in the result of study for European ethnic group, moreover the SNP site of each SDC3 is different with the fat cognation occurred.
Based on above-mentioned visible, if for fearing still disputable part using ESR1 or SDC3 gene as ob gene index separately, particularly, utilizing separately ESR1 or SDC3 gene test to cause risk of obesity and probably still having inaccurate doubt.
Summary of the invention
Because prior art detects the method causing risk of obesity, still have the inaccurate problem of detected result, the object of the present invention is to provide a kind of detection with raising accuracy rate to cause the method for risk of obesity.
In order to reach above-mentioned purpose, the invention provides a kind of in vitro measuring the method causing risk of obesity, it utilizes the genotype combination of ESR1 and SDC3 gene to judge obesogenous risk, and the genotype had compared to term single gene, the accuracy of prediction can be increased, to reduce Different Individual is only judged to cause the generation mistake of risk of obesity possibility by identical specific term single gene, and be available for the foundation as providing corresponding Health method.
On the one hand, the invention provides and a kind ofly to comprise the following steps: in vitro measuring the method causing risk of obesity
Complete one containing the sample of nucleic acid,
Detect the genotype of the estrogen receptor 1 (estrogen receptor1, ESR1) of this sample and the allel of syndecan 3 (syndecan3, SDC3), and,
Differentiate the genotype of ESR1 and the SDC3 allel of this sample, obtain an identification result, this identification result is that SDC3 and ESR1 allel makes a variation simultaneously, then this sample is stem from the individuality causing risk of obesity that has increase.
On the other hand, the invention provides the Genetic polymorphism mark that a kind of mensuration causes risk of obesity, it is the combination formed by ESR1 and SDC3 genotype.
According to the present invention, described variation is such as, but be not limited to: Nucleotide repetition, Nucleotide insertion, nucleotide deletion, duplicate variation or single Nucleotide polytypism (single nucleotidepolymorphism, SNP), described variation causes the sequence variations of intron (intron), nonsense mutation (nonsense mutation) or reading frame displacement (reading frame shift).
According to the present invention, should come from containing the sample of nucleic acid the individuality that is the group of Asia ethnic group; Specifically, this individuality is the Hans (Han Chinese).
According to the present invention, described nucleic acid is thymus nucleic acid or Yeast Nucleic Acid, preferably genomic deoxyribonucleic acid (genomic DNA).As everyone knows, when described nucleic acid is Yeast Nucleic Acid, complete one step containing the sample of nucleic acid comprises, and provides a Yeast Nucleic Acid, and forms complementary DNA (cDNA).
According to the present invention, the genotypic step of the allel of described detecting ESR1 and SDC3 comprise to utilize in this field known any with general genetic engineering, the methods such as biological chemistry differentiate the genotypic technology of the allel of ESR1 and SDC3, such as, but be not limited to: Polymerase Chain Reaction coordinates sequence analysis (PCR and Sequencing), instant Polymerase Chain Reaction (Real-time PCR), Restriction Fragment Length polytypism (restriction fragment lengthpolymorphism, RFLP), spectrometer analysis (Mass Spectrometry), or, the high-throughput screening method (high-throughput screeningmethod) of any other suitable analyzing gene type, such as be connected the biochip (Biochip) of sub-Polymerase Chain Reaction (Linker-PCR) or secondary generation sequencing (Next generation sequencing, NGS).
According to the present invention, the variation of described ESR1 allel betides promotor (promoter) with in interior aobvious son (intron) region, the genotype of ESR1 and the SDC3 allel of described this sample of discriminating comprises: the variation analyzing ESR1 and SDC3 allel, to obtain this identification result, wherein the variation of ESR1 allel betides the position being selected from the group be made up of following person: TA repeats (promoter region), rs2234693 (interior aobvious sub 1), rs9340799 (interior aobvious sub 1), rs712221 (interior aobvious sub 2); Particularly in the region with sequence as shown in SEQ ID NO.1, this SNP rs712221 position is in ESR1 gene in aobvious subregion, and the variation in this region may affect the risk that ESR1 genetic expression increases metabolic syndrome (Metabolic syndrome).
According to the present invention, the variation of described SDC3 allel betides in exon region, and wherein the SNP of SDC3 is selected from the group be made up of following person: rs2282440, rs2491132 and rs4949184.Particularly have in the region of sequence as shown in SEQ ID NO.2, this SNPrs2282440C → T allel variation position is on SDC3 gene extron subregion, and after this gene is translated, No. 329 amino acid makes a variation into Isoleucine (Isoleucine) by Threonine (Threonine).
According to the present invention, the genotype of ESR1 and the SDC3 allel of described this sample of discriminating comprises: the variation analyzing ESR1 and SDC3 allel, to obtain this identification result, wherein the variation lines promoter region TA of ESR1 allel repeats or betides the position being selected from the group be made up of following person: SNP rs2234693, rs9340799, rs712221.
According to the present invention, the variation of SDC3 allel betides the position being selected from the group be made up of following person: SNP rs2282440, rs2491132 and rs4949184.
According to the present invention, described mensuration causes the Genetic polymorphism mark of risk of obesity, and it is repeated and SNP rs2234693, rs9340799, rs712221 by the promoter region TA of ESR1; The combination formed with SNP rs2282440, rs2491132 and/or rs4949184 of SDC3.
Better, the genotypic step detecting ESR1 and the SDC3 allel of this sample comprises: combined by different from two for this sample specific molecular probe, described specific molecular probe is respectively for the SNP rs712221 of ESR1, and for the SNP rs2282440 of SDC3; And wherein the rs2282440 of this identification result to be the rs712221 of ESR1 be A SDC3 is simultaneously T, then this sample is the individuality stemming from the obesogenous risk with increase.
Described ESR1 allel is normal, and it does not morph in the region with sequence as shown in SEQ ID NO.1, and preferably, the 26th base positions of this sequence is A.
The variation of described SDC3 allel betides has sequence as shown in SEQ ID NO.2, and preferably, the 26th base positions of this sequence is T.
According to the present invention, described obesity is to be selected from the numerical value of following formed group for index: individual body-mass index (body mass index, BMI), waistline, waist-to-hipratio, body fat ratio, and triglyceride levels in blood.
According to the present invention, the body-mass index of described individuality as known in the art, is body weight (kilogram)/height
2(meter
2).
According to the present invention, described waistline carries out measuring obtained numerical value for the mode accepted in this field any, preferably refers to the clothing that removing waist covers, easily stand, both hands naturally droop, and tape measure is walked around waist, adjustment height, allow tape measure by left and right sides pelvis upper limb (ilium upper limb) to the centre of rib lower edge, note tape measure and ground keeping parallelism, and be close to, do not extrude skin, maintenance eupnea, at the end of feeling elated and exultant, the waistline numerical value measured.
According to the present invention, described waist-to-hipratio (Waist to Hip Ratio, WHR) refers to the ratio of waistline and hip circumference, and numerical value equals waistline divided by hip circumference, wherein one's waist measures as previously mentioned, and hip circumference refers to when both legs close up with the measurement value of horizontal its maximum width.Generally speaking, the overall target of waistline reflection amount of total fat and fat distribution, the developmental state of hip circumference reflection hip skeleton and muscle.When waist-to-hipratio is larger, represents and tend to obesity.
According to the present invention, aforesaid index can with normally artificial benchmark, and the obesity described in definition, preferably, when body-mass index (body mass index, BMI)≤27 kilogram/meter of individuality
2, waistline Nan≤90 centimeter, Nv≤80 centimeter, waist-to-hipratio Nan≤0.9, Nv≤0.85, body fat ratio Nan≤30%, Nv≤35% is assert obesity.
According to method of the present invention, it comprises further: record this identification result in a recording medium.Described method can comprise being applied to and matches with a recording medium, and this recording medium can be a high in the clouds hard disk, DVD, with oneself access/memory body, running gear or any other medium that can record information or link an operational software or workstation.
Based on above-mentioned, method of the present invention and mark, genotype by detecting SDC3 and ESR1 simultaneously more can confirm the obesogenous degree of risk of experimenter compared to simple SDC3 or ESR1 that only test, and when both be all middle and high risk genotype time, its obesogenous risk significantly improves.
Accompanying drawing explanation
Fig. 1 is the mean value histogram of the genotypic experimenter of different ESR1 and SDC3 single Nucleotide polytypism, its BMI.
Fig. 2 is the genotypic experimenter of different ESR1 and SDC3 single Nucleotide polytypism, the histogram of the mean value of its waistline.
Fig. 3 is the genotypic experimenter of different ESR1 and SDC3 single Nucleotide polytypism, the histogram of the mean value of its body fat.
Fig. 4 is the genotypic experimenter of different ESR1 and SDC3 single Nucleotide polytypism, the histogram of the mean value of its systolic pressure.
Fig. 5 is the genotypic experimenter of different ESR1 and SDC3 single Nucleotide polytypism, the histogram of the mean value of its fasting plasma glucose.
Embodiment
According to method of the present invention, wherein this sample is selected from by blood, hair, skin, saliva, seminal fluid, urine, fecal materials, sweat from one, and the biological sample of group that buccal mucosa sample is formed.
The present invention is illustratively illustrated by following examples, the preferred embodiment of the present invention, but its means specifically implemented are not as the restriction understanding claim.According to method of the present invention, its utilize the genotype combination of SDC3_rs2282440 and ESR1_rs712221 to can be used to inspect cognation that itself and testee's physiology and biochemistry analyze numerical value height, found that the BMI of SDC3_rs2282440_T allel and ESR1_rs712221_A allel and increase, waistline, waist-to-hipratio, fasting plasma glucose and systolic pressure have high correlation, it can thus be appreciated that as utilizing the type of the genotype combination of SDC3_rs2282440 and ESR1_rs712221 can the obesogenous risk of accurate evaluation testee.
In a preferred embodiment of the present invention, the genotypic step of the allel of described detecting ESR1 and SDC3 is the single Nucleotide polytypism of the allel of detecting ESR1 and SDC3, it comprises the test that any known mode is carried out, on multi-functional nucleic acid mass spectrometer, such as carry out the analytical procedure of SNP sizing, comprise three reactions steps: first carry out amplification reaction with PCR for target single nucleic acid polytypism position (target SNP site), then after carrying out single base extension, finally reaction product is used mass-spectrometric technique assay products molecular weight again, because single base extends four kinds of base A, T, C, the molecular weight of G is all not identical, by product point sample on wafer, with nucleic acid mass spectrograph acquisition signal, again by software automatic analysis SNP genotype.Particularly, described analytical procedure is such as genotypic for SNP
test (iPLEX Gold Assay for SNP Genotyping)
carry out SNP sizing again or in real-time and quantification PCR instrument, be for target single nucleic acid polytypism Position Design hydrolysis probes (hydrolysis probe), fluorescent signal is detected after carrying out the reaction of PCR amplification, and by the genotype of interpretation SNP after software analysis.Particularly, described analytical procedure is such as
sNP genotype identification is tested
Embodiment
Materials and methods
< subject recruitment >
This test is participated in together with memorial hospital's Family Medicine and invitation Taiwan, community medicine center grownup by horse, and get rid of have pregnancy, cancer, secondary obesity, congenital chromosome abnormalty to cause at present obesity (as Prader-Willi Syndrome), take loss of weight medicine person or once accepted loss of weight operator.Participate in 587 experimenters of test, according to the fat definition of Taiwan Department of Health of Executive Yuan adult, experimenter is divided into normal group (323 people, BMI < 27kg/m
2) and fat group of (264 people, BMI≤27kg/m
2).All experimenters all need to agree to signature human trial letter of consent, and record the data such as its age, sex, height, body weight, waist hip circumference, body fat rate, blood pressure, heartbeat.Content of the test all through horse together with the human trial council of hospital (IRB) examination & verification by after execution.
A < corpse or other object for laboratory examination and chemical testing gathers >
Experimenter gathers peripheral veins blood (about 3 ~ 5c.c) after 8 hours on an empty stomach and carries out blood biochemical analysis, and Interventions Requested comprise total cholesterol (total cholesterol), triglyceride (triglyceride), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (fasting blood sugar), serum insulin (serum insulin) and high-sensitivity C-reactive protein (hs-CRP).In addition, oral cavity adopt inspection brush gather buccal epithelial cells carry out DNA extraction and genotype identification.
< DNA extracts and SNP genotype identification >
Buccal epithelial cells adopts gSYNC
tMdNA extraction agent group (Geneaid) carries out DNA extraction, and measures DNA concentration and purity with ultramicrospectrophotometer (Nanodrop Spectrophotometer, Thermo).SNP genotype identification (SNP genotyping) adopts TaqMan genotype identification to test (TaqMan SNP genotyping assay, ABI; Test number Assay ID:C_3163596_10, C_15878257_10) coordinate real-time and quantification PCR instrument (StepOne Plus real-time PCR system, ABI) analyze, get 25ng DNA and genotype identification reagent and quantitative PCR reagent mixed liquor (probe fast qPCR Kit Master Mix, Kapa Biosystems) after micro tube mixes, put into real-time and quantification PCR instrument and perform quick mode.Single Nucleotide polytypism (single nucleotide polymorphism, SNP) genotype identification result is analyzed with StepONe software v2.2.2.
< statistical study >
Between normal group and fat group, the difference of continuous variable mean number is examined and determine (independent t-test) with independent sample t and is analyzed, and between two groups, the difference of SNP genotype frequency is analyzed with chi-square test (chi-square test).Analysis of covariance (analysis of covariance, ANCOVA) assess the difference of single SNP genotype or the continuous variable mean number of combination S NP genotype at correction age and sex afterwards, and carry out post hoc test (post hoc analysis) with LSD method.The stratagem ensuring success ratio (odds ratio, OR) that single SNP genotype or combination S NP genotype calculate after correcting age and sex to the risk of obesity with logistic regression (logistic regression) is assessed.All statistical methods perform with statistic software SPSS 16.0, and p value < 0.05 has been considered as statistically significant difference.
In the present embodiment, normal group organizes the clinical data of experimenter via questionnaire with fat, inspection of science and blood biochemical analysis obtain subject age, sex, height, body weight, waist hip circumference, body fat rate, blood pressure, heartbeat, blood fat, the data such as blood sugar, and extracted and SNP genotype identification through DNA by buccal epithelial cells, SNP genotype for SDC3_rs2282440 and ESR1_rs712221 is identified, when experimenter's identification and analysis result show its SDC3_rs2282440 have an allel to be C time, belong to SDC3_rs2282440C carrier (comprising SDC3_rs2282440 is C/C and C/T genotype), when experimenter's identification and analysis result show its ESR1_rs712221 have an allel to be T time, belong to the T carrier of ESR1_rs712221.
Receptor gene's type is as shown in table 1 below with the result compared afterwards through analysis of covariance with the numerical value of each biochemical studies.
Table 1 receptor gene type result combined effect is analyzed
* analysis of covariance (ANCOVA) corrects age-sex; * comparative analysis afterwards (Post hoc analysis), LSD method
Wherein, SDC3_rs2282440C carrier, SDC3_rs2282440_T/T and ESR1_rs712221_A/A genotype and ESR1_rs712221_T carrier (A/T+T/T) are SDC3_rs2282440_T/T genotype person simultaneously, the histogram of the mean value of its BMI, waistline, body fat rate, systolic pressure and fasting plasma glucose with stratagem ensuring success than stating shown in table 2 and Fig. 1 to 5 as follows respectively.
The combined effect venture analysis of table 2 receptor gene type
* logistic regression corrects age and sex
Result shows, experimenter is A/A genotype when SDC3rs2282440 site is T and ESR1rs712221 site, it is BMI no matter, waistline, body fat rate, the stratagem ensuring success of the group of systolic pressure and fasting plasma glucose is than being all that normal person is high relative to SDC3rs2282440 site, be respectively 2.18, 2.10, 2.60 and 1.51, therefore the SNP genotype simultaneously detecting SDC3 and ESR1 more can confirm the obesogenous degree of risk of experimenter compared to simple SDC3 or ESR1 that only test, and in both are all, during excessive risk genotype, its obesogenous risk significantly improves, its p value is less than 0.05 and shows and statistically have a significance.
Claims (10)
1., in vitro measuring the method causing risk of obesity, it comprises:
Complete one containing the sample of nucleic acid,
Detect the estrogen receptor 1 of this sample and the genotype of the allel of syndecan 3, and
Differentiate the genotype of ESR1 and the SDC3 allel of this sample, obtain an identification result, this identification result is that SDC3 and ESR1 allel makes a variation simultaneously, then this sample is stem from the individuality that has the obesogenous risk of increase.
2. according to claim 1 in vitro measuring the method causing risk of obesity, wherein this variation comprises Nucleotide repetition, Nucleotide insertion, nucleotide deletion or duplicate variation.
3. according to claim 1 in vitro measuring the method causing risk of obesity, wherein differentiate that the genotype of ESR1 and the SDC3 allel of this sample comprises: the variation analyzing ESR1 and SDC3 allel, to obtain this identification result, wherein the variation of ESR1 allel is that promoter region TA repeats or betides the position being selected from the group be made up of following person: SNP rs2234693, rs9340799 and rs712221.
4. according to claim 1 in vitro measuring the method causing risk of obesity, wherein the variation of SDC3 allel betides the position being selected from the group be made up of following person: rs2282440, rs2491132 and rs4949184.
5. according to claim 3 in vitro measuring the method causing risk of obesity, the genotypic step wherein detecting ESR1 and the SDC3 allel of this sample comprises:
Combined by different from two for this sample specific molecular probe, described specific molecular probe is respectively for the SNP rs712221 of ESR1, and for the SNP rs2282440 of SDC3; And,
Wherein this identification result is the rs2282440 that the rs712221 of two allels of ESR1 is all A at least one allel of SDC3 is simultaneously T, then this sample comes from the individuality causing risk of obesity that has about 1.5 to 3 times.
6. according to any one of claim 1 to 5 in vitro measuring the method for risk of obesity of causing, wherein said obesity is to be selected from the numerical value of following formed group for index: individual body-mass index, waistline, waist-to-hipratio, fasting plasma glucose and systolic pressure.
7. according to any one of claim 1 to 5 in vitro measuring the method for risk of obesity of causing, wherein should come from the individuality that is the Hans containing sample of nucleic acid.
8. according to any one of claim 1 to 5 in vitro measuring the method for risk of obesity of causing, it comprises further: record this identification result in a recording medium.
9. a mensuration causes the Genetic polymorphism mark of risk of obesity, and it is the combination formed by ESR1 and SDC3 genotype.
10. mensuration according to claim 9 causes the Genetic polymorphism mark of risk of obesity, and it is repeated and SNP rs2234693, rs9340799 and/or rs712221 by the promoter region TA of ESR1; The combination formed with SNP rs2282440, rs2491132 and/or rs4949184 of SDC3.
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Non-Patent Citations (2)
| Title |
|---|
| ALESSANDRA C. GOULART等: "Estrogen receptor 1 gene polymorphisms and decreased risk of obesity in women", 《METABOLISM CLINICAL AND EXPERIMENTAL》 * |
| EUNYOUNG HA等: "Positive Association of Obesity with Single Nucleotide Polymorphisms of Syndecan 3 in the Korean Population", 《THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》 * |
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