CN108897985A - A kind of method and its application of Glycohemoglobin HbA1c genetic locus scoring - Google Patents
A kind of method and its application of Glycohemoglobin HbA1c genetic locus scoring Download PDFInfo
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Abstract
The present invention relates to gene assessment technology field, in particular to a kind of method and its application of Glycohemoglobin HbA1c genetic locus scoring.The present invention assesses the scoring of HbA1c correlated inheritance site to the influence of Chinese population blood lipid, and HbA1c level increases the influence to Chinese population hyperlipidemia risk, provides more comprehensive, accurate, individuation scientific basis for the risk assessment and prevention and control of China's hyperlipidemia.
Description
Technical field
The present invention relates to belonging to gene assessment technology field, in particular to a kind of Glycohemoglobin HbA1c genetic locus
The method and its application of scoring.
Background technique
Hyperlipidemia is also known as hyperlipoprotememia, refers in fat metabolic process, and several lipid levels in blood plasma are than normal
It is higher.It is mainly shown as that serum cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) compare normal water
It puts down higher.Show that blood cholesterol level is higher than normal level and cardiovascular disease according to epidemiology and clinic study
Sick (CVD) is positively correlated.There is report to claim, be higher by 1mmol/L (> 5.2mmol/L) than normal cholesterol levels, suffers from hat
The risk of shape aortic heart disease increases 35%, meanwhile, reduce cholesterol in serum it is horizontal 1%, can will suffer from heart and brain blood
The risk of pipe disease reduces by 2%~3%.The main reason for leading to cardiovascular disease is atherosclerosis, and Atherosclerosis
First the risk factor of change is hypercholesterolemia.Low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) are fortune
Turn the important carrier of cholesterol.The physiological function of LDL-C is the group that the endogenous cholesterol that will be synthesized in liver is transported to surrounding
In knitting.And the free cholesterol in peripheral cells can be transported in liver by HDL, realize reverse cholesterol transport, be body
The main approach of excess cholesterol is discharged.HDL-C can maintain the balance of Blood Cholesterol level, prevention or alleviation artery
The generation of atherosis.
The more American-European crowd of asian population blood lipid level is significantly relatively low, and the past result of study also indicates that, the hat of asian population
Heart trouble disease incidence is relatively relatively low.However in recent years, with the process of China's reform, rural area and life of urban resident mode are equal
There is huge change earlier above, oneself is developing progressively a more universal health problem to hyperlipidemia in China.
The illness rate of China's diabetes is just being in zooming trend, becomes another after cardiovascular and cerebrovascular disease, tumour
A important Chronic Non-Communicable Diseases for seriously endangering people's health.2010, China national Center for Disease Control and Shanghai were handed over
The illness of investigation display China 18 years old of logical University Medical College attached Ruijin Hospital inner-sphere reorganization energy section or more crowd's diabetes
Rate is 11.6%, it has also become the most country of diabetes number of patients in the world.HbA1c be glucose in blood of human body with it is red
The valine of 2 β chain N-terminals in intracellular hemoglobin A (HbA) is condensed the product to be formed, the level in circulating with
The average life span that the blood sugar concentration in red blood cell average life span and the period has red blood cell in the human body that is closely connected is 90 to 120
It, therefore HbA1c can reflect in human body average blood glucose levels in the past 2-3 month.Under normal circumstances, HbA1c is not vulnerable to diet
With movable influence, it will not change with daily grape sugar intake and apparent fluctuation occur, when detection is not required to survey on an empty stomach
Amount, testing result are relatively stable.From 2010, american diabetes association (American Diabetes
Association, ADA) diagnosis index HbA1c new as one is added in new edition diabetes guide.Large sample gene closes
Connection result of study shows that HbA1c level is not only related to content of hemoglobin and blood glucose level, also by individual inheritance factor
Regulation.Domestic and international existing research has found some genetic locus based on single nucleotide polymorphism (SNP) and the horizontal phase of HbA1c
It closes.SNP is that the DNA sequence dna as caused by the change of single nucleotide acid changes, and causes the diversity of DNA sequence.SNP points
Cloth is wide, density is high, it has also become after restriction fragment length polymorphism (RFLP) mark and microsatellite (Short tandem repeatSTR, STR) mark
Third generation genetic marker after note, plays a significant role in the research of the complex diseases such as tumour, chronic disease.For example, G6PC2
Rs1402837, rs3755157 and ANK1 the site rs4737009 and rs6474359 and HbA1c level it is closely related.So
And document there is no to change to the total evaluation of the horizontal genetic locus of whole HbA1c, with blood HbA1c level and with blood lipid at present
Correlation reported, thus also fail to be further applied scientific research and clinical practice.
The existing largely research about HbA1c level and blood lipid correlation at present, however for HbA1c correlated inheritance site
Latent effect in blood lipid transformation does not have research also.In the case that HbA1c increases phase same level, due to the genetic locus of carrying
Difference, the situation of change of TG, TC, LDL-C and HDL-C is also likely to be present significant difference between individual.With individuality medicine and
The successive proposition of the concepts such as accurate medicine, when assessing tradition risk factors as blood lipid, the wind that is also considered as between individual
Dangerous difference.
Further, since the hereditary basis of Chinese and western crowd and living environment have apparent difference, individually with west crowd
The site found by research object may there are different degrees of differences with East Asia crowd.Such as in the crowd of East Asia, HbA1c phase
The frequency of the allele T of correlation gene site rs855791 is 39% in European crowd, and in the crowd of East Asia is only 5%-
11%.
To sum up, the influence of the relevant genetic locus of HbA1c and its total evaluation to blood lipid level is still not clear at present, does not have
It is included into risk assessment and diagnosis system.Therefore, existing hyperlipidemia diagnosis and HbA1c level comment lipid effect
It is not comprehensive enough to estimate mode.
In the case that HbA1c increases phase same level, since the genetic locus of carrying is different, blood lipid change is also deposited between individual
In difference.Therefore, the existing inadequate individuation of hyperlipidemia risk assessment mode.
Although the existing related research result of foreign countries, the hereditary basis of Chinese and western crowd and living environment have apparent
Difference, accuracy of the foreign study achievement in Chinese population lack the verifying of extensive epidemiological survey research.
Summary of the invention
The present invention discloses a kind of method and its application of Glycohemoglobin HbA1c genetic locus scoring, mesh of the invention
Be to assess the scoring of HbA1c correlated inheritance site to increase to China the influence and HbA1c level of Chinese population blood lipid
The influence of crowd's hyperlipidemia risk, for China's hyperlipidemia risk assessment and prevention and control provide it is more comprehensive, accurate, a
The scientific basis of body.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions：
A kind of method of Glycohemoglobin HbA1c genetic locus scoring, includes the following steps:
(1) Genotyping is carried out to HbA1c related locus；
(2) weighted model is established, using the every point effect value of HbA1c related locus as weight, establishes base for each sample
Because of risk score, specific formula for calculation is：Wherein indicate that GRS is base
Because of risk score, k is the SNP number being included in, and n is SNP serial number, and β is the effect value that SNP acts on phenotype；
HbA1c related locus in the step (1), including rs7072268, rs1402837, rs13266634,
Rs855791, rs1046896, rs4737009, rs552976, rs11667918, rs6684514, rs9399137,
Rs9933309, rs1799884, rs6474359, rs2779116, rs1387153, rs7903146 and rs7772603.
A kind of application of Glycohemoglobin HbA1c genetic locus scoring, it is characterised in that：The GRS calculates institute's score
Several rises with HbA1c are positively correlated.
A kind of application of Glycohemoglobin HbA1c genetic locus scoring, it is characterised in that：The GRS calculates institute's score
Several rises with log-TG are positively correlated.
A kind of application of Glycohemoglobin HbA1c genetic locus scoring, it is characterised in that：The GRS calculates institute's score
Several rises with TC are positively correlated.
A kind of application of Glycohemoglobin HbA1c genetic locus scoring, it is characterised in that：The GRS calculates institute's score
Several rises with LDL-C are positively correlated.
The beneficial effects of the invention are as follows：
1, its and Different Individual horizontal to HbA1c is assessed using HbA1c correlated inheritance site scoring (GRS) for the first time in the world
The influence of blood lipid level, assessment result is more comprehensively.
2, research achievement comes from extensive epidemiological survey, is suitable for Chinese, and assessment result is more acurrate.
3, detection means economy is convenient, is conducive to promote on a large scale in crowd.
Detailed description of the invention
Fig. 1 is HbA1c and HbA1c-GRS correlation fitted figure.
Fig. 2 is Log-Tg and HbA1c-GRS correlation fitted figure.
Fig. 3 is TC and HbA1c-GRS correlation fitted figure.
Fig. 4 is LDL-C and HbA1c-GRS correlation and fitted figure.
Specific embodiment
Below with reference to embodiment, the invention will be further described：
Embodiment 1
This research uses weighted model, and the every point effect value reported in GWAS research is specific gravity, establishes for each sample
Gene risk score (Genetic risk score, GRS), and the further correlation of analysis GRS and items blood lipids index.
Specific formula for calculation is：Wherein indicate that k is the SNP number being included in, n
The effect value that phenotype is acted on for SNP serial number, the SNP that β is reported by GWAS.The calculating process for now demonstrating GRS, is detailed in following table：
Table 1.GRS calculation method example
Note：Weighted value is derived from the related coefficient of the HbA1c of GWAS research report；In HbA1c risk/non-risk allele
Capitalization represents risk genes, and small letter represents non-risk genes；Scoring is that gene score and weighted value obtain product after weight；
The summation of SNP, that is, non-weighting GRS value.
Constructed HbA1c_GRS scoring and crowd HbA1c level significantly correlated (β=0.03, SE=as the result is shown
0.004, P < 0.0001)；It correcting the age, gender, body mass index, blood pressure, smoking, situation of drinking, physical exertion and glycosuria
After the equiprobable Confounding Factor of disease, HbA1c_GRS scoring is still in significantly correlated with HbA1c level：1 standard deviation of every raising
(SD), i.e., 2.83 points, HbA1c may make to increase about 0.066% (β=0.066, SE=0.008, P < 0.0001, Fig. 1).Male
In, HbA1c_GRS scoring and HbA1c level are significantly correlated (β=0.063, SE=0.009, P < 0.0001)；In women, β=
0.071, SE=0.014, P < 0.0001；60 years old crowd of age <, β=0.037, SE=0.012, P=0.0012；Age >=
60 years old crowds, β=0.086, SE=0.010, P < 0.0001, specially HbA1c=4.9444+0.0656UnitSD-GRS+
0.0049Age+0.002Sex+0.0096BMI-0.0011DBP-0.0009SBP-0.0452Physical-activity+
0.0549Smoking-0.1367Drinking+1.4459Diabetes。
Using the correlation of Mendelian randomization analysis and research and TG, TC, LDL-C and HDL-C, the results showed that, it is correcting
Age, gender, body mass index, systolic pressure, diastolic pressure, tobacco smoking status, situation of drinking, physical exertion situation and diabetes illness
After the common metabolics index such as situation, HbA1c_GRS 1 standard deviation (SD) of every raising, can be such that log-TG increases by that is, 2.83 points
0.127 unit (β=0.127, SE=0.005, P=0.0057, Fig. 2), specially Log-TG=-1.2564+
0.0127UnitSD-GRS-0.0015Age+0.0734Sex+0.0345BMI+0.0066DBP+0.0003SBP-
0.0295Physical-activity+0.1129Smoking+0.0001Drinking+1.1376Diabetes；TC is increased
0.0274mmol/L (β=0.0274, SE=0.011, P=0.0102, Fig. 3), specially TC=2.4596+
0.0274UnitSD-GRS-0.0074Age+0.5351Sex+0.0168BMI+0.0131DBP+0.0025SBP+
0.0619Physical_activity+0.1749Smoking+0.1182Drinking+0.0244Diabetes；LDL-C is increased
0.0217mmol/L (β=0.0217, SE=0.008, P=0.0075, Fig. 4), specially LDL-C=1.1758+
0.0217UnitSD-GRS-0.0042Age+0.2676Sex+0.0209BMI+0.0081DBP+0.0013SBP+
0.0347Physical-activity+0.1365Smoking-0.0408Drinking-0.024Diabetes；And HDL-C water
Flat nothing significantly changes,
Wherein：HbA1c：Glycated hemoglobin levels；UnitSD-GRS：The HbA1c-GRS of unity standard deviation；Age：Year
Age；Sex：Gender, wherein 1 is women, 2 be male；SBP：Systolic pressure；DBP：Diastolic pressure；Physical-activity, if
Physical training, 1 be it is yes, 0 is no；Smoking：Whether smoking, 1 be it is yes, 0 is no；Drinking：Whether drinking, 1
Be it is yes, 0 is no；Diabetes：Whether suffer from diabetes, 1 be it is yes, 0 is no.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent defines.
Claims (6)
1. a kind of method of Glycohemoglobin HbA1c genetic locus scoring, includes the following steps:
(1) Genotyping is carried out to HbA1c related locus；
(2) weighted model is established, using the every point effect value of HbA1c related locus as weight, establishes gene wind for each sample
Danger scoring, specific formula for calculation are：Wherein indicate that GRS is gene
Risk score, k are the SNP number being included in, and n is SNP serial number, and β is the effect value that SNP acts on phenotype；
2. the method for Glycohemoglobin HbA1c genetic locus scoring according to claim 1, it is characterised in that：It is described
The step of (1) in HbA1c related locus, including rs7072268, rs1402837, rs13266634, rs855791,
Rs1046896, rs4737009, rs552976, rs11667918, rs6684514, rs9399137, rs9933309,
Rs1799884, rs6474359, rs2779116, rs1387153, rs7903146 and rs7772603.
3. a kind of application of Glycohemoglobin HbA1c genetic locus scoring described in claim 1, it is characterised in that：It is described
GRS calculates obatained score and the rise of HbA1c is positively correlated.
4. a kind of application of Glycohemoglobin HbA1c genetic locus scoring described in claim 1, it is characterised in that：It is described
GRS calculates obatained score and the rise of log-TG is positively correlated.
5. a kind of application of Glycohemoglobin HbA1c genetic locus scoring described in claim 1, it is characterised in that：It is described
GRS calculates obatained score and the rise of TC is positively correlated.
6. a kind of application of Glycohemoglobin HbA1c genetic locus scoring described in claim 1, it is characterised in that：It is described
GRS calculates obatained score and the rise of LDL-C is positively correlated.
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Application publication date: 20181127 |