CN107653311B - Single nucleotide polymorphism rs4883263 detection system related to blood lipid level and related application - Google Patents
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Abstract
The invention provides a detection system for single nucleotide polymorphism rs4883263 related to blood lipid level and application thereof; specifically, the invention determines that the single nucleotide polymorphism rs4883263 is related to the blood lipid level, provides the application of a reagent material and/or instrument equipment for detecting the polymorphism of the rs4883263 site in a sample from an individual to be detected in the preparation of a detection system for evaluating the blood lipid level and/or the risk of the onset of dyslipidemia, and also provides the detection system for evaluating the blood lipid level and/or the risk of the onset of dyslipidemia, which comprises the following steps: a reagent material and/or instrumentation to detect a polymorphism of the rs4883263 site in a sample from an individual to be tested; wherein rs4883263 is significantly related to HDL-C level, and the carrier of the C allele at rs4883263 locus has lower HDL-C level and higher incidence risk of dyslipidemia than the non-carrier.
Description
Technical Field
The invention relates to a detection system of single nucleotide polymorphism rs4883263 related to blood lipid level and related application, in particular to application of reagent materials and/or instrument equipment for detecting polymorphism of rs4883263 locus of CD16 gene in a sample from an individual to be detected in preparation of the detection system for evaluating blood lipid level and/or blood lipid abnormality onset risk, and further relates to the detection system for evaluating blood lipid level and/or blood lipid abnormality onset risk.
Background
A large number of research data show that dyslipidemia is an independent risk factor for coronary heart disease, myocardial infarction, sudden cardiac death and ischemic stroke. It causes occult, gradual, progressive, systemic and organic damage to the body by accelerating systemic atherosclerosis. Research shows that the blood cholesterol level of people is increased by 1 percent, and the incidence of coronary heart disease is increased by 2 to 3 percent. The increase of the total number of dyslipidemia patients in China is a remarkable trend, and the research results of diabetes and metabolic disorder in China in 2007-2008 indicate that the cholesterol level of people over 20 years old in China is increased by 23.9% compared with that in 2002, and dyslipidemia becomes an important public health problem for residents in China. The reported data of the sanitation and crowd health conditions of Beijing City in 2011 show that the prevalence rate of dyslipidemia of more than half of residents in Beijing City is 58.5% of the residents in the Beijing City, wherein the prevalence rate of dyslipidemia of 18-30-year-old men is already high.
Plasma Total Cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and Triglyceride (TG) concentrations are the most important risk factors for cardiovascular disease and targets for therapeutic intervention. The latest data of the world health organization indicate that the contribution of the control of the risk factors of dyslipidemia is the largest in the benefit of the prevention and control of cardiovascular diseases. The death of coronary heart disease is reduced by half during 1980-2000 in the United states, which is completely attributed to the contribution of developing national cholesterol education.
Most dyslipidemia has a complex etiologic mechanism, which is the result of long-term interactions between multiple genes or between multiple genes and the environment. Genome-wide association studies have successfully identified multiple genetic loci associated with blood lipids. However, almost all of these sites were originally identified in populations of european descent, lacking research data in asian populations, particularly in chinese populations. The environment exposure and the genetic background between Chinese and European people are greatly different, so that the identification of the specific blood lipid variation site of Chinese Han people is urgently needed, and the method is beneficial to the prevention, the development, the diagnosis and the individual treatment of the hyperlipemia of Chinese people.
Disclosure of Invention
The invention mainly aims to determine specific genetic loci related to blood lipid levels of Asian people, particularly east Asian people, provide a method for evaluating the blood lipid levels or evaluating the onset risk of dyslipidemia by detecting the related genetic loci, and provide a detection system for evaluating the blood lipid levels and/or the onset risk of dyslipidemia and related application.
The inventor takes east Asian population including Chinese, Philippines, American, Singapore Hispanic, Singapore Hispanic Malaysia and the like as research objects, analyzes and researches the association relation between 11 ten thousand Single Nucleotide Polymorphisms (SNPs) and TC, LDL-C, HDL-C, TG, and determines that the single nucleotide polymorphism site rs4883263 is related to blood fat level. The rs4883263 site is a genetic site which is specific to east Asian population and is related to blood lipid level. Research data in the preliminary screening experiment stage show that rs4883263 in the CD163 gene region is significantly related to HDL-C, and reaches the significance level of the whole genome (P is 5.24 multiplied by 10)-11) (ii) a In the repeated validation stage, the P value of the site is still significant (P is 1.45 multiplied by 10)-3) The correlation reliability is strong; the two stage samples were combined and analyzed to reach a P value of 1.71X 10-13. The invention further discovers that the frequency of the C allele of rs4883263 is 0.69, and the C allele can cause the reduction of high density lipoprotein cholesterol (HDL-C).
Therefore, the method can be used for evaluating the blood lipid level of an individual to be detected, particularly the high density lipoprotein cholesterol (HDL-C) level, and also can be used for evaluating the incidence risk of the blood lipid abnormality of the individual to be detected by detecting the polymorphism of the rs4883263 site in a sample from the individual to be detected.
In one aspect, the invention provides the use of a reagent material and/or an apparatus for detecting a polymorphism at the rs4883263 site in a sample from an individual to be tested in the manufacture of a test system for assessing blood lipid levels and/or risk of developing dyslipidemia.
According to a specific embodiment of the present invention, the blood lipid levels comprise high density lipoprotein cholesterol (HDL-C).
According to a specific embodiment of the present invention, in the present invention the risk allele of rs4883263 is C.
According to a specific embodiment of the present invention, the carrier of the rs4883263 locus C allele has a lower high density lipoprotein cholesterol level and/or a higher risk of developing dyslipidemia than a non-carrier. In particular, the rs4883263 locus C allele carrier has a lower high density lipoprotein cholesterol level, a higher risk of elevated total cholesterol levels in plasma, and/or a higher risk of elevated low density lipoprotein cholesterol levels than a non-carrier.
According to the specific implementation scheme of the invention, the individuals to be detected are east Asian people including Chinese, Philippines, American China, Singapore Hippocampus Hispanic, Singapore Hispanic Malaysia and the like. In particular, for detection, the sample may be from blood, urine, saliva, gastric juice, hair, biopsy, or the like of the subject, preferably blood.
The single nucleotide polymorphic sites described herein can be detected at the DNA level, RNA level, using any available technique in the art. For example: the sequence difference between the control gene and the gene carrying the mutation can be directly revealed by direct DNA sequencing by a direct DNA sequencing method, specifically, the direct DNA sequencing can be directly carried out by using a traditional commercial sequencing kit or an automatic sequencer, or Pyrosequencing (Pyrosequencing), micro-sequencing (SNaPshot) and the like which are developed in recent years. Hybridization-based methods may also be employed, including specifically the Taqman probe method, DNA chip method, and the like. Primer extension-based methods such as matrix-assisted laser desorption ion time-of-flight mass spectrometry (MALDI-Tof-MS) can also be used. Conformation-based methods, such as Restriction Fragment Length Polymorphism (RFLP) analysis, single-strand conformation polymorphism (SSCP) analysis, Denaturing Gradient Gel Electrophoresis (DGGE) analysis, denaturing high performance liquid chromatography (hplc) analysis, and the like, may also be used. High resolution dissolution curve analysis techniques (HRM) may also be employed. In practice, one skilled in the art can select any one of the above techniques to detect the single nucleotide polymorphic site in vitro, or a combination of multiple techniques to detect the single nucleotide polymorphic site in vitro.
According to a specific embodiment of the present invention, the reagent material and/or the apparatus for detecting the polymorphism of the rs4883263 site may be any reagent material and/or apparatus and the like used in any feasible technology for detecting the single nucleotide polymorphism site. For example: reagents for direct sequencing; or reagents for polymerase chain reaction combined with restriction fragment length polymorphism analysis; or reagents for polymerase chain reaction coupled with direct sequencing; or reagents for polymerase chain reaction coupled with direct sequencing; or a reagent for use in any one of the following SNP typing methods: hybridization-based methods, primer extension-based methods, conformation-based methods, or high resolution melting curve analysis techniques, among others.
In another aspect, the present invention provides a test system for assessing blood lipid levels and/or risk of developing dyslipidemia, comprising: a reagent material and/or an instrument device for detecting the polymorphism of the rs4883263 site in a sample from an individual to be tested.
According to a particular embodiment of the invention, the test system for assessing blood lipid levels and/or the risk of developing dyslipidemia of the present invention comprises a test unit and an assessment unit, wherein:
the detection unit comprises a reagent material and/or instrument equipment for detecting the polymorphism of the rs4883263 locus in a sample from the individual to be detected, and is used for obtaining the detection result of the condition that the individual to be detected carries the risk allele of the rs4883263 locus;
the evaluation unit comprises a processing unit for carrying out evaluation processing according to the detection result of the detection unit; wherein, the carrier of the rs4883263 site C allele has lower high density lipoprotein cholesterol level and/or dyslipidemia incidence risk than a non-carrier.
The detection system for evaluating the blood lipid level and/or the onset risk of dyslipidemia of the present invention may be a virtual device as long as the functions of the detection unit and the evaluation unit can be realized. The detection unit can comprise various detection reagent materials and/or detection instrument equipment and the like; the data analysis unit may be any computing instrument, module or virtual device capable of analyzing and processing the detection result of the detection unit to obtain the blood fat level and/or dyslipidemia risk assessment status, for example, a data chart may be prepared by combining various possible detection results with corresponding blood fat level (including HDL-C level) and/or dyslipidemia risk in advance, and the blood fat level and/or dyslipidemia risk assessment result may be obtained by comparing the detection result of the detection unit with the data chart.
By applying the technology provided by the invention, the blood lipid level and/or the blood lipid abnormality occurrence risk of east Asian population can be evaluated by detecting the rs4883263 locus polymorphism, an individual health action scheme aiming at a research object is worked out, and the technology is favorable for the prevention, new drug development, diagnosis and individual treatment of the hyperlipemia of Chinese people.
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FIG. 1 shows the meta analysis result of rs 4883263.
Detailed Description
In order that the invention may be more clearly understood, it will now be further described with reference to the following examples and the accompanying drawings. The examples are for illustration only and do not limit the invention in any way. The experimental methods in the examples, in which specific conditions are not noted, are conventional methods and conventional conditions well known in the art, or conditions as recommended by the manufacturer.
Example one
The invention detects and analyzes the genetic variation and the genetic variation related to TC, LDL-C, HDL-C and TG in two stages (primary screening stage and verification stage).
The study population included 47532 subjects from the first stage and 13408 subjects from the validation stage, with the total study including 61669 from the east asian population. Each study was approved by its research institute and by the ethical committee of the local research institute. All participants signed informed consent in paper.
In the first stage, exome association study meta-analysis was performed on 47532 panelists of the east asian population. 47532 subjects from 23 ophthalmology research (CHES), Chinese Health and Nutrition Survey (CHNS), Male health examination for defense in urban harbor (FAMHES), Bijie type 2 diabetes research in Guizhou (GBTDS), Special research program for hong Kong university (HKU-TRS), Hubei coronary heart disease research (HuCAD), and Nutrition and health survey of the elderly population in China (NHAPC)And (5) researching. The basic information of the population is shown in table 1. The conditions of genotyping platforms, genotype-phenotype analysis software, etc. used in the 23 independent lipid level studies are shown in table 2. All samples were pooled for association analysis, and after the single-state locus was excluded, 110986 genetic variations were finally included in association analysis, and the statistical significance of the study was set as P<4.5×10-7. Sites significantly correlated with blood lipid levels of east asian populations were selected for repeat validation in independent samples.
In the first stage, the HDL-C, LDL-C, TG and TC measurements from each cohort were adjusted for age, age squared and study specific covariates and converted to a standard normal distribution with a mean of 0 and standard deviation of 1 to improve comparability between the different variables. The correlation between genetic variation and HDL-C, LDL-C, TC and TG in each research sample is analyzed by RARE ETALWORKER or RVTESST software, and then meta analysis is carried out by RAREMETALS software to combine the results of each research. The lipid level analysis protocol of each study in the validation phase was consistent with that of the first phase. Finally, the two-stage results are combined by applying fixed effect reciprocal weighted meta analysis of METAL.
TABLE 1 first stage exon chip detection of basic information of human population
Abbreviations: CHES, chinese ophthalmic study; CHNS, chinese health and nutrition survey; CLHNS, longitudinal health and nutrition survey of cebu; fames, urban harbor defense male health examination survey; GBTDS is a type 2 diabetes study in Guizhou Bijie; HKU-TRS, hong Kong university Special research project; HuCAD, study of coronary heart disease in north of huh; NHAPC, a survey of nutritional and health status of the chinese elderly population; PUUMA, the health science center of beijing university and the study of myocardial infarction of michigan university medical school; SBCS, shanghai breast cancer study; SCES, singapore chinese ophthalmic study; SiMES, singapore mare ophthalmic study; SMHS, shanghai male health study; SP2, singapore prospective research project; SWHS, shanghai female health study; TUDR, taiwan diabetic retinopathy study; TC, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglycerides; BMI, body mass index.
TABLE 2 first stage research sample exon chip detection technology platform and analysis software
In the present invention, in the first stage, the correlation between 11 million SNPs and TC, LDL-C, HDL-C, and TG was evaluated among 47532 subjects from the east Asia population.
The first stage analysis results showed that rs4883263 in the CD163 gene region was significantly associated with HDL-C, reaching the genome-wide significance level (P ═ 5.24 × 10)-11) The results of meta analysis are shown in FIG. 1.
The second stage, the verification stage. China's atherosclerosis research I and II (CAS, CAS-II), Beijing atherosclerosis research (BAS), and salt sensitive genetic epidemiology network (GenSalt) populations were selected for repeat validation, and the total of 13408 samples were included. The basic information of the population is shown in table 3. Sites from these GWAS studies where the first stage is significantly associated with blood lipid levels were selected to view their typing results and to validate their correlation with blood lipid levels. The genotyping platform and genotype-phenotype analysis software used in the five independent lipid level studies are shown in table 4.
TABLE 3 basic crowd information at repeated verification stages
Abbreviations: CAS, chinese atherosclerosis study; BAS, beijing atherosclerosis study; GenSalt, salt sensitive genetic epidemiological network study; TC, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglycerides; BMI, body mass index.
Table 4, second-stage research sample GWAS research genotyping technology platform and analysis software
In the repeated verification, overnight venous blood was collected by venipuncture of all sample vacuum blood collection needles, and the level of total cholesterol and HDL-C, TG was measured. The blood sample determination is completed in the clinical examination center of the population genetic research laboratory of Fuweisan Hospital, Chinesemedicine academy of medicine, Beijing. The laboratory is involved in the lipid standardization program of the united states centers for disease control and prevention. Hitachi 7060 full-automatic biochemical analyzer measures total cholesterol HDL-C and triglyceride. The LDL-C concentration was calculated using the Friedewald equation.
In the verification phase, the standard normal conversion of blood lipid levels is performed in agreement with the first phase, a linear regression model is applied, and an additive model analyzes the correlation of blood lipid levels (continuous variables) and selected site typing, and corrects for age, age square, gender and body mass index variables.
In the repeated verification stage, the value of P at rs4883263 locus is still significant (P is 1.45 × 10)-3) This correlation is strong in reliability.
The two-stage results were combined using fixed effect reciprocal weighted meta analysis of METAL.
Table 5 lists the data of the correlation between rs4883263 and blood lipid in the study of the present invention.
Table 5, rs4883263 results associated with blood lipid
Data from the preliminary screening stage study show that rs4883263 in the CD163 gene region is significantly associated with HDL-C, reaching the genome-wide significance level (P ═ 5.24X 10)-11) The results of meta analysis are shown in FIG. 1; in the repeated validation stage, the P value of the site is still significant (P is 1.45 multiplied by 10)-3) The correlation reliability is strong; the two stage samples were combined and analyzed to reach a P value of 1.71X 10-13As shown in Table 5, the C allele frequency of rs4883263 is 0.69, which can cause HDL-C reduction.
Claims (4)
1. Use of a reagent material for detecting a polymorphism at the rs4883263 site in a sample from an individual to be tested in the preparation of a test system for assessing the level of high density lipoprotein cholesterol HDL-C, wherein the risk allele of rs4883263 is C; the high density lipoprotein cholesterol level of the rs4883263 site C allele carrier is lower than that of a non-carrier;
the individuals to be detected are east Asian population.
2. Use according to claim 1, wherein the sample is derived from blood, urine, saliva, gastric juice or hair of the subject to be tested.
3. Use according to claim 1, wherein the sample is derived from the blood of an individual to be tested.
4. The use of claim 1, wherein the reagent material for detecting the polymorphism of the rs4883263 site in the sample from the individual to be tested comprises:
reagents for direct sequencing; or reagents for polymerase chain reaction combined with restriction fragment length polymorphism analysis.
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| 第一部分：基因多态性及其交互作用与糖尿病并发冠心病患者的相关性研究 第二部分：临床研究：（一）他汀类药物致160例肌病相关不良反应的临床分析（二）急性心肌梗死合并左心室血栓形成的危险因素分析;江岳鑫;《中国优秀博士论文数据库》;20160501;全文 * |
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