一项针对中国队列人群颈动脉内膜中层厚度10年进展情况的全基因组关联研究。
Genome-wide association study on progression of carotid artery intima media thickness over 10 years in a Chinese cohort.
作者信息
Xie Gaoqiang, Myint Phyo Kyaw, Voora Deepak, Laskowitz Daniel T, Shi Ping, Ren Fuxiu, Wang Hao, Yang Ying, Huo Yong, Gao Wei, Wu Yangfeng
机构信息
Peking University Clinical Research Institute, Beijing, China.
Epidemiology Group, Institute of Applied Health Sciences, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, United Kingdom; Clinical Gerontology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Norwich Research Park Cardiovascular Research Group, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Stroke Research Group, Norfolk and Norwich University Hospital, Norwich, United Kingdom.
出版信息
Atherosclerosis. 2015 Nov;243(1):30-7. doi: 10.1016/j.atherosclerosis.2015.08.034. Epub 2015 Sep 5.
BACKGROUND
Carotid artery intima media thickness (IMT) in human is a marker of subclinical atherosclerosis with high heritability. Many genome-wide association studies (GWAS) were performed in European and American populations, yet discovery efforts have been limited in Asians.
OBJECTIVE
To identify the genetic determinants of 10-year progression of IMT using GWA approach in a Chinese cohort.
METHODS
Cardiovascular epidemiologic survey was carried out in 810 Chinese adults in 2012. 302,218 single-nucleotide polymorphisms (SNP) in whole genome were genotyped using gene chip and carotid IMT was measured. Most of these participants, had previous carotid IMT measurements in 2002 (n = 572), 2005 (n = 750), 2007 (n = 747), and 2010 (n = 671). General linear model (GLM) and multiple linear mixed-model (MLM) were used to assess the association between SNPs and carotid IMT.
RESULTS
The mean age (SD) of the sample was 61.3 (5.1) years; 33.6% were men. The adjusted GLM showed no SNP with significance association at genome-level (all p > 1 × 10(-7)). However, using MLM, after adjusting for age, sex, number of cigarettes smoked per day, systolic blood pressure, use of antihypertensive drugs in the past 2 weeks, serum cholesterol, body mass index, fasting glucose levels, use of insulin or hypoglycemic drugs, time of measuring IMT and its interaction with SNP, we identified two novel SNPs (rs36071027 in EBF1 gene on chromosome 5 and rs975809 close to PCDH15 gene on chromosome 10) that are significantly associated with carotid IMT at genome level (p < 1 × 10(-7)) and seven novel SNPs (rs2230307 in AGL gene on chromosome 1, rs12040273 in GALNT2 gene on chromosome 1, rs4536103 in NEUROG3 gene on chromosome 10, rs9855415 in LOC647323 gene on chromosome 3, rs2472647 in PCDHGA1 gene on chromosome 5, rs17433780 in GBP3 gene on chromosome 1, and rs7625806 in DLEC1 gene on chromosome 3) which are suggestive of significant association (p < 10(-5)).
CONCLUSION
The study represents the first GWAS of association between SNPs and carotid IMT in an Asian population. We identified 2 novel loci associated with carotid IMT progression over 10 years.
背景
人类颈动脉内膜中层厚度（IMT）是具有高遗传性的亚临床动脉粥样硬化的一个标志物。许多全基因组关联研究（GWAS）已在欧美人群中开展，但在亚洲人群中的发现工作仍很有限。
目的
采用全基因组关联方法在中国队列中鉴定IMT 10年进展的遗传决定因素。
方法
2012年对810名中国成年人进行了心血管流行病学调查。使用基因芯片对全基因组中的302,218个单核苷酸多态性（SNP）进行基因分型，并测量颈动脉IMT。这些参与者中的大多数在2002年（n = 572）、2005年（n = 750）、2007年（n = 747）和2010年（n = 671）曾有过颈动脉IMT测量值。采用一般线性模型（GLM）和多重线性混合模型（MLM）评估SNP与颈动脉IMT之间的关联。
结果
样本的平均年龄（标准差）为61.3（5.1）岁；33.6%为男性。校正后的GLM显示在全基因组水平无SNP具有显著关联（所有p>1×10⁻⁷）。然而，使用MLM，在调整年龄、性别、每日吸烟量、收缩压、过去2周内使用降压药物情况、血清胆固醇水平、体重指数、空腹血糖水平、使用胰岛素或降糖药物情况、测量IMT的时间及其与SNP的相互作用后，我们鉴定出两个新的SNP（位于5号染色体上EBF1基因的rs36071027和位于10号染色体上靠近PCDH15基因的rs975809）在全基因组水平与颈动脉IMT显著相关（p<1×10⁻⁷），以及七个新的SNP（位于1号染色体上AGL基因的rs2230307、位于1号染色体上GALNT2基因的rs12040273、位于10号染色体上NEUROG3基因的rs4536103、位于3号染色体上LOC647323基因的rs9855415、位于5号染色体上PCDHGA1基因的rs2472647、位于1号染色体上GBP3基因的rs17433780和位于3号染色体上DLEC1基因的rs7625806）提示有显著关联（p<10⁻⁵）。
结论
该研究是亚洲人群中首个关于SNP与颈动脉IMT关联的GWAS。我们鉴定出2个与颈动脉IMT 10年进展相关的新位点。
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