Genome-wide association study on progression of carotid artery intima media thickness over 10 years in a Chinese cohort

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.