Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

Abstract

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10−7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci—PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser—also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

PNPLA3 gene in liver diseases

“…Since the physiopathology of NAFLD is tightly related to the metabolic syndrome, a link between rs738409[G] and the parameters that define the metabolic syndrome was a likely hypothesis. Indeed, some authors have observed an association between PNPLA3 and insulin resistance [20], and lower fasting triglycerides in severely obese patients and in individuals from Asian descent [21,22]. However, the vast majority of studies have shown that PNPLA3 was not associated with BMI, serum lipid, or glycaemic traits [6,13,23].…”

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

“…Discovery cohort The discovery stage involved a total of 5640 Southern Han Chinese participants (3652 cases and 1988 controls) from the HKU-TRS cohort who participated in a previous exome-chip association study for blood lipid traits [2]. The study participants were recruited from the Hong Kong West Diabetes Registry (HKWDR) [14], the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) [15] and the Hong Kong Chinese coronary artery disease (CAD) cohort.…”

“…All participants were recruited from these clinic-based or community-based studies conducted at the Queen Mary Hospital, Hong Kong, People's Republic of China. Details of the corresponding cohorts have been previously reported [2]. Type 2 diabetes cases were defined as meeting at least one of the following criteria: fasting plasma glucose (FPG) ≥ 7 mmol/l, 2 h glucose during OGTT ≥ 11.1 mmol/l, taking glucose-lowering agents or physician-diagnosed diabetes.…”

“…The functional consequences of these susceptibility variants, which are mostly present in intronic or intergenic regions, remained difficult to interpret. In the past few years, the role of low-frequency (minor allele frequency [MAF] = 1-5%) and rare (MAF < 1%) coding variants with various complex traits [2][3][4][5][6][7] is being increasingly studied. It has been suggested that most current rare variants were introduced by mutational events during the recent explosive growth of the human population [8,9].…”

“…The advancement in array-based genotyping technology, such as exome arrays, has provided a more cost-effective approach than whole-genome or exome sequencing for assessing 9 Institute of Applied Health Research, University of Birmingham, Birmingham, UK the association of rare and low-frequency coding variants that may be population specific. In a joint collaborative study, our group has recently reported several novel or Asian-specific coding variants associated with blood lipids [2] using a tailored Illumina HumanExome BeadChip (Asian Exomechip [13]). In the present study, we aimed to detect novel loci for type 2 diabetes in the Chinese population using this Asian Exomechip.…”