Exome-wide association study of plasma lipids in >300,000 individuals

Abstract

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.

Unexplained reciprocal regulation of diabetes and lipoproteins

“…Mendelian randomization (based on 130 SNPs) demonstrated that genetic risk for increased LDL-cholesterol increases coronary artery disease risk and lowers type 2 diabetes risk [13]. Likewise, there is an inverse correlation between the effects of 113 coding variants on LDL-cholesterol and type 2 diabetes [14]. However, the substantial heterogeneity in this effect highlights that associations between LDL-cholesterol and diabetes may be mechanism-specific.…”

“…In addition to HMGCR , at least seven other loci are associated with both lower LDL-cholesterol and higher diabetes risk. This includes NPC1L1, HNF4A, and GCKR [10▪▪,14], and multiple variants in or near APOE [14–16]. The same holds for variants at PCSK9 [9,10▪▪,14,17].…”

“…This includes NPC1L1, HNF4A, and GCKR [10▪▪,14], and multiple variants in or near APOE [14–16]. The same holds for variants at PCSK9 [9,10▪▪,14,17]. It is worth noting that individual studies of PCSK9 inhibitors have not shown an effect of these drugs on glycemia or diabetes diagnosis [18–24].…”

“…However, the follow-up periods in these studies were all 2.2 years or less, and a meta-analysis across 20 PCSK9 inhibitor trials did identify increases in plasma glucose and HbA1c, in proportion to LDL-cholesterol-lowering [25▪▪]. Two additional gene variants, in TM6SF2 and PNPLA3 , were recently found to be associated with low LDL-cholesterol and increased type 2 diabetes in a study of more than 300 000 individuals [14]. The small effect size may explain why multiple smaller prior studies did not find any effect of these variants on insulin sensitivity [26].…”

“…For example, GCKR, TM6SF2, and PNPLA3 are all associated with high liver fat [14]. Given the well established correlation between liver fat and insulin resistance, it would be reasonable to predict that for these variants, high liver fat – rather than LDL-cholesterol – is the driver of increased diabetes risk.…”