Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).
SUMMARY Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D) 1 , 2 , however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1 , PTF1A , SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation 3 . At another locus, eQTLs at two overlapping T2D signals affect two genes, NKX6-3 and ANK1 , in different tissues 4 – 6 . Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide1,2. Although 58 genomic regions have been associated with CAD to date3–9, most of the heritability is unexplained9, indicating additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and meta-analysed results with 194,427 participants previously genotyped to give a total of 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD-associations (P < 5x10-8, in fixed effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leucocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 [p.Ser219Gly]) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell type-specific gene expression and plasma protein levels shed light on potential novel disease mechanisms.
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