Novel protein-altering variants associated with serum apolipoprotein and lipid levels

Abstract

Dyslipidemia is a major risk factor for cardiovascular disease. While common genetic variants are known to modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesteremia and other genetic disorders of lipid metabolism. Aiming to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits, we analyzed whole-exome and whole-genome sequencing data of 481 and 573 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 97 serum lipid, apolipoprotein, or other metabolic phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance (NMR) technology. Single variant analysis identified a novel association between LIPC p.Thr405Met (rs113298164) and serum apolipoprotein-A1 levels (p=7.8×10-8). In the APOB gene, we identified novel associations at two protein-truncating variants (PTVs) resulting in lower serum apolipoprotein B levels (p=5.6×10-4). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, and, GTF3C5 (p<2.9×10-6). The RBM47 gene is required for apolipoprotein-B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III levels was led by a rare 21 base pair Ala496-Ala502 deletion; as replication, the burden of rare deleterious variants in RBM47 was associated with TG-to-HDLC ratio in WES of 20,917 individuals (p=0.0093). Two PAVs in GTF3C5 were highly Finnish-enriched and associated with cardiovascular phenotypes in external data, whereby the TRMT5 p.Ser185Cys lead variant was associated with stroke phenotypes. Altogether, we identified both novel variant associations in known lipid genes, as well as novel genes implicated in lipoprotein metabolism.

Genetic Architecture And Clinical Outcomes Of The Fredrickson-Levy-Lees Dyslipoproteinemias

“…The RBM47 locus is recently reported as a putative novel CAD risk locus among individuals of Middle Eastern ancestry(44). Further, in exome sequencing of diverse ancestry populations there was an association between the burden of deleterious variants in RBM47 and TG/HDL-C ratio, and specific variants have been shown to significantly alter apoC-III concentrations(45). This may indicate that the type IIb phenotype would benefit from apo-CIII-lowering therapies in addition to LDL-C-lowering therapies.…”