Rare and common variants in LPL and APOA5 in Thai subjects with severe hypertriglyceridemia: A resequencing approach

•Genetic basis of severe hypertriglyceridemia in Asians is unknown.•We resequenced LPL, APOA5, and APOC2 in 101 Thai subjects with triglyceride > 10 mM.•Rare variants in LPL and APOA5 were found in 15% in the high-triglyceride group.•One common APOA5 variant was more prevalent in the high-triglyceride group.•1/3 of hypertriglyceridemic subjects had ≥1 rare or common variant in LPL or APOA5.

BackgroundSevere hypertriglyceridemia usually results from a combination of genetic and environmental factors. Few data exist on the genetics of severe hypertriglyceridemia in Asian populations.ObjectiveTo examine the genetic variants of 3 candidate genes known to influence triglyceride metabolism, LPL, APOC2, and APOA5, which encode lipoprotein lipase, apolipoprotein C-II, and apolipoprotein A-V, respectively, in a large group of Thai subjects with severe hypertriglyceridemia.MethodsWe identified sequence variants of LPL, APOC2, and APOA5 by sequencing exons and exon-intron junctions in 101 subjects with triglyceride levels ≥ 10 mmol/L (886 mg/dL) and compared with those of 111 normotriglyceridemic subjects.ResultsSix different rare variants in LPL were found in 13 patients, 2 of which were novel (1 heterozygous missense variant: p.Arg270Gly and 1 frameshift variant: p.Asp308Glyfs*3). Four previously identified heterozygous missense variants in LPL were p.Ala98Thr, p.Leu279Val, p.Leu279Arg, and p.Arg432Thr. Collectively, these rare variants were found only in the hypertriglyceridemic group but not in the control group (13% vs 0%, P < .0001). One common variant in APOA5 (p.Gly185Cys, rs2075291) was found at a higher frequency in the hypertriglyceridemic group compared with the control group (25% vs 6%, respectively, P < .0005). Altogether, rare variants in LPL or APOA5 and/or the common APOA5 p.Gly185Cys variant were found in 37% of the hypertriglyceridemic group vs 6% in the controls (P = 3.1 × 10−8). No rare variant in APOC2 was identified.ConclusionsRare variants in LPL and a common variant in APOA5 were more commonly found in Thai subjects with severe hypertriglyceridemia. A common p.Gly185Cys APOA5 variant, in particular, was quite prevalent and potentially contributed to hypertriglyceridemia in this group of patients.