Association of BUD13-ZNF259-APOA5-APOA1-SIK3 cluster polymorphism in 11q23.3 and structure of APOA5 with increased plasma triglyceride levels in a Korean population.

In this association study on chromosome 11, the data from 12,537 Korean individuals within the Health Examinee (HEXA) and the Korea Association Resource (KARE) projects were analysed to identify genetic loci correlating with increased and decreased plasma triglyceride (TG) levels. We identified a locus in chromosomal region 11q23.3 that harbours genes BUD13, ZNF259, APOA5, APOA1, and SIK3, which may be associated with plasma TG levels. In this locus, 13 relevant single-nucleotide polymorphisms (SNPs) were found: rs184616707, rs118175510, rs60954647, rs79408961, and rs180373 (near BUD13); rs11604424 (in ZNF259); rs2075291, rs651821, and rs7123666 (in or near APOA5); rs525028 (near APOA1), and rs645258, rs10160754, and rs142395187 (in or near SIK3). All 13 SNPs satisfied the genome-wide significance level (P < 5.0 × 10-8) in both meta-analysis and conditional analysis. Haplotype analysis of six SNPs (rs79408961, rs180373, rs2075291, rs651821, rs525028, and rs10160754) that were selected based on the β coefficient and conditional P values, revealed nine common haplotypes (with frequency 0.02-0.34) associated with both increased and reduced TG levels. Furthermore, to shed light on possible structural implications, we modelled and simulated the G185C variant of APOA5 (corresponding to rs2075291), which showed the strongest association. Molecular dynamics simulation results showed that this polymorphic variant of APOA5 has a different hydrogen bond network, increased average distance between chains, and an ability to form distinct clusters. Owing to the orientation of cysteine, the possibility of disulphide bond formation with other proteins is evident. In summary, our association and modelling analyses provided evidence that genetic variations in chromosomal region 11q23.3 are associated with elevated TG levels.