โครงการวิจัยการศึกษารหัสพันธุกรรมในคนไทยที่มีไขมันในเลือดชนิดเอชดีแอลสูงมาก โดยวิธีถอดรหัสและวิเคราะห์การเปลี่ยนแปลงหน้าที่ = Genetic characterization of patients with hyperalphalipoproteinemia using resequencing approach and functional analysis / วีรพันธุ์ โขวิฑูรกิจ ... [และคณะ]
Objective: Genetic factors associated with high HDL-cholesterol levels or hyperalphalipoproteinemia are incompletely understood. We resequenced 3 candidate genes, CETP, LIPC and LIPG, which encode cholesteryl ester transfer protein, hepatic lipase, and endothelial lipase, respectively, in Thai subjects with very high levels of HDL-cholesterol compared with healthy controls.
Materials and Methods: Sequence variants of the CETP, LIPC and LIPG genes were identified by sequencing the exon and exon-intron junctions in 64 subjects with HDL-cholesterol levels ≥ 2.59 mmol/L (100 mg/dL) and compared with 113 normolipidemic subjects.
Results: In the CETP gene, we found 2 novel mutations in the coding sequence, a deletion mutation in exon 9 (c.785-788 delTCCC or p.Leu262ProfsX31) and a duplication in exon 13 (c.1226-1230 dupAGACT or p.ValArgfsX6). Four other novel mutations in the CETP promoter, one deletion mutation (g.4989-5006delGGGCGGACATACATATAC) and 3 point mutations (g.4982 > T, g.4961C > T, g.4659C > T) were also identified. In the LIPC gene, 2 novel missense mutations (p.Gly141Ser and p.Val173Met) were found. None of these mutations were found in the control group. Site-directed mutagenesis and functional studies in vitro confirmed that the 18-bp deletion mutation in the CETP promoter was associated with a reduction in transcriptional activity. One common variant in the CETP gene (p.Asp459Gly ot D459G) was also found more commonly in the hyperalphalipoproteinemia group compared to the control group (23% vs 4%, respectively, P < 0.0001). No rare or novel variants in the LIPG gene were identified.
Conclusion: Several variants were found in the CETP and LIPC genes in subjects with high HDL-cholesterol levels. Rare and common variants in the CETP and LIPC genes contribute to approximately one-third of the Thai subjects with hyperalphalipoproteinemia.
