Lipoprotein lipase gene sequencing and plasma lipid profile

• Published in: Journal of lipid research Vol. 55; no. 1; pp. 85 - 93
• Main Authors: Pirim, Dilek, Wang, Xingbin, Radwan, Zaheda H., Niemsiri, Vipavee, Hokanson, John E., Hamman, Richard F., Barmada, M.Michael, Demirci, F.Yesim, Kamboh, M.Ilyas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2014; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adult; Aged; candidate gene; Case-Control Studies; Cholesterol, HDL - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Female; Gene Frequency; genetic association; Genetic Association Studies; genotyping; Haplotypes; Humans; Linkage Disequilibrium; lipid metabolism; Lipoprotein Lipase - genetics; Male; Middle Aged; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; rare variants; Sequence Analysis, DNA; triglycerides; Triglycerides - blood; rare variants; genetic association; candidate gene; triglycerides; lipid metabolism; genotyping
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M043265

Lipoprotein lipase (LPL) plays a crucial role in lipid metabolism by hydrolyzing triglyceride (TG)-rich particles and affecting HDL cholesterol (HDL-C) levels. In this study, the entire LPL gene plus flanking regions were resequenced in individuals with extreme HDL-C/TG levels (n = 95), selected from a population-based sample of 623 US non-Hispanic White (NHW) individuals. A total of 176 sequencing variants were identified, including 28 novel variants. A subset of 64 variants [common tag single nucleotide polymorphisms (tagSNP) and selected rare variants] were genotyped in the total sample, followed by association analyses with major lipid traits. A gene-based association test including all genotyped variants revealed significant association with HDL-C (P = 0.024) and TG (P = 0.006). Our single-site analysis revealed seven independent signals (P < 0.05; r2 < 0.40) with either HDL-C or TG. The most significant association was for the SNP rs295 exerting opposite effects on TG and HDL-C levels with P values of 7.5.10−4 and 0.002, respectively. Our work highlights some common variants and haplotypes in LPL with significant associations with lipid traits; however, the analysis of rare variants using burden tests and SKAT-O method revealed negligible effects on lipid traits. Comprehensive resequencing of LPL in larger samples is warranted to further test the role of rare variants in affecting plasma lipid levels.