Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations

Yingchang Lu, Martijn E.T. Dollé, Sandra Imholz, Ruben van 't Slot, W.M.M. Verschuren, Cisca Wijmenga, Edith J. M. Feskens, and Jolanda M. A. Boer

Division of Human Nutrition, Wageningen University and Research Center, Wageningen 6700 EV

Corresponding Author: kevin.lu{at}wur.nl

The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. 384 single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. 353 SNPs in 239 genes passed the quality control criteria. Seven SNPs (rs1800777 and rs5882 in CETP; rs3208305, rs328 and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1) were associated with plasma HDL-C levels with false discovery rate adjusted q-values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1 and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed but their significance disappeared after adjustment for multiple testing (p = 0.008, FDR_q = 0.221 for rs3135506; p = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1 and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.

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