Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics

Context: Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent. Objective: SEPP1 single nucleotide polymorphisms (SNPs) were selected for analysis with glucometabolic measures. Participants and measures: The study included1424 Hispanics from families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Additionally, the multi-ethnic Insulin Resistance Atherosclerosis Study was used. A frequently sampled intravenous glucose tolerance test was used to obtain precise measures of acute insulin response (AIR) and the insulin sensitivity index (S_I). Design: 21 SEPP1 SNPs (tagging SNPs (n. = 12) from HapMap, 4 coding variants and 6 SNPs in the promoter region) were genotyped and analyzed for association. Results: Two highly correlated (r²=1) SNPs showed association with AIR (rs28919926; Cys368Arg; p=0.0028 and rs146125471; Ile293Met; p=0.0026) while rs16872779 (intronic) was associated with fasting insulin levels (p=0.0097). In the smaller IRAS Hispanic cohort, few of the associations seen in the IRASFS were replicated, but meta-analysis of IRASFS and all 3 IRAS cohorts (N=2446) supported association of rs28919926 and rs146125471 with AIR (p=0.013 and 0.0047, respectively) as well as rs7579 with S_I (p=0.047). Conclusions: Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance.