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

Abstract

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 (SI).

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 (r(2)=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 SI (p=0.047).

Conclusions: Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance.

Keywords: AA; AIR; Acute Insulin Response; Acute insulin response (AIR); African American; ApoB; Apolipoprotein B; BMI; Body Mass Index; DI; Disposition Index; EA; European American; FSIGT; Fibrinogen; Frequently Sampled Intravenous Glucose Tolerance Test; HA; HDL; HOMA-IR; High-density Lipoprotein; Hispanic American; Hispanic Americans; Homeostasis model assessment of insulin resistance; IL6; IRAS; IRASFS; Insulin Resistance Atherosclerosis Family Study; Insulin Resistance Atherosclerosis Study; Insulin Sensitivity Index; Insulin resistance; Interleukin 6; LDL; Low-density Lipoprotein; MAF; MCRI; Metabolic Clearance Rate of Insulin; Minor Allele Frequency; PAI-1; Plasminogen Activator Inhibitor-1; S(I); SAT; SNP; SOLAR; SeP; Selenium; Selenoprotein P; Selenoproteins; Sequential Oligogenic Linkage Analysis Routines; Single Nucleotide Polymorphism; Subcutaneous Adipose Tissue; T2D; TNF; Tumor Necrosis Factor; Type 2 Diabetes Mellitus; UTR; VAT; Visceral Adipose Tissue; WHR; Waist:Hip ratio; untranslated region.