Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

Abstract

Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 x 10(-8)); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 x 10(-9), 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 x 10(-4)). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits.

Polymorphism of rs2767485 in Leptin Receptor Gene is Associated With the Occurrence of Adolescent Idiopathic Scoliosis

“…17 In humans, circulating soluble OB-R is formed by ectodomain shedding of membrane-anchored OB-R. 18 , 19 There is strong association between sOB-R levels and 3 SNPs (including rs2767485, rs1751492, and rs4655555) in LEPR gene according to the fi nding of a recent genomewide association study, which indicated the role of LEPR as a candidate gene for regulating sOB-R levels. 13 In current study, we observed that AIS patients had significantly higher frequency of both TT genotype and T allele of rs2767485 polymorphism in LEPR gene than normal controls, which supported our prior fi nding that patients with AIS have signifi cantly higher sOB-R level than normal healthy girls. 7 As the main binding protein for leptin in the circulation, sOB-R might affect the leptin bioavailability to the cells by competing with membrane-anchored LEPR and inhibiting the transport of free leptin into cells and across the blood-brain barrier.…”

“…12 Previous studies had reported higher sOB-R level in patients with AIS, 7 and genome-wide association study had also identifi ed genetic determinants of plasma sOB-R levels in LEPR gene. 13 Hence, we conducted this casecontrol study to investigate whether the polymorphisms of LEPR gene were associated with inherent genetic susceptibility to AIS.…”

High-Carbohydrate/Low-Fat Diet-Induced Gender-Specific Serum Lipid Profile Changes Are Associated with <b><i>LEPR</i></b> Polymorphisms in Chinese Youth

“…A genome-wide association study has suggested a role for the LEPR Lys109Arg polymorphism as a regulator of LEPR plasma levels [26]. However, Oliveira et al [13] found that the LEPR Lys109Arg variant was associated with increased TC and TG, suggesting its contribution to the induction of an atherogenic lipid profile in obese individuals.…”

“…The A allele of the LEPR gene may contribute to changes in HDL-C levels by regulating hepatic lipase, phospholipid transfer protein, cholesteryl ester transfer protein, and/or lipoprotein lipase [29]. Sun et al [26], treated CAD patients with simvastatin (a HMG-CoA reductase inhibitor), and found that the increases in HDL-C in AA subjects were lower than in GG subjects. Treatment with statins and HC/LF diets may have a different mechanism in modulating the HDL-C.…”

Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms

“…Five SNPs associated with: serum amyloid A (rs1275319, (18)), soluble Ob-R (rs2767485, (19)), and CRP: (rs4420065 (20), rs6700896 (21) and rs1892534 (22) were forced in. From 412 cases (Supplementary Table 1), DNA was extracted from buffy coat using QIAGEN QIAmp and whole genome amplified using GE Healthcare GenomiPhi.…”