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.

Figure 1.

Genome-wide scan of plasma sOB-R levels in the Nurses' Health Study. P-values were adjusted for age at blood draw, fasting and diabetes case–control status, BMI, menopausal status and postmenopausal hormone use. The Y-axis was minus log-transformed observed P-values; the value of 7.3 corresponded to a P-value of 5 × 10⁻⁸. P-values for loci on chromosome X (i.e. chromosome 23) were based on genotyped SNPs only.

Figure 2.

P-values and pairwise LDs with rs2767485 for SNPs in and adjacent to LEPR region between position 65400 kb and 65900 kb on chromosome 1. SNPs included in this panel included all SNPs [108 genotyped () and 384 imputed () SNPs, including rs2767485 (), rs1751492 (), rs1137100 (), rs1137101 (), and rs4655555 ()] within the region. Recombination rates in this region were plotted in the background in light blue. Pairwise LDs between rs2767485 and other SNPs were estimated using HapMap LD data. For 12 SNPs that are covered only in Affymetrix 6.0, we calculated the pairwise LDs using our observed data. The size of the diamonds represents the strength of LD; the largest diamonds represent a LD (r²) ≥ 0.80, whereas other sizes (from large to small) represent a LD of ≥0.5, ≥0.2 and <0.2, respectively.