Novel locus FER is associated with serum HMW adiponectin levels

Abstract

Objective: High molecular weight (HMW) adiponectin is a predominant isoform of circulating adiponectin and has been related to type 2 diabetes. Previous linkage studies suggest that different genetic components might be involved in determining HMW and total adiponectin levels.

Research design and methods: We performed a genome-wide association study (GWAS) of serum HMW adiponectin levels in individuals of European ancestry drawn from the Nurses' Health Study (NHS) (N = 1,591). The single nucleotide polymorphisms (SNPs) identified in the GWAS analysis were replicated in an independent cohort of Europeans (N = 626). We examined the associations of the identified variations with diabetes risk and metabolic syndrome.

Results: We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 × 10(-8)). We also confirmed that variations near the adiponectin-encoding ADIPOQ locus (3q27) were related to serum HMW adiponectin levels. In addition, we found that FER SNP rs10447248 was related to HDL cholesterol levels (P = 0.009); ADIPOQ variation was associated with fasting glucose (P = 0.04), HDL cholesterol (P = 0.04), and a metabolic syndrome score (P = 0.002).

Conclusions: Our results suggest that different loci may be involved in regulation of circulating HMW adiponectin levels and provide novel insight into the mechanisms that affect HMW adiponectin homeostasis.

FIG. 1.

Region plot of FER locus. Association signals at chromosome 5q21, across a region centering on SNP rs10447248, with HMW adiponectin levels in NHS. The vertical axis represents the –log₁₀ P values from the linear regression analysis for the genotyped and imputated SNPs.

FIG. 2.

Associations of SNP rs10447248 with adiponectin isoforms. Levels of circulating HMW, MMW, and LMW adiponectin by the genotypes of SNP rs10447248 in Italian samples. The P values are from the trend test in linear regression model. The analyses were adjusted for age, sex, and BMI.