A variant near the interleukin-6 gene is associated with fat mass in Caucasian men

Abstract

Context: Regulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity.

Objective: To systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity.

Design and study subjects: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-year-old men (n=1049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2851) and MrOS US (n=5611) multicenter population-based studies.

Main outcome: The genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry.

Results: Out of 18 evaluated tag SNPs near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A (minor allele frequency=29%) 3' of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size -0.11 standard deviation (s.d.) units per A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size -0.05 s.d. units per A allele, P=0.002). When all three cohorts were combined (n=8927, Caucasian subjects), rs10242595(*)A showed a negative association with total body fat mass (effect size -0.05 s.d. units per A allele, P<0.0002). Furthermore, the rs10242595(*)A was associated with low body mass index (effect size -0.03, P<0.001) and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat.

Conclusions: The IL6 gene polymorphism rs10242595(*)A is associated with decreased fat mass in three combined cohorts of 8927 Caucasian men.

Figure 1

The LD pattern of the interleukin 6 gene (IL6, also known as interferon, beta 2) based on results from tag-SNP genotyping in the GOOD cohort. The location of each tested SNP along the chromosome is indicated on top and the number in each square indicates the magnitude of linkage disequilibrium (LD) expressed as D′ between respective pairs of SNPs. Color scheme: bright red squares indicate strong LD (D′≈1); squares colored by lighter shades of pink indicate weaker LD; white color indicates very weak or no LD (D′≈0). Modified from Haploview (37).