A common interleukin 18 haplotype is associated with higher body mass index in subjects with diabetes and coronary heart disease.

The pleiotropic proinflammatory cytokine, interleukin 18, plays a role in innate immunity and, based on mouse models, influences obesity. We investigated variation within the IL18 gene and its effect on markers of the metabolic syndrome. A tagging single nucleotide polymorphism set of 5 SNPs for the gene encoding interleukin 18 was selected and genotype was determined in 3 separate studies. In 2775 healthy middle-aged men, 6 common haplotypes were seen, but none was associated with body mass index (BMI). In 439 patients who underwent coronary artery bypass graft surgery, Hap2 (frequency, 22%) was present at a lower frequency than in healthy subjects and was associated with higher mean BMI compared with Hap1 (P = .011). In 483 men with type 2 diabetes mellitus, Hap2 was again associated with a higher haplotypic mean BMI (P = .002). Those homozygous for Hap2 had a BMI of 31.2 (1.3) kg/m(2), mean (SE), compared with 28.3 (1.0) kg/m(2) in those not carrying a copy of Hap2. No single SNP could fully explain the effects seen. Therefore, variation within IL18, previously shown to be associated with lower IL18 levels, is influencing measures of obesity both in men with type 2 diabetes mellitus and those with advanced coronary heart disease.