Genetics of serum resistin: a paradigm of population-specific regulation?

Keywords Insulinresistance.Population-specificeffect.Resistincirculatinglevels.RETNAdipocytes release a number of peptide hormones, collec-tively known as adipokines, which are essential inregulation of intermediate metabolism, and which maycontribute to the pathogenesis of insulin resistance andrelated disorders [1].Among these is resistin, a 12.5 kDa cysteine-rich proteinthat is secreted also by macrophages [2–4]. Several piecesof evidence suggest that this molecule antagonises insulinaction and fosters inflammation [2–4]. In humans, mostcross-sectional studies have reported that elevated resistinlevels are associated with insulin resistance [5–7] and type2 diabetes [8]. In most [9–11], although not all [12],prospective studies, resistin turned out to be a predictor oftype 2 diabetes and cardiovascular disease. Taken together,these findings highlight the role of serum resistin as anemerging pathogenic factor and a potential therapeutictarget for insulin resistance-related disorders. This latterpossibility is reinforced by the observation that resistinexpression in human adipose tissue is inhibited bythiazolidinediones [13], insulin-sensitising molecules thatare used as oral hypoglycaemic agents in the treatment ofpatients with type 2 diabetes.The mechanisms regulating resistin expression, secretionand circulating levels are still poorly understood. Recentdata clearly indicate that resistin serum levels are undergenetic control [6, 14]. Several single-nucleotide poly-morphisms (SNPs) in the RETN gene coding for resistin,have been associated with serum resistin levels and insulinresistance traits [6 ,8 14–18].Among others, rs1862513 at position g.−420 in theRETN 5′ flanking region has attracted much attention. ThisSNP has been associated with high resistin levels [8, 16],insulin resistance [ 17], obesity [15 , 18] and type 2diabetes [8, 19]. A recent meta-analysis, including morethan 3,500 individuals, has shown that those homozygousfor the G allele at rs1862513 have a 30% increase in theodds of being affected by type 2 diabetes [8]. Along thesame lines, the G allele was predictive of glycaemicdeterioration in a Chinese population followed for 5 years[20]. These associations are supported by functional datademonstrating a stronger activation of the RETN promoterby Sp1 and Sp3 transcription factors in the presence of theG allele [8]. In agreement with these data, the same allelehas been reported to be associated with higher abdominal-fat resistin mRNA levels [21]. Thus, so far, so good forSNP rs1862513.Recently, a fine-mapping analysis of the RETN gene hasbeen carried out in a sample of more than 2,500 individualsof European ancestry [14]. The authors found that alleles at