Interaction of the -308G/A Promoter Polymorphism of the Tumor Necrosis Factor-[Alpha] Gene with Single-Nucleotide Polymorphism 45 of the Adiponectin Gene: Effect on Serum Adiponectin Concentrations in a Spanish Population (Endocrinology and Metabolism) (Survey‪)‬

Several endocrine and autocrine/paracrine mediators derived from adipose tissue play essential roles in the regulation of adipocyte functions, in particular those related to insulin action (1). Among these adipocytokines, tumor necrosis factor-[alpha] (TNF-[alpha]) (3) and adiponectin are of paramount importance (2). Of major interest is the -308G/A polymorphism in the TNF-[alpha] gene, a single base-pair polymorphism located at position 308 in the promoter region of the TNF-[alpha] gene that maps to human chromosome 6 (p21.1-p21.3) and causes substitution of the nucleotide guanine (G) by (A). This polymorphism has been shown to be involved in insulin resistance, although association studies in different populations have produced conflicting results (3, 4). The presence of the A allele alters the binding of nuclear factors to the -308 region; thus this mutation may be responsible for an increase in transcriptional activity compared with the G allele (5). Plasma concentrations of the soluble TNF-[alpha] receptor 2 (sTNFR2) seem to be good markers of TNF-[alpha]-induced insulin resistance (6, 7), whereas the circulating concentration of TNF-[alpha] is usually not informative, probably because of its instability and very low concentration in plasma. sTNFR2, a very stable protein, has been associated with body mass index (BMI), waist-to-hip ratio (WHR), and insulin resistance (7); it therefore might be a better predictor of local TNF-[alpha] system activation than are circulating TNF-[alpha] concentrations (6). Serum adiponectin concentrations have been shown to be decreased in the presence of obesity, type 2 diabetes, insulin resistance, and cardiovascular disease (8-10). The adiponectin gene is located on chromosome 3q27, on which a diabetes susceptibility locus has recently been mapped (11). Several single-nucleotide polymorphisms (SNPs) in the adiponectin gene have been reported (12). Among those, SNPs 45TG and 276GT were originally selected for association studies because of their high frequencies in all populations tested, whereas other reported polymorphisms were rare. Both SNPs 45TG and 276GT have been associated with obesity, insulin resistance, and type 2 diabetes (13-15) and with the development of hyperglycemia (16). Most recently, these 2 SNPs have also been reported to be predictors of the conversion from impaired glucose tolerance to type 2 diabetes (17). The exact mechanisms through which SNPs 45 and 276 influence insulin resistance or impaired glucose tolerance are not known at present. SNP 45 is located in exon 2 and is a synonymous mutation, and SNP 276 is located in intron 2. It is also possible, however, that the presence of unknown functional SNPs or other functional genetic loci in linkage disequilibrium with SNPs 45 and 276 are responsible for alterations in insulin sensitivity and glucose homeostasis.