Single Nucleotide Polymorphisms in the Proximal Promoter Region of the Adiponectin (APM1) Gene Are Associated With Type 2 Diabetes in Swedish Caucasians

Abstract

Adiponectin (APM1) is an adipocyte-derived peptide.The APM1 gene is located on chromosome 3q27 and linked to type 2 diabetes. In patients with type 2 diabetes, the adiponectin level in plasma is decreased in comparison to healthy subjects. To identify genetic defects of the APM1 gene that contribute to the development of type 2 diabetes, we genotyped 13 single nucleotide polymorphisms (SNPs) in 106 patients with type 2 diabetes, 325 patients with impaired glucose tolerance (IGT), and 497 nondiabetic control subjects in Swedish Caucasians by using dynamic allele-specific hybridization (DASH). We found that SNPs ؊11426(A/G) and ؊11377(G/C) in the proximal promoter region had significant differences of allele frequencies between type 2 diabetic patients and nondiabetic control subjects (P ‫؍‬ 0.02 and P ‫؍‬ 0.04, respectively). SNP-11426(A/G) was significantly associated with fasting plasma glucose in type 2 diabetic patients (P ‫؍‬ 0.02) and in IGT subjects (P ‫؍‬ 0.04), while the patients carrying CC and CG genotypes for SNP-11377(G/C) had a higher BMI than the patients with the GG genotype (P ‫؍‬ 0.03). Haplotype analysis of 13 SNPs in the APM1 gene showed that estimates of haplotype frequencies in Swedish Caucasians are similar to those estimated in French Caucasians. However, no significant association of haplotypes with type 2 diabetes and IGT was detected in our study. The present study provides additional evidence that SNPs in the proximal promoter region of the APM1 gene contribute to the development of type 2 diabetes. Diabetes 53 (Suppl. 1):S31-S35, 2004 A diponectin (APM1, also known as ACRP30, GBP28, or AdipoQ) is secreted from adipose tissue and regulates insulin sensitivity (1,2). The APM1 gene has been identified and is located on chromosome 3q27 (3-5). In this chromosome region, genome-wide scans have revealed a susceptibility locus for type 2 diabetes (6), coronary heart disease (7), and measures of adiposity (8). Several studies have demonstrated that the adiponectin level in plasma is decreased in patients with type 2 diabetes or obesity in comparison to healthy subjects (9,10). Thus, adiponectin may play a role in the pathogenesis of type 2 diabetes and insulin resistance. Recently, mutation screening of the APM1 gene in Japanese and French populations was performed, and 13 single nucleotide polymorphisms (SNPs) were found in the APM1 gene (11,12). SNPs ϩ45T/G and ϩ276G/T in exon 2 and intron 2, respectively, of the APM1 gene were found to be significantly associated with type 2 diabetes in Japanese patients with normal body weight (BMI Ͻ24 kg/m 2 ) mainly due to decreased insulin sensitivity (11). Stumvoll et al. (13) demonstrated that SNP ϩ45T/G in the APM1 gene increases the risk for obesity and secondarily for insulin resistance in nondiabetic Caucasians of German ancestry. Furthermore, in another group of nondiabetic Caucasians, a haplotype defined by SNPs ϩ45T/G and ϩ276G/T was strongly associated with many components of the insulin resistance syndrome (14).A recent report from French Ca...

Polymorphisms of the gene encoding adiponectin and glycaemic outcome of Chinese subjects with impaired glucose tolerance: a 5-year follow-up study

“…For the other SNPs studied, we found no association with hyperglycaemia, in contrast to previous reports on SNPs A-11426G [9], C-11377G [8,9] and G276T [7,11]. This may again be explained by differences in ethnicity and study design.…”

“…An increased risk of diabetes mellitus was shown in subjects with the GG genotype (OR=1.70) in a Japanese population [7], and the G allele was also associated with reduced insulin sensitivity and increased BMI in a German cohort [10]. However, another group found that the T allele contributed to the risk of hyperglycaemia [11], and others failed to find any association of the T45G polymorphism with diabetes mellitus in Europids [8,9,18] and Pima Indians [19]. Most of the conflicting results among reported case-control studies could have been caused by statistical fluctuations, such as sampling errors related to small sample sizes, and reporting biases consequent to inadequate allowance for type 1 error and multiple testing.…”

“…Several single-nucleotide polymorphisms (SNPs) and mutations of the ADIPOQ gene were shown in Japanese and Europid populations to be associated with diabetes [7][8][9], obesity [10] or the metabolic syndrome [11]. However, the association of SNPs of the ADIPOQ gene with type 2 diabetes and IGT/IFG in various populations has been very inconsistent, different studies finding associations with different SNPs; these results were subsequently replicated in some studies but not others [6][7][8][9][10][11]. No systematic analysis of the ADIPOQ gene with regard to diabetes or IGT has yet been performed in Chinese people.…”

Adiponectin Gene Polymorphism and its Association with Type 2 Diabetes Mellitus

“…Study on Italians by Nannipieri et al [17], French population based study by Vasseur F et al [18] and Gu et al [19] study report on Swedish subjects also showed no association among SNP45 T [ G of adiponectin gene and insulin resistance. This may be due to variation in the ethnic group.…”

A polymorphism in the adiponectin gene influences adiponectin expression levels in visceral fat in obese subjects

“…9 Variations in the adiponectin gene (APM1) have been associated with type 2 diabetes in many populations. [10][11][12][13][14][15][16] The adiponectin gene has thus emerged as a susceptibility gene for type 2 diabetes, as well as for cardiovascular disease and obesity. The intronic G276T variant, located in intron 2, is one of the most extensively studied variants within the adiponectin gene and has the most consistent published results.…”