Common Variants in the Adiponectin Gene (ADIPOQ) Associated With Plasma Adiponectin Levels, Type 2 Diabetes, and Diabetes-Related Quantitative Traits

Abstract

OBJECTIVE-Variants in ADIPOQ have been inconsistently associated with adiponectin levels or diabetes. Using comprehensive linkage disequilibrium mapping, we genotyped single nucleotide polymorphisms (SNPs) in ADIPOQ to evaluate the association of common variants with adiponectin levels and risk of diabetes. RESEARCH DESIGN AND METHODS-Participants in theFramingham Offspring Study (n ϭ 2,543, 53% women) were measured for glycemic phenotypes and incident diabetes over 28 years of follow-up; adiponectin levels were quantified at exam 7. We genotyped 22 tag SNPs that captured common (minor allele frequency Ͼ0.05) variation at r 2 Ͼ 0.8 across ADIPOQ plus 20 kb 5Ј and 10 kb 3Ј of the gene. We used linear mixed effects models to test additive associations of each SNP with adiponectin levels and glycemic phenotypes. Hazard ratios (HRs) for incident diabetes were estimated using an adjusted Cox proportional hazards model. RESULTS-Twopromoter SNPs in strong linkage disequilibrium with each other (r 2 ϭ 0.80) were associated with adiponectin levels (rs17300539; P nominal [P n ] ϭ 2.6 ϫ 10 Ϫ8 ; P empiric [P e ] ϭ 0.0005 and rs822387; P n ϭ 3.8 ϫ 10 Ϫ5 ; P e ϭ 0.001). A 3Ј-untranslated region (3ЈUTR) SNP (rs6773957) was associated with adiponectin levels (P n ϭ 4.4 ϫ 10 Ϫ4 ; P e ϭ 0.005). A nonsynonymous coding SNP (rs17366743, Y111H) was confirmed to be associated with diabetes incidence for the minor C allele; P n ϭ 0.01) and with higher mean fasting glucose over 28 years of follow-up (P n ϭ 0.0004; P e ϭ 0.004). No other significant associations were found with other adiposity and metabolic phenotypes.CONCLUSIONS-Adiponectin levels are associated with SNPs in two different regulatory regions (5Ј promoter and 3ЈUTR), whereas diabetes incidence and time-averaged fasting glucose are associated with a missense SNP of ADIPOQ. Diabetes 57: 3353-3359, 2008A diponectin is an adipokine produced by adipocytes that has drawn attention over the past few years for its potential role in diabetes physiology (1). Adiponectin is believed to have anti-inflammatory and insulin-sensitizing properties. High levels of circulating adiponectin have been associated with lower diabetes incidence in many prospective studies (1).Adiponectin is encoded by the gene ADIPOQ located in the chromosomal region 3q27. ADIPOQ spans 16 kb and contains three exons. Previous genome-wide linkage scans have identified 3q27 as a susceptibility locus for diabetes (2,3). Various single nucleotide polymorphisms (SNPs) in ADIPOQ have been reported to be associated with adiponectin levels and/or diabetes but with inconsistent results. A recent comprehensive review (4) showed that a few ADIPOQ SNPs were associated with adiponectin levels and insulin resistance, but none was consistently associated with diabetes or with adiposity as measured by BMI. As underlined by Menzaghi et al. (4), the lack of consistent findings emphasizes the need for comprehensive characterization of the genetic variation in and around the ADIPOQ gene. They also emphasized the need to address th...

Genome-wide association study for adiponectin levels in Filipino women identifies CDH13 and a novel uncommon haplotype at KNG1–ADIPOQ

“…The Framingham Offspring Study, which systematically examined the associations with 22 SNPs that captured all common variation at r 2 . 0.8 across ADIPOQ and its flanking regions, observed that adiponectin level was significantly associated with SNPs in two different regulatory regions, the 5 ′ -promoter (rs17300539) and the 3 ′ -untranslated regions (rs6773957) (17). A recent study dissecting the genetic architecture of plasma adiponectin suggested that two ADIPOQ variants (rs17300539 and rs182052) exhibited independent association (18), and a recent GWAS of 4659 European individuals suggested association with at least nine SNP groups near ADIPOQ (29) Fig.…”

“…Several SNPs including rs17300539 (211391G.A), rs2241766 (+45T.G) and rs1501299 (+276G.T) have been reproducibly reported to be associated with circulating adiponectin (11)(12)(13)(14)(15)(16). Two reports suggested the presence of distinct association signals for adiponectin levels represented by 5 ′ -promoter SNP rs17300539 and either rs6773957 (17) or rs182052 (18), and a gene-wide tagSNP investigation revealed that two haplotype blocks mapping to the ADIPOQ promoter and the relevant exons showed association with adiponectin (19). Only limited evidence has been provided for the functional relevance of these SNPs (20,21), and the common genetic variants identified thus far explain only a fraction of the estimated heritability for adiponectin (22).…”

Relation of a common variant of the adiponectin gene to serum adiponectin concentration and metabolic traits in an aged Japanese population

“…In the Framingham Offspring study, 35 two SNPs in the promoter region of ADIPOQ (rs822387, rs17300539) were shown to be strongly associated with plasma adiponectin level, whereas rs17366743 (Tyr111His) was associated with the prevalence of type II diabetes. However, in this study, none of these three SNPs was associated with adiponectin level or hyperglycemia in the screening population.…”

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

“…We also addressed the issue of whether or not circulating adiponectin isoforms share a common genetic background with ACR and, if so, if it is partly explained by ADIPOQ gene variability. To this latter purpose, we genotyped single nucleotide polymorphisms (SNPs) in the ADIPOQ gene or their proxies (as indicated by r 2 >0.9) (see Electronic supplementary material [ESM] Table 1), which have been consistently associated with adiponectin levels [25][26][27][28].…”