Adiponectin, Serum Level Of, Quantitative Trait Locus 1


A number sign (#) is used with this entry because the serum level of adiponectin as a quantitative trait is associated with variation in the ADIPOQ gene (605441).

Additional quantitative trait loci for serum level of adiponectin have been mapped to chromosome 5 (ADIPQTL2; 606770), chromosome 14 (ADIPQTL3; 606771), chromosome 11 (ADIPQTL4; 612629), and chromosome 16q (ADIPQTL5; 613836).

Molecular Genetics

In a nonobese individual with coronary artery disease, lung thrombosis, autoimmune disease, and a markedly low concentration (1.16 microg/ml) of plasma adiponectin, Takahashi et al. (2000) identified a 383C-T transition in exon 3 of the ADIPOQ gene, resulting in an arg112-to-cys (R112C; 605441.0001) substitution.

Vasseur et al. (2002) identified 12 SNPs in the ADIPOQ coding region and 5-prime sequences, as well as 4 rare nonsynonymous mutations, in exon 3. The 10 most frequent SNPs were genotyped in 1,373 type II diabetes (NIDDM; 125853) and obese French Caucasian subjects and in all subjects available from 148 type II diabetes multiplex families. A haplotype including 2 5-prime SNPs was associated with adiponectin levels (P less than 0.0001) and with type II diabetes (P = 0.004). The presence of at least 1 nonsynonymous mutation in exon 3 showed evidence of association with adiponectin levels (P = 0.0009) and with type II diabetes (P = 0.005). The authors failed to detect any association with insulin resistance indices. Although family-based association analysis with type II diabetes did not reach significance, results suggested that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 may contribute to the variation of adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for type II diabetes in the French Caucasian population.

In 253 nondiabetic Italian subjects, Filippi et al. (2004) found that the 276G-T SNP (rs1501299) in intron 2 of the ADIPOQ gene was associated with higher body mass index (BMI; 606641) (p less than 0.01), plasma insulin (p less than 0.02), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (p less than 0.02). When the subjects were divided according to BMI above or below 26.2, subjects in both subgroups carrying the 276G-T SNP had a higher HOMA-IR; however, the difference was highly significant among leaner (p less than 0.001) but not among heavier individuals, indicating that BMI status and the adiponectin gene interact in modulating insulin resistance. In a subgroup of 67 subjects, carriers of the 276G-T SNP had significantly lower (p less than 0.05) mean serum adiponectin levels compared to noncarriers. Filippi et al. (2004) concluded that there is an association between the 276G-T SNP of the adiponectin gene and insulin resistance, and that among leaner individuals, the adiponectin gene appears to determine an increased risk of developing insulin resistance.

In a study of young Finnish men, Mousavinasab et al. (2006) found significant association between the 276G-T polymorphism and serum adiponectin and triglyceride levels and diastolic blood pressure, and a trend towards a protective effect in carriers of the 45TT genotype in terms of anthropometric and metabolic parameters. Mousavinasab et al. (2006) noted, however, that it is possible that the 2 polymorphisms are in linkage disequilibrium with other loci that may be responsible for the observed associations.

Mackevics et al. (2006) replicated a strong association of ADIPOQ 45T-G (rs2241766)/276G-T genotypes and haplotypes with adiponectin levels that was previously reported by Menzaghi et al. (2002).

Cesari et al. (2007) estimated genetic variance and heritability of adiponectin levels and BMI using ANOVA and path analysis methods. They genotyped for the 45T-G and -11377G-C (rs266729) SNPs in the ADIPOQ gene in 30 pairs of monozygotic (MZ) and 30 pairs of dizygotic (DZ) twins. Adiponectin levels showed significant genetic variance and heritability, which was independent of BMI and partly accounted for by the 45T-G but not the -11377G-C SNP.

Vimaleswaran et al. (2008) analyzed the ADIPOQ gene in 250 Asian Indian patients with type 2 diabetes and 250 normal glucose-tolerant controls and identified 4 SNPs, only 1 of which (10211T-G; rs17846866) was significantly associated with type 2 diabetes. The authors then genotyped rs17846866 in 2,000 Asian Indian patients with type 2 diabetes and 2,000 normal glucose-tolerant controls and found that individuals with the TG genotype had a significantly higher risk for diabetes compared to TT (odds ratio, 1.28; p = 0.008); however, no association with diabetes was observed with the GG genotype. Stratification of all study individuals by BMI showed that the odds ratio for obesity with the TG genotype was 1.53 (p less than 10(-7)) and for the GG genotype, 2.10 (p = 0.002). Among the normal glucose-tolerant controls, mean serum adiponectin levels were significantly lower among the GG and TG genotypes compared to TT (p = 0.007 and p = 0.001, respectively).

Hivert et al. (2008) genotyped 22 tag SNPs in and around the ADIPOQ gene in 2,543 participants in the Framingham Offspring Study (Kannel et al., 1979), in whom adiponectin levels were quantified and glycemic phenotypes and incident diabetes measured. Two promoter SNPs in strong linkage disequilibrium with each other, rs17300539 and rs822387, were associated with adiponectin levels, as was the 3-prime untranslated region SNP rs6773957. A coding SNP (Y111H; rs17366743) was confirmed to be associated with diabetes incidence and with higher mean fasting glucose over 28 years of follow-up.

In a family-based sample of 640 nondiabetic Caucasian Italians, Menzaghi et al. (2010) measured serum adiponectin isoform concentrations and genotyped 3 ADIPOQ SNPs, rs17300539, rs1501299, and rs6773957. All isoforms were highly heritable, and the 3 SNPs explained a significant proportion of high molecular weight (HMW) adiponectin variance. In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin. Significant genetic correlations were observed between HMW adiponectin and fasting insulin, homeostasis models of insulin resistance, HDL cholesterol, and metabolic syndrome score. The SNP rs1501299, previously reported as 276G-T, was found to account for the correlation between HMW adiponectin and insulin and metabolic syndrome score.