Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.3 | Adiponectin deficiency | 612556 | Autosomal dominant | 3 | ADIPOQ | 605441 |
A number sign (#) is used with this entry because adiponectin deficiency (ADPOD) is caused by heterozygous mutation in the ADIPOQ gene (605441) on chromosome 3q27.
Adiponectin is an adipocyte-derived hormone that exerts pleiotropic effects that promote insulin sensitivity, inhibit cell death, and decrease inflammation. Adiponectin forms an obligate trimer and circulates as trimers, hexamers, and high molecular weight multimers that target multiple tissues and cell types including liver, kidney, cardiac myocytes, and pancreatic beta cells. Levels of adiponectin are decreased in obesity and may lead to insulin resistance, type 2 diabetes, myocardial infarction, nonalcoholic steatohepatitis, and kidney disease. The antiapoptotic, insulin-sensitizing, antiinflammatory, and antisteatotic effects have been linked to its role in sphingolipid metabolism and its receptor-mediated activation of ceramidase activity which reduces levels of lipotoxic ceramides (summary by Simeone et al., 2022).
Genetic Heterogeneity of Quantitative Trait Loci for Serum Level of Adiponectin
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).
Takahashi et al. (2000) measured adiponectin levels in 219 unrelated Japanese patients, including 77 who were obese, and screened for mutations in the ADIPOQ gene. They identified 1 missense mutation (605441.0001), which was present in 1 nonobese man with a low adiponectin level, coronary artery disease, lung thrombosis, and autoimmune disease. The man had a son and 3 daughters, and only 1 daughter carried the mutation and had a low adiponectin level.
In 6 members of a multigenerational family with type 2 diabetes mellitus (T2D; see 125853), end-stage renal disease, and markedly low levels of adiponectin, Simeone et al. (2022) identified a deletion in the ADIPOQ gene (605441.0002). Four additional carriers of the deletion were detected: 2 had diabetes only (III-3 and III-8) and 2 (III-2 and IV-1) were nondiabetic when first enrolled in the study. No follow-up data were available for family members III-2 and IV-1. Among the carriers of the ADIPOQ 10-bp deletion, only 3 possessed either the DR3 or DR4 risk allele of the human leukocyte antigen (HLA-DRA; 142860), suggesting that diabetes was likely not due to the autoimmune form of the disease. All carriers of the mutation had less that 20% of the circulating adiponectin levels found in noncarriers in the family (p less than 0.05). Fast protein liquid chromatography (FPLC) and Western blot analysis of mutant and wildtype adiponectin revealed lack of high molecular weight (HMW) adiponectin complexes in carriers of the mutation, whereas HMW adiponectin was the most abundant isoform in noncarriers. The investigators used liquid chromatography with tandem mass spectrometry (LC-MS/MS) to analyze ceramide levels in carriers, as adiponectin had been reported to reduce lipotoxic ceramides. Carriers of the ADIPOQ mutation had on average 35% increase in C16.0 ceramide levels compared to noncarriers (p less than 0.037). The authors created gene expression constructs to allow expression of wildtype and the mutant adiponectin within a single vector in HEK293T cells. Functional studies demonstrated that the wildtype and mutant adiponectin interacted, leading to decreased stability of wildtype adiponectin. Simeone et al. (2022) suggested that the mutated adiponectin protein acts as a dominant-negative through its interaction with wildtype adiponectin, decreasing circulating adiponectin, and correlating with metabolic disease.
In a nonobese Japanese man 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 heterozygous missense mutation in the ADIPOQ gene (R112C; 605441.0001). Only 1 of his 4 children carried the mutation and had a low concentration of adiponectin. No other description of his daughter was provided and no functional studies of the variant were performed.
Simeone et al. (2022) used unified linkage analysis and rare variant association testing on 6 family members with type 2 diabetes mellitus and ESRD and 524 ethnically matched background controls. They identified a heterozygous 10-bp deletion in exon 3 of the ADIPOQ (605441.0002) shared by all 6 affected family members. Sanger sequencing confirmation of the ADIPOQ variant was performed in all 6 individuals as well as in 8 additional family members for whom DNA was available. Four of the additional family members carried the deletion, 2 of whom had diabetes only and 2 who were unaffected. The deletion was seen only once among 56,810 exome and genome sequences from non-Finnish Europeans reported in gnomAD.
Association Studies
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 2 diabetes and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. A haplotype including 2 5-prime SNPs was associated with adiponectin levels (p less than 0.0001) and with T2D (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 T2D (p = 0.005). The authors failed to detect any association with insulin resistance indices. Although family-based association analysis with T2D 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 T2D 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 T2D. The authors then genotyped rs17846866 in 2,000 Asian Indian patients with T2D 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.
Cesari, M., Narkiewicz, K., De Toni, R., Aldighieri, E., Williams, C. J., Rossi, G. P. Heritability of plasma adiponectin levels and body mass index in twins. J. Clin. Endocr. Metab. 92: 3082-3088, 2007. [PubMed: 17535986] [Full Text: https://doi.org/10.1210/jc.2007-0403]
Filippi, E., Sentinelli, F., Trishitta, V., Romeo, S., Arca, M., Leonetti, F., Di Mario, U., Baroni, M. G. Association of the human adiponectin gene and insulin resistance. Europ. J. Hum. Genet. 12: 199-205, 2004. [PubMed: 14673476] [Full Text: https://doi.org/10.1038/sj.ejhg.5201120]
Hivert, M.-F., Manning, A. K., McAteer, J. B., Florez, J. C., Dupuis, J., Fox, C. S., O'Donnell, C. J., Cupples, L. A., Meigs, J. B. Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study. Diabetes 57: 3353-3359, 2008. [PubMed: 18776141] [Full Text: https://doi.org/10.2337/db08-0700]
Kannel, W. B., Feinleib, M., McNamara, P. M., Garrison, R. J., Castelli, W. P. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am. J. Epidemiol. 110: 281-290, 1979. [PubMed: 474565] [Full Text: https://doi.org/10.1093/oxfordjournals.aje.a112813]
Mackevics, V., Heid, I. M., Wagner, S. A., Cip, P., Doppelmayr, H., Lejnieks, A., Gohlke, H., Ladurner, G., Illig, T., Iglseder, B., Kronenberg, F., Paulweber, B. The adiponectin gene is associated with adiponectin levels but not with characteristics of the insulin resistance syndrome in healthy Caucasians. Europ. J. Hum. Genet. 14: 349-356, 2006. [PubMed: 16418740] [Full Text: https://doi.org/10.1038/sj.ejhg.5201552]
Menzaghi, C., Ercolino, T., Di Paola, R., Berg, A. H., Warram, J. H., Scherer, P. E., Trischitta, V., Doria, A. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes 51: 2306-2312, 2002. [PubMed: 12086965] [Full Text: https://doi.org/10.2337/diabetes.51.7.2306]
Menzaghi, C., Salvemini, L., Paroni, G., De Bonis, C., Mangiacotti, D., Fini, G., Doria, A., Di Paola, R., Trischitta, V. Circulating high molecular weight adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic white Caucasians from Italy: evidence from a family-based study. J. Intern. Med. 267: 287-294, 2010. [PubMed: 19761474] [Full Text: https://doi.org/10.1111/j.1365-2796.2009.02141.x]
Mousavinasab, F., Tahtinen, T., Jokelainen, J., Koskela, P., Vanhala, M., Oikarinen, J., Keinanen-Kiukaanniemi, S., Laakso, M. Common polymorphisms (single-nucleotide polymorphisms SNP+45 and SNP+276) of the adiponectin gene regulate serum adiponectin concentrations and blood pressure in young Finnish men. Molec. Genet. Metab. 87: 147-151, 2006. [PubMed: 16256387] [Full Text: https://doi.org/10.1016/j.ymgme.2005.08.010]
Simeone, C. A., Wilkerson, J. L., Poss, A. M., Banks, J. A., Varre, J. V., Guevara, J. L., Hernandez, E. J., Gorsi, B., Atkinson, D. L., Turapov, T., Frodsham, S. G., Morales, J. C. F., O'Neil, K., Moore, B., Yandell, M., Summers, S. A., Krolewski, A. S., Holland, W. L., Pezzolesi, M. G. A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia. NPJ Genomic Med. 7: 43, 2022. [PubMed: 35869090] [Full Text: https://doi.org/10.1038/s41525-022-00314-z]
Takahashi, M., Arita, Y., Yamagata, K., Matsukawa, Y., Okutomi, K., Horie, M., Shimomura, I., Hotta, K., Kuriyama, H., Kihara, S., Nakamura, T., Yamashita, S., Funahashi, T,, Matsuzawa, Y. Genomic structure and mutations in adipose-specific gene, adiponectin. Int. J. Obes. Relat. Metab. Disord. 24: 861-868, 2000. [PubMed: 10918532] [Full Text: https://doi.org/10.1038/sj.ijo.0801244]
Vasseur, F., Helbecque, N., Dina, C., Lobbens, S., Delannoy, V., Gaget, S., Boutin, P., Vaxillaire, M., Lepretre, F., Dupont, S., Hara, K., Clement, K., Bihain, B., Kadowaki, T., Froguel, P. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum. Molec. Genet. 11: 2607-2614, 2002. [PubMed: 12354786] [Full Text: https://doi.org/10.1093/hmg/11.21.2607]
Vimaleswaran, K. S., Radha, V., Ramya, K., Babu, H. N. S., Savitha, N., Roopa, V., Monalisa, D., Deepa, R., Ghosh, S., Majumder, P. P., Rao, M. R. S., Mohan, V. A novel association of a polymorphism in the first intron of adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia in Asian Indians. Hum. Genet. 123: 599-605, 2008. [PubMed: 18465144] [Full Text: https://doi.org/10.1007/s00439-008-0506-8]