Several studies have clearly established the important role of adiponectin in the pathogenesis of insulin resistance-related disorders [2
]. More recently, it has been shown that adiponectin is secreted, and then circulates, in several multimeric forms [5
], of which the HMW isoform is the most biologically active in peripheral target tissues [19
In the present study, we investigated for the first time several aspects of the genetics of adiponectin isoforms. Our findings show that these isoforms are highly heritable and are therefore likely to be under a strong genetic control. Heritability estimates observed in our population are consistent with those of total adiponectin levels previously reported in studies with similar family structures [9
], although we acknowledge that under these circumstances (i.e. family structures prevalently composed by nuclear families and sib pairs rather than extended pedigrees) heritability is usually overestimated and different from that estimated by twin studies [22
]. In addition, HMW, but not MMW or LMW adiponectin levels are genetically correlated with fasting insulin, HOMAIR
, HDL-cholesterol and the metabolic syndrome score. This implies that a common set of genes that controls some of the insulin-resistance traits also controls HMW adiponectin. ADIPOQ
SNPs rs17300539 and rs1501299 were strongly and independently associated with HMW adiponectin levels and explained a proportion of its variance. In addition, ADIPOQ
rs1501299 partly accounted for the common genetic background shared by HMW and insulin resistance traits. Taken together, these data indicate an impact of ADIPOQ
gene variability on HMW, but not on MMW and LMW isoforms. The presentation of circulating adiponectin under each different isoform is entirely due to a post-translational modification process [5
]. However, the production of HMW isoform is more likely to be affected by reduced gene expression, as compared to that of MMW and LMW [18
]. This makes possible that the observed associations between ADIPOQ
SNPs and HMW, but not MMW and LMW, is a consequence of an impact of these SNPs on gene expression. In this context it is of note that, while rare gene variants harbored in the ADIPOQ
coding region (i.e. G84R and G90S) may influence the ability to form HMW oligomer and consequently adiponectin isoforms levels [17
], no common variants in the coding sequence have been so far described with the potential to influence circulating adiponectin at a post transcriptional level.
A recent comprehensive analysis of the evidence published thus far on the role of ADIPOQ
gene common variants on adiponectin circulating levels and insulin resistance traits has clearly indicated the existence of two distinct signals, corresponding to the two linkage disequilibrium blocks in the ADIPOQ
]. SNP rs17300539 in the promoter region and SNPs rs1501299 in the 3’UTR block are the variants that best capture these associations [7
]. More recently rs6773957 in the 3’UTR has been associated to total adiponectin levels [8
]. Our present data on adiponectin isoforms confirm the association of rs17300539 and rs1501299 with adiponectin levels and indicate that this is due exclusively to an effect on the HMW fraction. On the other hand, a clear functional role has been shown for rs17300539 [24
], but not for rs1501299 [24
]. Thus, additional fine-mapping and functional studies are needed to pin point the causal variant(s) responsible for this association. Given the lack of association between ADIPOQ
SNPs and MMW and LMW levels, as well as the large proportion of unexplained variability of HMW levels, after taking into account ADIPOQ
SNPs, other yet unidentified genetic determinants are certainly playing a role in modulating adiponectin isoforms levels.
Although not a primary aim of this study, we also confirmed previous observations [25
] indicating that, of the three adiponectin isoforms, HMW is the one showing the best correlation with insulin resistance traits.
The main strength of our findings relates to the novelty of studying all circulating adiponectin isoforms in a family based cohort. In addition, our sample of non-diabetic White Caucasians comes from a genetically homogeneous population [10
], further minimizing the risk of false results due to population stratification. Nonetheless, our study has some limitations. Our genotyping was limited to the three SNPs reported to be associated with total adiponectin levels in previous studies and we cannot exclude that other ADIPOQ
SNPs play also a role on the genetics of adiponectin isoforms. In addition, whether our data can be generalized to other populations with different study design (i.e. sample with extended pedigrees where genetic heritability can be more accurately estimated), and with different environmental and/or genetic background is not known and deserves further investigation.
In conclusion, our data indicate that circulating levels of adiponectin isoforms are under a strong additive genetic control which, as far as HMW is concerned, is shared with other traits related to insulin resistance. Our results also point to a role of the ADIPOQ locus in influencing both HMW adiponectin and insulin resistance. Taken together, these data reinforce the hypothesis that differences in HMW isoform levels play a pathogenic role in the development of insulin resistance-related abnormalities.