Genetic Determinants of Circulating Adiponectin Levels, a Complex Multifactorial Intermediate Phenotype

Circulating adiponectin represents a complex trait with a multifactorial background influenced by internal and external genetic and non-genetic factors, as well as physiological and pathological conditions. It is an important intermediate phenotype characterized by unusually high levels, paradoxical associations with obesity or mortality, and analytical difficulties. Family studies, genome-wide linkage and association analyses demonstrate genetics as a major determinant, though possibly of lesser importance than in similar traits. Heritability values estimated by classical family studies vary significantly (30-93%), depending on study design, age, sex and ancestry. The strongest signals characterized by population differences are on chromosome 3 and 16, where ADIPOQ and CDH13 encoding adiponectin and T-cadherin reside, but tens of other loci situated on almost all chromosomes and genetic variants related to over 150 genes are suspected to modulate plasma levels, frequently by unexplained mechanisms. Population-specific high-impact rare missense mutations (e.g., G45R, R55C, G84R, G90S, R112C, I164T) and common synonymous exon (rs2241766), intron (e.g., rs1501299, rs17366568) or regulatory sequence (e.g., rs17300539, rs266729, rs6773957) variants of ADIPOQ, often in linkage disequilibrium, affect circulating adiponectin levels, usually by altering multimer assembly or gene expression regulation. Three decades of adiponectin genetics research contributed significantly to deciphering adiponectin biology, and emerging genomic technologies may clarify current knowledge gaps.