Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population

Objectives: There is currently uncertainty about whether metabolic syndrome has a common underlying process. We performed a gene-centric association study of metabolic syndrome in 98 major cardiometabolic genes in the large, well phenotyped Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. We followed this with functional studies to elucidate a possible mechanism for the top association signal. Methods: From the PAMELA cohort, we sampled 1407 individuals with information on the metabolic syndrome (ATPIII criteria). We analyzed 1324 tagging single-nucleotide polymorphisms (SNPs) in 98 candidate genes selected, based on known pathways involved in sympathetic nervous system, oxidative stress, renin-angiotensin system and sodium balance. Results: The SNP rs17055869 near the alpha-1A-adrenoreceptor gene (ADRA1A) showed the strongest association with metabolic syndrome (odds ratio 1.7, CI 1.3-2.2; P = 0.00007, P = 0.000098 after permutation). In order to determine a functional basis for this association, we examined in a subgroup of metabolic syndrome patients whether the allelic distribution of the above-mentioned gene is different according to the different degree of the metabolic syndrome-related sympathetic activation, directly assessed by the gold standard method to assess neuroadrenergic drive, that is microneurographic recording of efferent postganglionic muscle sympathetic nerve traffic. All metabolic syndrome patients with a lesser degree of sympathetic activation were homozygous for the major allele (C), whereas those with a very pronounced sympathetic overdrive had an over-representation of the minor T allele (P < 0.0001). Conclusion: Thus, the rs17055869 SNP near the 3′ end of ADRA1A is significantly associated with metabolic syndrome and it may be involved in determining a greater level of sympathetic activation in metabolic syndrome patients.