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

Grassi, Guidoa,b; Padmanabhan, Sandoshc; Menni, Cristinaa,b,c; Seravalle, Ginod; Lee, Wai Kc; Bombelli, Michelea,b; Brambilla, Gianmariae; Quarti-Trevano, Foscaa,b,e; Giannattasio, Cristinaa,b; Cesana, Giancarloa,b; Dominiczak, Annac; Mancia, Giuseppea,b

doi: 10.1097/HJH.0b013e328346d72c
Original papers: Genetic aspects
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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.

aClinica Medica, Ospedale San Gerardo, Monza, Italy

bDepartment of Prevention and Clinical Medicine, University of Milano-Bicocca, Milan, Italy

cBHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

dIstituto Auxologico Italiano, Italy

eIstituto Scientifico Multimedica, Sesto S Giovanni, Milan, Italy

Received 19 October, 2010

Revised 20 February, 2011

Accepted 16 March, 2011

Correspondence to Professor Guido Grassi, Clinica Medica, Ospedale S. Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy Tel: +39 039 233 357; fax: +39 039 322 274; e-mail: guido.grassi@unimib.it

© 2011 Lippincott Williams & Wilkins, Inc.