title: Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinica Medica, Ospedale San Gerardo, Monza, Italy. guido.grassi@unimib.it
authors.forename: Guido
authors.initials: G
authors.lastname: Grassi
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: Gino
authors.initials: G
authors.lastname: Seravalle
authors.forename: Wai K
authors.initials: WK
authors.lastname: Lee
authors.forename: Michele
authors.initials: M
authors.lastname: Bombelli
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Brambilla
authors.forename: Fosca
authors.initials: F
authors.lastname: Quarti-Trevano
authors.forename: Cristina
authors.initials: C
authors.lastname: Giannattasio
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cesana
authors.forename: Anna
authors.initials: A
authors.lastname: Dominiczak
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancia
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics*
chemical_list: C547713:ADRA1A protein, human; D018340:Receptors, Adrenergic, alpha-1