Abstract
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.
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.
| Original language | English |
|---|---|
| Article number | N/A |
| Pages (from-to) | 1121-1127 |
| Number of pages | 7 |
| Journal | Journal of Hypertension |
| Volume | 29 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2011 |
Keywords
- Adult
- Aged
- Cohort Studies
- Female
- Humans
- Male
- Metabolic Syndrome X
- Middle Aged
- Polymorphism, Single Nucleotide
- Receptors, Adrenergic, alpha-1