A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm

Abstract

Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5a reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C4T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P¼0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs. Keywords: aorta; aneurysm; sex hormones INTRODUCTION Abdominal aortic aneurysm (AAA) primarily affects men, with population-screening studies demonstrating an increased prevalence of approximately fivefold compared with women. 1 Currently, the reasons for the male propensity for AAA are not known, but maybe linked to sex hormones, as in experimental models androgens have been positively linked to aortic dilatation. 2 The production, metabolism and response to sex hormones are controlled by an array of enzymes and receptors, including steroid 5a reductase, aromatase (estrogen synthetase), androgen and estrogen receptors. 3,4 Steroid 5a reductase enzymes are responsible for the conversion of testosterone to the more potent androgen dihydrotestosterone. 3 Aromatase (estrogen synthetase) is a cytochrome P450 enzyme that converts androgen precursor steroids to estrogens. 4 The responses to circulating sex hormones are determined by the androgen and estrogen receptors. Genetic factors appear to have an important role in the production, metabolism and response to male sex hormones, and therefore maybe relevant to AAA, which has been shown to have inherited risk factors. 5,6 We selected four genes important in the production, metabolism and response to sex hormones to examine the association of genetic polymorphisms with aortic dilatation. We hypothesized that single-nucleotide polymorphisms (SNPs) in the steroid 5a reductase,

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

“…As genetic factors appear to have a role in the production, metabolism, and response to male sex hormones, an association was found between small AAAs and 1 SNP located in intron 1 of CYP19A1, but this finding was not confirmed in an independent cohort of large aneurysms. 27 As receptors of female sex hormones mediate their effects in vascular SMCs and in endothelial cells, genes encoding for these receptors provide biologically plausible candidate genes for genetic studies. A small study with 99 AAA cases and 225 controls revealed a polymorphism in the estrogen receptor b (ESR2) but not estrogen receptor a (ESR1), elastin (ELN ), progesterone receptor (PR), or transforming growth factor b1 (TGFB1) genes to be associated with AAA.…”

Expression Pattern and Clinical Value of Key m6A RNA Modification Regulators in Abdominal Aortic Aneurysm

“…Some metabolic process-related genes, such as AHCY, CYP19A1, DNMT3A and EZH2, have been reported to participate in AAA. [31][32][33][34] For identified autophagy-related genes, MCL1, HIF1A, VEGFA, PARP1, AFT4 and CANX are essential for the survival and function of vascular cells and underlie AAA. 2,[35][36][37][38][39] Meanwhile, recent studies proved…”

Predicting Abdominal Aortic Aneurysm Target Genes by Level-2 Protein-Protein Interaction

“…Some previously reported genes that influence AAA, such as Epidermal Growth Factor Receptor (EGFR) [ 42 ], Smad family member 1 (Smad1) [ 43 ], Estrogen Receptor (ESR2) [ 44 ], and STAT family member 3 (STAT3) [ 45 ], were successfully predicted by our level-2 PPI network, but not by the level-1 PPI network. These reported genes were not positive in our network because they were identified in animals, whereas only human genome-wide association study (GWAS) reports were used in the construction of our networks.…”