RESUMO
[Figure: see text].
Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Glucose/metabolismo , Músculo Esquelético/metabolismo , Comunicação Parácrina , Animais , Células Cultivadas , Humanos , Peróxido de Hidrogênio/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismoRESUMO
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.
Assuntos
Aorta/metabolismo , Aneurisma da Aorta Abdominal/genética , Loci Gênicos/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Interpretação Estatística de Dados , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Masculino , Razão de Chances , Especificidade de Órgãos , Fatores de Risco , Proteína de Ligação a Elemento Regulador de Esterol 1/genéticaRESUMO
Extracellular superoxide dismutase (EC-SOD) is the main SOD isoform in the arterial wall contributing to cardiovascular defense against oxidative stress by removing the superoxide anion. In our study, the Thr40Ala and Arg213Gly polymorphic variants of the EC-SOD gene (SOD ( 3 )) were investigated for associations with atherosclerosis and other related factors in 144 subjects with significant atheroma (having one, two, or three major coronary arteries with >50% obstruction, and/or peripheral artery lesions, and/or carotid artery stenosis demonstrated by angiography and echography) and in 150 subjects with no significant atheroma. For the Arg213Gly polymorphism, only five heterozygous subjects were found. Although the difference in the genotype distribution for the Thr40Ala polymorphism was not statistically significant between patients with atheroma (AA 49.3%, AG 34.7%, GG 16.0%) and those without significant atheroma (AA 41.3%, AG 43.3%, GG 15.3%), there was an association of the Thr40 allele with diabetes (P = 0.03) and hypertension (P = 0.04).
