Association between common genetic variants of α2A-, α2B- and α2C-adrenoceptors and the risk of silent brain infarction

Abstract

Abstract. Silent brain infarction (SBI) is an asymptomatic cerebrovascular disorder. The aim of the present study was to investigate the association between adrenoceptor-α2 (ADRA2) gene polymorphisms and SBI. A total of 361 patients with SBI and 467 healthy control subjects were examined. The polymerase chain reaction was performed to genotype the ADRA2A 1780G>A, ADRA2B 301-303 insertion/deletion (I/D) and ADRA2C 322-325I/D polymorphisms. The frequency of the ADRA2C 322-325I/D polymorphism was significantly different between patients with SBI and control subjects. When interaction analyses were performed for vascular risk factors, the ADRA2C 322-325ID genotype increased the risk for SBI in the presence of hypertension and elevated plasma homocysteine levels. The ADRA2C 322-325ID genotype and plasma homocysteine levels showed a significant synergistic effect for SBI. In addition, the ADRA2A 1780AA genotype was associated with elevated plasma homocysteine levels. Although further analysis of the association between ADRA2 polymorphisms and clinical risk factors of SBI is required, the present study of a limited set of SBI risk factors with ADRA2 polymorphisms provides the first evidence of the involvement of ADRA2 gene family members in the development of SBI. Further studies using larger and more heterogeneous populations are required to validate the association of ADRA2 polymorphisms with SBI. Introduction Silent brain infarction (SBI) is a cerebrovascular disorder.The clinical and pathological aspects of SBI are distinct from those of ischemic stroke; while vascular brain lesions are evident using magnetic resonance imaging (MRI), SBI is clinically asymptomatic (1,2). SBI and white matter lesions are frequently observed using brain MRI in healthy elderly individuals and are associated with an increased risk of stroke and dementia (1-6). SBI is a risk factor for stroke (7). SBI has been associated with several cardiovascular risk factors. Previous studies strongly suggest that SBI can be significantly influenced by multiple risk factors, including hypertension, homocysteine levels, cigarette smoking and metabolic syndrome (7-11). However, relatively little is known about the genes involved in SBI pathogenesis. The present study was a candidate gene association study focusing on the association between the adrenoceptor-α2 (ADRA2) genes and SBI. The rationale was two-fold: i) ADRA2 genes are responsible for blood flow vasoconstriction, which is linked to thrombosis; ii) ADRA2 defects are associated with an increased likelihood of ischemic stroke (12,13).There are three subtypes of α2-adrenoceptors (α2-ARs), α2A, α2B and α2C, which are encoded by the ADRA2A, ADRA2B and ADRA2C genes, respectively (10,11). The α2-AR, a membrane receptor for norepinephrine and epinephrine, mediates physiological responses to endogenous catecholamine. The α2-AR is involved in blood pressure reduction, inhibition of presynaptic neurotransmitter release, lipolysis and insulin secretion, as well as augmentation of platelet aggregation (13)...

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

“…6 ), which have long been thought to be the primary cause for cold-induced vasospastic attacks characteristic of RP 4,28–30 . Three highly homologous subtypes of α 2 -adrenoreceptors exist: α 2A , α 2B , and α 2C 17 , which are encoded on different chromosomes by ADRA2A, ADRA2B , and ADRA2C 31 . They mediate the response to stress in the central and peripheral autonomous nervous system 16 and contribute to vasoconstriction in the small arteries and arterioles 17 .…”