Genetic variants of connexin37 are associated with carotid intima-medial thickness and future onset of ischemic stroke.
BACKGROUND
Carotid intima-medial thickness (IMT) is a surrogate marker of subclinical atherosclerosis. This study aimed to investigate the impacts of genetic variants on IMT and future development of ischemic stroke in a cohort, followed by an independent replication study.


METHODS
B-mode carotid ultrasound was performed among 3330 healthy adults in the CVDFACT cohort study, and the genetic effects of atherosclerosis-related genes including connexin37 (GJA4), C-reactive protein (CRP), paraoxonase (PON1), adiponectin (ACDC), angiotensin-converting enzyme (ACE), beta-adrenergic receptor (ADRB1, ADRB2), antithrombin III (SERPINC1), and kinesin family member 6 (KIF6) were evaluated by a multivariate regression model, adjusting for traditional vascular risk factors. Study subjects were prospectively followed for the development of ischemic stroke to assess the prognostic impacts of these genetic variants. An independent case-control study was performed to replicate the genetic association from the cohort study.


RESULTS
The T allele of connexin37 C1019T polymorphism significantly affected IMT (β=0.014, p=0.013) after adjusting for traditional risk factors. During an average follow-up period of 10.7 years, 80 patients with ischemic stroke (2.4%) were identified. The connexin37 1019T allele was significantly associated with an increased rate of ischemic stroke under an additive model, with hazard ratios (HR) of 2.83 (95% confidence interval, 1.2-6.66) and 1.69 (95% confidence interval, 1.06-2.71), comparing TT and CT genotype with CC, respectively. After Cox analysis, age (HR, 1.78 every 10 years), diabetes mellitus (HR, 2.63), hypertension (HR, 2.08), and the T allele of C1019T polymorphism of GJA4 (HR, 1.69) were identified as independent predictors of ischemic stroke. The relationship between T allele of C1019T polymorphism of GJA4 gene and ischemic stroke was also confirmed by an independent association study.


CONCLUSIONS
Connexin 37 genetic variants significantly affect carotid IMT and contribute to future development of ischemic stroke.
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Hsin-Bang
HB
Leu
Chia-Min
CM
Chung
Shao-Yuan
SY
Chuang
Chyi-Huey
CH
Bai
Jiunn-Rong
JR
Chen
Jaw-Wen
JW
Chen
Wen-Harn
WH
Pan
D000368:Aged; D000483:Alleles; D002339:Carotid Arteries / Q000473:pathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D006801:Humans; D007511:Ischemia / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*; D000097006:Gap Junction alpha-4 Protein
D017630:Connexins; D007703:Peptidyl-Dipeptidase A; D000097006:Gap Junction alpha-4 Protein