Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men.
OBJECTIVE
Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (-44G --> A and +71A --> G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals.


METHODS
Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic).


RESULTS
We found a significant contribution of the minor Cx40 allele or genotype (-44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the -44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (-44GG; P = 0.033).


CONCLUSIONS
These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.
Firouzi
Mehran
M
Department of Medical Physiology, University Medical Center, Utrecht, The Netherlands.
Kok
Bart
B
Spiering
Wilko
W
Busjahn
Andreas
A
Bezzina
Connie R
CR
Ruijter
Jan M
JM
Koeleman
Bobby P C
BP
Schipper
Maria
M
Groenewegen
W Antoinette
WA
Jongsma
Habo J
HJ
de Leeuw
Peter W
PW
D000368:Aged; D001794:Blood Pressure; D017630:Connexins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
D017630:Connexins; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein