Long-term survival after ischemic stroke in postmenopausal women is affected by an interaction between smoking and genetic variation in nitric oxide synthases.
BACKGROUND
We aimed to study whether variations in vasoregulatory endothelial nitric oxide synthase (eNOS 4a/b) and tissue-injury-associated inducible nitric oxide synthase (iNOS R5/4) genes and smoking might explain gender differences in long-term survival after stroke.


METHODS
A total of 486 consecutive acute stroke patients, subjected to MRI, were followed up for a mean of 7.6 years. The eNOS 4a/b (n = 300) and iNOS R5/4 (n = 310) genotypes were determined by PCR. Of these patients, 213/300 (71.0%; eNOS 4a/b) and 223/310 (71.9%; iNOS R5/4) had died.


RESULTS
Despite the fact that women were older than men (72.3 vs. 69.5 years, p = 0.001) at recruitment, poor long-term survival was not sex-related, but instead predicted by age (p < 0.0001), cardiac failure (p = 0.004), smoking (p = 0.017), diabetes (p = 0.049), and variation in the eNOS gene locus (p = 0.033). Smoking and variations in both eNOS [hazard ratio (HR) = 1.53, p = 0.011] and iNOS loci (HR = 1.52, p = 0.073) were found to impact upon poor survival. We found a strong interaction between smoking, female sex, and the iNOS R5/4 genotype with the risk of death (HR = 3.23, CI = 1.51-6.90, p = 0.002). Compared with nonsmoking noncarriers, postmenopausal women who had been smokers and carried either the rare iNOS R5 allele (17.1%; HR = 4.23, CI = 1.84-9.75, p = 0.001) or the common eNOS 4b allele (71%; HR = 3.14, CI = 1.49-6.62, p = 0.003) were at a higher risk of death during the follow-up. These interactions were independent of each other, and were not found among men.


CONCLUSIONS
The interaction between smoking and genetic variants of eNOS and iNOS predicts survival after stroke, especially among postmenopausal women.
Oksala
N K J
NK
Division of Vascular Surgery, Department of Surgery, School of Medicine Tampere University and Tampere University Hospital, Tampere, Finland. niku.oksala@tuubi1.net
Oksala
A
A
Erkinjuntti
T
T
Pohjasvaara
T
T
Kunnas
T
T
Vataja
R
R
Kaste
M
M
Karhunen
P J
PJ
D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D017698:Postmenopause; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*; D020521:Stroke / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D017741:Survivors; D013997:Time Factors
C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III