A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.
OBJECTIVE
Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways, including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion, have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors.


METHODS
We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 control subjects from 6 case-control association studies conducted in the United States, Europe, and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant, and recessive models of inheritance.


RESULTS
Although 7 polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, 2 lymphotoxin-alpha polymorphisms, which are in strong linkage disequilibrium, were significantly associated among nonhypertensive individuals: LTA 252A>G (additive model; OR, 1.41 with 95% CI, 1.20 to 1.65; P=0.00002) and LTA 26Thr>Asn (OR, 1.19 with 95% CI, 1.06 to 1.34; P=0.003). LTA 252A>G remained significant after adjustment for multiple testing using either the false discovery rate or by permutation testing. The 2 single nucleotide polymorphisms showed no association in hypertensive subjects (eg, LTA 252A>G, OR, 0.93; 95% CI, 0.84 to 1.03; P=0.17).


CONCLUSIONS
These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.
Wang
Xingyu
X
Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China.
Cheng
Suzanne
S
Brophy
Victoria H
VH
Erlich
Henry A
HA
Mannhalter
Christine
C
Berger
Klaus
K
Lalouschek
Wolfgang
W
Browner
Warren S
WS
Shi
Yu
Y
Ringelstein
E Bernd
EB
Kessler
Christof
C
Luedemann
Jan
J
Lindpaintner
Klaus
K
Liu
Lisheng
L
Ridker
Paul M
PM
Zee
Robert Y L
RY
Cook
Nancy R
NR
D001317:Austria / Q000453:epidemiology; D002545:Brain Ischemia / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D002681:China / Q000453:epidemiology; D005060:Europe / Q000453:epidemiology; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics*; D010024:Osteoporosis / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012042:Registries; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D008233:Lymphotoxin-alpha