title: A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.
abstract: 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.
authors.affiliation: Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cheng
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Brophy
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lalouschek
authors.forename: Warren S
authors.initials: WS
authors.lastname: Browner
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: E Bernd
authors.initials: EB
authors.lastname: Ringelstein
authors.forename: Christof
authors.initials: C
authors.lastname: Kessler
authors.forename: Jan
authors.initials: J
authors.lastname: Luedemann
authors.forename: Klaus
authors.initials: K
authors.lastname: Lindpaintner
authors.forename: Lisheng
authors.initials: L
authors.lastname: Liu
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Robert Y L
authors.initials: RY
authors.lastname: Zee
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cook
mesh_terms: 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
chemical_list: D008233:Lymphotoxin-alpha