Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.
OBJECTIVE
The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial.


METHODS
Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes.


RESULTS
A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (P=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (chi2(8df)=45.58, P<0.000001). Sequence analysis of the PON1 gene from seventy stroke cases revealed a novel nonsense mutation at codon 32 in one stroke case, which was not detected in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke.


CONCLUSIONS
These results suggest that Gln192Arg genotype is an important risk factor for stroke.
Ranade
Koustubh
K
Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ 08543-5400, USA. koustubh.ranade@bms.com
Kirchgessner
Todd G
TG
Iakoubova
Olga A
OA
Devlin
James J
JJ
DelMonte
Terrye
T
Vishnupad
Priya
P
Hui
Lester
L
Tsuchihashi
Zenta
Z
Sacks
Frank M
FM
Sabatine
Marc S
MS
Braunwald
Eugene
E
White
Thomas J
TJ
Shaw
Peter M
PM
Dracopoli
Nicholas C
NC
D001120:Arginine / Q000737:chemistry; D043303:Aryldialkylphosphatase / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005973:Glutamine / Q000737:chemistry; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use; D012306:Risk; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*
D008077:Lipoproteins, LDL; D005973:Glutamine; D001120:Arginine; D043303:Aryldialkylphosphatase; D017035:Pravastatin