title: Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study.
abstract: Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mellitus. Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variability in PLA2G2A were identified and distinguished six common haplotypes (frequencies > 5%). In the 523 Caucasian T2D patients, levels of sPLA(2)IIa, independent of CRP, were negatively correlated with total antioxidant status (P = 0.003) and high-density lipoprotein cholesterol (P = 0.006) in men and correlated with CAD status in women (P = 0.002) (Odds ratio of top two tertiles versus bottom = 2.50) [95% CI (1.13-5.53) P = 0.024]. Overall, tSNP haplotypes showed a highly significant association with sPLA(2)IIa levels (P < 0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA(2)IIa levels [3.25 ng/ml (+/- 0.14)] compared with the combined other haplotypes [2.13 ng/ml (+/- 0.09), P < 0.00001]. Five of the six tSNPs were associated with significant effects on sPLA(2)IIa levels but the raising haplotype could not be distinguished by a single tSNP and none are likely to be functional. These data confirm the relationship between elevated sPLA(2)IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA(2)IIa levels will help clarify the causality of this association.
authors.affiliation: Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK.
authors.forename: Peter T E
authors.initials: PT
authors.lastname: Wootton
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Simon R
authors.initials: SR
authors.lastname: Thompson
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Stephens
authors.forename: Eva
authors.initials: E
authors.lastname: Hurt-Camejo
authors.forename: Olov
authors.initials: O
authors.lastname: Wiklund
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
mesh_terms: D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology*; D005260:Female; D040461:Gene Components; D005838:Genotype; D054501:Group II Phospholipases A2; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008131:London; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000097:blood* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human