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 A2-IIa (sPLA2IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA2IIa and variation in the sPLA2IIa 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 sPLA2 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 sPLA2IIa levels (P<0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA2IIa 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 sPLA2IIa 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 sPLA2IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA2IIa levels will help clarify the causality of this association. © The Author 2005. Published by Oxford University Press. All rights reserved.