Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study

Recent prospective analysis identified secretory phospholipase A 2 -Ila (sPLA 2 Ila) 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% Cl (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.