Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(2):355-361; doi:10.1093/hmg/ddi453
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Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study
1Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK, 2The Medical School, University of Wales Swansea, Singleton Park, Swansea, MA SA2 8PP, USA, 3AstraZeneca, R&D, Molecular Pharmacology, Mölndal S-43183, Sweden and 4Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Goteborg SE-413 45, Sweden
* To whom correspondence should be addressed. Tel: +44 2076796968; Fax: +44 2076796212; Email: p.talmud{at}ucl.ac.uk
Received October 5, 2005; Accepted December 9, 2005
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 sPLA2IIa, 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.
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