Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study
1 Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK, 2 The Medical School, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK, 3 Department of Diabetes and Endocrinology, UCL Hospitals, London W1T 3AA, UK, 4 AstraZeneca, R&D, Molecular Pharmacology, Mölndal S-43183, Sweden and 5 Wallenberg Laboratory for Cardiovascular Research, l, 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 January 25, 2007; Revised March 19, 2007; Accepted April 6, 2007
Animal and human studies suggest that both secretory PLA2 (sPLA2)-V and sPLA2-IIA (encoded, respectively, by the neighbouring PLA2G5 and PLA2G2A genes) contribute to atherogenesis. Elevated plasma sPLA2-IIA predicts coronary heart disease (CHD) risk, but no mass assay for sPLA2-V is available. We previously reported that tagging single nucleotide polymorphism (tSNP) haplotypes of PLA2G2A are strongly associated with sPLA2-IIA mass, but not lipid levels. Here, we use tSNPs of the sPLA2-V gene to investigate the association of PLA2G5 with CHD risk markers. Seven PLA2G5 tSNPs genotypes, explaining >92% of the locus genetic variability, were determined in 519 patients with Type II diabetes (in whom PLA2G2A tSNP data was available), and defined seven common haplotypes (frequencies >5%). PLA2G5 and PLA2G2A tSNPs showed linkage disequilibrium (LD). Compared to the common PLA2G5 haplotype, H1 (frequency 34.9%), haplotypes H2–7 were associated with overall higher plasma LDL (P < 0.00004) and total cholesterol (P < 0.00003) levels yet lower oxLDL/LDL (P = 0.006) and sPLA2-IIA mass (P = 0.04), probably reflecting LD with PLA2G2A. Intronic tSNP (rs11573248), unlikely itself to be functional, distinguished H1 from LDL-raising haplotypes and may mark a functional site. In conclusion, PLA2G5 tSNP haplotypes demonstrate an association with total and LDL cholesterol and oxLDL/LDL, not seen with PLA2G2A, thus confirming distinct functional roles for these two sPLA2s.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.