Journal Article

Tagging SNP haplotype analysis of the secretory PLA2-V gene, <i>PLA2G5</i>, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study

Peter T.E. Wootton, Nupur L. Arora, Fotios Drenos, Simon R. Thompson, Jackie A. Cooper, Jeffrey W. Stephens, Steven J. Hurel, Eva Hurt-Camejo, Olov Wiklund, Steve E. Humphries and Philippa J. Talmud

in Human Molecular Genetics

Volume 16, issue 12, pages 1437-1444
Published in print June 2007 | ISSN: 0964-6906
Published online June 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm094
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

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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.

Journal Article.  4551 words.  Illustrated.

Subjects: Genetics and Genomics

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