Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi453
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1 Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University St, London WC1E 6JF, UK
* To whom correspondence should be addressed. 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 mellitus (T2D). Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variance in the sPLA2IIa gene PLA2G2A, were identified and distinguished 6 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 HDL 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 (<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 to 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 themselves likely to be functional. These data confirm the relationship between elevated sPLA2IIa levels and CAD risk reported in both case: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA2IIa levels will help clarify the causality of this association.
Received October 5, 2005
Revised December 2, 2005
Accepted December 9, 2005
Article
Tagging SNP haplotype analysis of the secretory PLA2-IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study
Peter TE Wootton 1,
Fotios Drenos 1,
Jackie A Cooper 1,
Simon R. Thompson 1,
Jeffrey W Stephens 2,
Eva Hurt-Camejo 3,
Olov Wiklund 4,
Steve E Humphries 1,
and
Philippa J Talmud 1 *
2 The Medical School, University of Wales Swansea, Singleton Park, Swansea, SA2 8PP
3 AstraZeneca, R&D, Molecular Pharmacology, Mölndal S-43183, Sweden; Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden
4 Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden
Philippa J Talmud, E-mail: p.talmud{at}ucl.ac.uk
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