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.
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.
Wootton
Peter T E
PT
Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School,5 University Street, London WC1E 6JF, UK.
Arora
Nupur L
NL
Drenos
Fotios
F
Thompson
Simon R
SR
Cooper
Jackie A
JA
Stephens
Jeffrey W
JW
Hurel
Steven J
SJ
Hurt-Camejo
Eva
E
Wiklund
Olov
O
Humphries
Steve E
SE
Talmud
Philippa J
PJ
D000368:Aged; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D054501:Group II Phospholipases A2; D054505:Group V Phospholipases A2; D006239:Haplotypes; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D054467:Phospholipases A2; D020641:Polymorphism, Single Nucleotide
D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054505:Group V Phospholipases A2; C516287:PLA2G2A protein, human; C516293:PLA2G2D protein, human; C516299:PLA2G5 protein, human; D054467:Phospholipases A2