The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men

Marileia Scartezini , Christina Hubbart , Ros A Whittall , Jackie A Cooper , Andrew Hw Neil , Steve E Humphries (1)

1 Medicine

We have determined the relative frequency of the R46L, I474V and E670G variants in the protein convertase subtilisin/kexin type 9 (PCSK9) gene and its association with plasma lipid levels and coronary heart disease (CHD) in UK healthy men and patients with clinically-defined definite familial hypercholesterolaemia (FH). Genotypes were determined using PCR and Restriction Enzyme digestion in 2444 healthy middle-aged (50-61 years) men from the prospective NPHSII Study, with 275 CHD events (15 years followup) and in 597 UK FH patients from the Simon Broome Register. In the NPHSII healthy men the R46L genotype distribution was in Hardy-Weinberg equilibrium and the frequency of 46L was 0.009 (95% CI 0.007-0.012), with one man homozygous for the 46L allele. There was significant association of the 46L allele with lower mean (+SD) total cholesterol (RR 5.74 ± 1.01 vs RL 5.22 ± 1.05; p=0.001), apo B (RR 0.87 ± 0.24 vs RL 0.73 ± 0.27; p<0.0001) and LDL-C (RR 4.01 ± 0.95 vs RL 3.55 ± 1.01;p=0.02) levels, after adjustment for age, GP practice, smoking, BMI and SBP. As expected, 46L carriers had a low risk of definite or possible CHD HR=0.46 (0.11-1.84)) but this was not statistically significant (p=0.27). Two other common PCSK9 variants I474V (frequency V = 0.179, CI 0.17-0.19) and E670G (frequency G = 0.034 CI 0.03-0.04) were not associated with any significant effects on lipid levels or CHD risk. In FH patients the frequency of 46L was 0.003 (95% CI 0.00-0.01) which was significantly lower (p=0.037) than the healthy subjects. In the four FH patients carrying 46L mean untreated total cholesterol levels were not different in carriers and non-carriers (median.10.3 mmol/l vs 10.2mmol/l p=0.91 after adjustment for age, gender and mutation type). Conclusions. The PCSK9 46L allele is more frequent in UK healthy men than in FH patients and is strongly associated with a protective plasma lipid profile risk to CHD. Its low frequency (~2% carriers) means that it is not making a major contribution to determining population CHD risk in the UK.

Mots clés: Medicine

Marileia Scartezini, Christina Hubbart, Ros A Whittall, Jackie A Cooper, Andrew Hw Neil, et al.. The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clinical Science, 2007, 113 (11), pp.435-441. ⟨10.1042/CS20070150⟩. ⟨hal-00479382⟩