Abstract 2739: The Proprotein Convertase Subtilisin-kexin Type 9 (PCSK9) R46L Variant Is Associated With Reduced Serum Low-density Lipoprotein Cholesterol In The Italian Population
Mutations in the proprotein convertase subtilisin-kexin type 9 (PCSK9) gene have been associated with reduced plasma levels of low-density lipoprotein (LDL) and total cholesterol, and with lower coronary heart disease (CHD) risk. In particular, the R46L variation has been associated with a reduction of LDL cholesterol (LDL-C) of 15% and a 47% reduction in the risk of CHD in white Americans. We investigated the association of the R46L variation with the risk of myocardial infarction (MI) in 1883 Italian patients who suffered from an MI event before the age of 45, and an equal number of healthy controls. All subjects were unrelated; cases and controls were matched for sex (1667 males and 216 females) and age (mean ± SD in cases: 39.6 ± 4.9 years). The R46L variation was hence genotyped using an in-house developed Taqman assay. The genotypic distributions of R46L were in Hardy-Weinberg equilibrium in both groups. Frequency of the L46 allele was 0.010 in cases (38 carriers) and 0.014 in controls (53 carriers, 1 homozygous) (OR 0.69, 95%CI 0.56 – 0.85, p=0.089). A clear trend towards a ``protective” effect of the L46 allele was observed, even though the association with lower MI risk did not reach statistical significance. This is probably due to the combined effect of the young age of the analyzed cohort (for whom the impact of coronary atherosclerosis is known to be less important) and of the low frequency of R46L in the Italian population. Most importantly, LDL-C resulted significantly lower in L46 carriers (117.5 ± 35 mg/dl) than in non-carriers (137.4 ± 47.4 mg/dl; p=0.00071), and a similar reduction in total cholesterol was also observed (192.3 ± 37.8 in carriers vs 211.9 ± 49 mg/dl in non-carriers). In conclusion, our study shows that the R46L variation in PCSK9 is significantly associated with lower plasma levels of LDL-C (14.5% reduction) also in the Italian population.