Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers

Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysi s of triglyceride (TG)-rich particles, may contribute to ischaemic heart di sease (IHD) risk. We have examined the risk of IHD in carriers of two commo n LPL variants, asparagine substitution for aspartic acid at residue 9 (D9N ) and serine for asparagine at residue 291 (N291S) in 2708 middle-aged heal thy European men, followed for over 6 years. The carrier frequencies were 2 .6% for N9, and 3.9% for S291. Both variants were associated with higher pl asma TG at baseline of 9% and 14%, respectively. At baseline, 28% of men we re current smokers and smoking was unrelated to genotype. Associations betw een LPL variants and disease outcome, according to smoking status, were ass essed by Cox's proportional hazards analysis. S291 carriers showed no incre ased risk of IHD compared to non-carriers, while there was strong evidence of interaction between D9N genotype and smoking status (P = 0.0003) in dete rmining the risk of IHD. In 2248 non-carriers of N9, smoking increased the risk of an II-ID event by 1.6 (95% CI: 1.1-2.4%) times. Among 58 N9 carrier s, no IHD events occurred in 42 who were non-smokers, whereas five events w ere reported in 16 who smoked. The combined effect of smoking and N9 allele was to increase the risk of an IHD event by 10.4 (95% CI: 4.7-22.8%) times compared with D9 non-smokers. These findings could not be explained by con founding effects of baseline TG. Carriers of N9 appear to be especially vul nerable to the adverse effects of cigarette smoking on IHD risk, but this s usceptibility is unrelated to the influence of this variant on plasma TG le vels. (C) 2000 Elsevier Science Ireland Ltd. Ail rights reserved.