Clin Genet 1999: 55: 450–454 Printed in Ireland. All rights resered Short Report A common truncation variant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study Gagne ´ SE, Larson MG, Pimstone SN, Schaefer EJ, Kastelein JJP, Wilson PWF, Ordovas JM, Hayden MR. A common truncation vari- ant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study. Clin Genet 1999: 55: 450–454. © Munksgaard, 1999 Genetic variation at the lipoprotein lipase (LPL) locus has been shown to influence plasma lipids and to modulate risk of coronary heart dis- ease (CHD). Recently, we found that the most frequent variant at this locus, involving a C-terminal truncation of two amino acids (Ser447X), was associated with both higher LPL activity and high density lipo- protein cholesterol (HDL-C) in patients with CHD. However, the im- pact of this S447X variant on lipids and CHD in the general population was hitherto unknown. We, therefore, analyzed a total of 1114 men and 1144 women randomly ascertained from the Framing- ham Offspring Study (FOS) for the presence of this LPL variant. Car- rier frequency of the S447X allele was 17%, and in men carrier status was associated with higher total cholesterol ( =6.2 mg/dl, p =0.03), higher HDL-C ( =2.3 mg/dl, p =0.01), and lower triglyceride (TG) levels ( =-19.4 mg/dl, p =0.02). Moreover, in men, the S447X allele conferred significant protection against CHD (odds ratio: 0.43; p = 0.04). These effects on lipids and CHD were not seen in women. Our study represents the first report on the impact of this mutation on CHD in men from the general population, and we conclude, therefore, that the S447X variant may confer significant protection against high TG levels, low HDL-C, and premature CHD in these subjects. SE Gagne ´ a , MG Larson b , SN Pimstone a , EJ Schaefer d , JJP Kastelein e , PWF Wilson c , JM Ordovas d and MR Hayden a a Department of Medical Genetics, University of British Columbia, Vancouver, Canada, b Framingham Heart Study, Boston University, Framingham, c Framingham Heart Study, National Heart, Lung and Blood Institute, d Lipid Metabolism Laboratory, US Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA, e Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Key words: coronary heart disease – gene – lipoprotein lipase – polymorphisms Corresponding author: Dr Michael R Hayden, Center for Molecular Medicine and Therapeutics, 980 West 28th Avenue, Van- couver, BC V5Z 4H4, Canada. Fax: +1 604 875 3819; e-mail: mrh@cmmt.ubc.ca Received 25 February 1999, revised and accepted for publication 25 March 1999 Evidence from twin studies indicates that genetic factors play a major role in susceptibility to atherosclerosis (1). Genetic variation in lipoprotein levels primarily manifests as elevated low density lipoprotein cholesterol (LDL-C) and decreased high density lipoprotein cholesterol (HDL-C), both asso- ciated with an increased risk for atherosclerotic vascular disease (2, 3). In addition, it is now also accepted that increased levels of plasma triglyce- rides (TGs) constitute a risk factor for coronary heart disease (CHD) (4). Lipoprotein lipase (LPL) as a pivotal enzyme in lipoprotein metabolism is a recognized determinant of both plasma TG and HDL-C levels, and therefore represents an impor- tant candidate for atherogenesis (5). We, and others, have reported that three com- mon variants in the gene for LPL, N291S, D9N, and S447X (premature truncation at codon 447) are associated with altered levels of both TG and HDL-C (6–11). We have specifically shown that the N291S variant leads to a decrease in HDL levels in CHD patients (6), while the D9N variant is associated with higher TG levels and leads to more rapid progression of coronary atherosclerosis (9). In contrast, we have shown that the Ser447X variant, occurring at a high frequency in Cau- casians, is associated with lower TG and higher HDL-C levels in both normolipidemic men and CHD patients (10, 11). 450