Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease: The Veterans Affairs HDL intervention trial

Margaret E. Brousseau, Allison L. Goldkamp, Dorothea Collins, Serkalem Demissie, Allison C. Connolly, L. Adrienne Cupples, Jose M. Ordovas, Hanna E. Bloomfield, Sander J. Robins, and Ernst J. Schaefer

Lipid Metabolism Laboratory, JM-USDA-HNRCA at Tufts University, Boston, MA 02111

Corresponding Author: margaret.brousseau{at}tufts.edu

Objective Our goal was to examine the relationships between variation at the lipoprotein lipase (LPL) gene locus, plasma lipoprotein levels, and coronary heart disease (CHD) risk in men from the Veterans Affairs HDL Intervention Trial (VA-HIT). Methods We determined the frequencies of 3 LPL polymorphisms (D9N, N291S, and S447X) in 899 men with CHD and low HDL-C (=40 mg/dL) from VA-HIT and compared them with those of men without CHD from the Framingham Offspring Study (FOS), who were classified as having an HDL-C level of =40 or >40 mg/dL. We also tested for associations between each LPL variant, concentrations of plasma lipids and lipoproteins, and CHD endpoints in VA-HIT. Results In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3%, 4.5%, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P=0.06), 1.5% (P<0.01), and 18.2% (P<0.01). The only significant difference observed for the comparison of men in VA-HIT with men in FOS having low HDL-C was the increased frequency of the LPL D9N allele in VA-HIT (5.3% vs. 1.7%, P<0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had significantly lower levels of large LDL (-32%), but significantly higher levels of small, dense LDL (+59%), than did non-carriers. Consequently, mean LDL particle diameter was significantly (P<0.003) smaller in carriers (20.14±0.87 nm) of the LPL N9 allele than in noncarriers (20.63±0.80 nm). Conclusions In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, while the X447 allele is less frequent and 2) the LPL N9 allele is associated with variation in the LDL subclass response to gemfibrozil.

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