J.A. Thorn

DNA polymorphisms at the lipoprotein lipase gene: associations in normal and hypertriglyceridaemic subjects

Lipoprotein lipase is a rate determining enzyme for the removal of triglyceride-rich lipoproteins from the blood stream. We examined whether genetic variation at the lipoprotein lipase gene locus was related to the fasting plasma level of triglycerides in both a normal and hypertriglyceridaemic population. Two restriction fragment length polymorphisms revealed by the enzymes PvuII and HindIII generated alleles designated H1, 17.5 kb;H2, 8.7 kb;P1, 7.0 kb;P2, 4.4 and 2.5 kb, respectively. These were studied in 46 Caucasian hypertriglyceridaemic subjects in comparison with 86 normolipidaemic controls. The respective allelic frequencies were H1 0.211, H2 0.789 and H1 0.414, H2 0.586 (p less than 0.01). Similar differences in allelic frequencies were found in a smaller group of Japanese hypertriglyceridaemic subjects (n = 29) compared to Japanese controls (n = 41, p less than 0.01). Ninety-three healthy Caucasians were genotyped for both polymorphic sites to relate to levels of plasma triglyceride. We found that individuals with genotype P1P1 had fasting triglyceride levels of 0.96 +/- 0.31 mmol/l (n = 20) compared to genotype P2P2 with levels of 1.31 +/- 0.66 mmol/l (n = 30, p less than 0.02); heterozygous subjects (P1P2) had intermediate levels of plasma triglyceride (1.15 +/- 0.46 mmol/l, n = 43). The HindIII alleles were not significantly associated with variation in levels of plasma triglyceride, cholesterol, or HDL-cholesterol. We conclude that DNA variations at, or around, the lipoprotein lipase gene may constitute genetic determinants for both the population variation in plasma triglyceride levels as well as for the common metabolic disorder of primary hypertriglyceridaemia.

Lipoprotein and hepatic lipase gene variants in coronary atherosclerosis

Lipoprotein lipase is the rate determining enzyme for the removal of triglyceride rich lipoproteins from the blood stream. We examined whether genetic variation at the lipoprotein lipase gene locus is related to the occurrence of premature coronary artery disease. Two restriction fragment length polymorphisms, revealed by the enzymes HindIII and PvuII, demonstrated alleles designated H1 (17.5 kb), H2 (8.7 kb), P1 (7.0 kb), P2 (4.4 kb and 2.5 kb) respectively. These were studied in 70 Caucasian subjects with severe coronary atherosclerosis in comparison with 122 Caucasian healthy controls. The allelic frequencies for cases and controls were respectively: H2 0.770, 0.579 (P less than 0.001); P2 0.575, 0.554 (P NS). The allelic frequencies of the HindIII and BglII polymorphic sites at the hepatic lipase gene locus were also studied in the same groups of subjects. These showed no differences between cases and controls. We conclude that DNA variation at or adjacent to the lipoprotein lipase gene may contain genetic determinants for the occurrence of premature coronary artery disease.

The Ser447–Ter mutation of the lipoprotein lipase gene relates to variability of serum lipid and lipoprotein levels in monozygotic twins

Studies on monozygotic twins support a role for genetic determinants of plasma lipid, lipoprotein, and apolipoprotein levels. Gene variants of the enzyme lipoprotein lipase have been shown to associate with dyslipidemia and coronary artery disease. We assessed the gene-environment interaction by investigating the relationship between the lipoprotein lipase gene and plasma lipid, lipoprotein, and apolipoprotein variability and levels among 54 male monozygotic twin pairs (aged 18-28 years). The Ser447-Ter mutation (C-->G transversion) was associated with significantly smaller within-pair differences in plasma high density lipoprotein-cholesterol (CG [n = 10] vs. CC [n = 44], 3.7+/-5.3 mg/dl vs. 6.4+/-5.2 mg/dl, P < 0.03) and total cholesterol (CG [n = 10] vs. CC [n = 44], 7.9+/-9.4 mg/dl vs. 15.8+/-12.7 mg/dl, P < 0.05), indicating attenuated variability in response to environmental stimuli. This observation of a restrictive variability gene effect further supports a role for the lipoprotein lipase gene in the genetic regulation of lipids and lipoproteins and suggests that the Ser447-Ter mutation exerts multiple effects. This study also raises the possibility of a genetically determined responsiveness to dyslipidemia therapies.

Genetic Variation at the Lipoprotein Lipase Gene Associates with Coronary Arteriosclerosis

The aggregation of coronary artery disease (CAD) within families is well established 14,13,10 and concordance rates for the disease are known to be higher in mono -than dizygotic twins, 2,3.