A Common Promoter Polymorphism in the Hepatic Lipase Gene (LIPC-480C>T) Is Associated With an Increase in Coronary Calcification in Type 1 Diabetes

Abstract

Type 1 diabetes is associated with coronary heart disease (CHD) and coronary artery calcification (CAC), a measure of subclinical CHD. The hepatic lipase gene promoter polymorphism (LIPC-480C>T) is a common variant affecting lipid metabolism. This study examined the relation between the LIPC-480C>T and CAC in type 1 diabetes. In the type 1 diabetic patients studied, 56% had CAC >0 Agatston units (AU). These subjects had a longer duration of diabetes (26.2 ؎ 1.3 vs. 17.8 ؎ 1.4 years; P < 0.001), lower HDL cholesterol levels (55.7 ؎ 2.4 vs. 61.0 ؎ 2.5 mg/dl; P ‫؍‬ 0.05), higher triglyceride levels (101 ؎ 17.3 vs. 66 ؎ 7.6 mg/dl; P < 0.05), and higher diastolic blood pressure (79.7 ؎ 1.0 vs. 76.0 ؎ 1.4 mmHg; P < 0.05). The LIPC-480 T allele was more common in subjects with CAC (frequency ‫؍‬ 0.31 ؎ 0.05 vs. 0.14 ؎ 0.04; P ‫؍‬ 0.006). The proportion with CAC was 44% in LIPC-480CC subjects, 71% in heterozygotes, and 83% in LIPC-480TT subjects (P < 0.01). LIPC-480 T allele frequency increased as the amount of CAC increased (P ‫؍‬ 0.007). LIPC-480 genotype was independently associated with the CAC (odds ratio ‫؍‬ 2.90, 95% CI 1.22-6.92, P < 0.05) after adjusting for duration of diabetes, age, sex, diastolic blood pressure, HDL cholesterol, and triglyceride levels. In conclusion, the LIPC-480C>T polymorphism was associated with subclinical CHD in type 1 diabetes. This genetic variant may identify subjects in which early intervention to prevent CHD may be appropriate.

Genetic variation in the hepatic lipase gene and the risk of coronary heart disease among US diabetic men: potential interaction with obesity

“…The extent of coronary atherosclerosis determined by angiography was reported to be higher in participants with the T allele [27]. The LIPC −514 T allele was also reported to be associated with a decrease in coronary flow reserve [28] and the presence of subclinical CHD [26]. In contrast, no association of the LIPC C(−514)T polymorphism with the risk for CHD or coronary artery disease was observed in a study of Finnish men [20].…”

“…While several studies suggested a pro-atherogenic role of this polymorphism [24,[26][27][28][29][30][31], others reported no association or even an inverse association with CHD risk [20,[32][33][34]. For instance, in a Danish cohort, participants with the TT genotype were observed to have a 1.5-fold (95% CI 1.0, 2.2) increased risk of ischaemic heart disease compared with those with the CC genotype [29].…”

“…Findings from several studies suggested a pro-atherogenic role of this polymorphism [24,[26][27][28][29][30][31]. The LIPC C(−514)T polymorphism was associated with reduced coronary flow reserve (an early marker of atherosclerosis) [28], coronary artery calcification [26] and increased risk of CHD [27,[29][30][31].…”

Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis

“…8 -14 In humans, low hepatic lipase activity has been associated with increased risk of CAD. [15][16][17][18] Furthermore, premature CAD has been reported in patients with complete hepatic lipase deficiency, 19 although the manner in which these very few individuals have been identified raises the issue of ascertainment bias. Other studies have concluded that decreased hepatic lipase activity does not influence susceptibility to CAD.…”

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes

“…While chronic hyperglycaemia [3,4] and insulin resistance [5,6] partially explain this excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes [7][8][9][10].…”