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The –250G>A Promoter Variant in Hepatic Lipase Associates with Elevated Fasting Serum High-Density Lipoprotein Cholesterol Modulated by Interaction with Physical Activity in a Study of 16,156 Danish Subjects

Steno Diabetes Center (N.G., C.H.A., M.K.A., K.B.-J., T.H., O.P.), 2820 Gentofte, Denmark; Department of Medicine (M.K.A.), University of Helsinki and Helsinki University Central Hospital, FIN-00290 Helsinki, Finland; Department of Biostatistics (A.A.), University of Copenhagen, DK-1017 Copenhagen, Denmark; Departments of General Practice (A.S., T.L.) and Clinical Pharmacology (O.S.), and Faculty of Health Sciences (K.B-J., O.P.), University of Aarhus, DK-8000 Aarhus, Denmark; Research Centre for Prevention and Health (K.B.-J., T.J.), Glostrup University Hospital, DK-2600 Glostrup, Denmark; and Department of Endocrinology and Diabetes (O.S.), Aarhus University Hospital, DK 8200 Aarhus, Denmark

Address all correspondence and requests for reprints to: Niels Grarup, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte, Denmark. E-mail: ngrp{at}steno.dk.

Context: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein.

Objectives: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study.

Design: The LIPC –250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360).

Results: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039–0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10^–10) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024–0.053); P = 2 x 10^–7). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P_interaction = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22–0.37) increase in HDL-c compared with homozygous G-allele carriers.

Conclusions: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the –250 A allele. This interaction may have potential implications for public health and disease prevention.