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

Objective: To investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Since behavioral factors influence HL 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=6,070), the ADDITION Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n=8,662) and in additional type 2 diabetic patients (n=1,064) and glucose-tolerant control subjects (n=360).

Result: In the Inter 99 study the A-allele of rs2070895 associated with a 0.057 (95% CI 0.039–0.075) mmol/l increase in fasting serum HDL-cholesterol (HDL-c) (P=8x10^-10) supported by association in the ADDITION study (0.038 [95% CI 0.024–0.053] mmol/l per allele; P=2x10^-7). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P_interaction=0.002) since vigorous physically active homozygous A-allele carriers had a 0.30 (95% CI 0.22–0.37) mmol/l increase in HDL-c compared to homozygous G-allele carriers.

Conclusion: In conclusion, 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.