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.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.
Grarup
Niels
N
Steno Diabetes Center, Niels Steensens Vej 1, Gentofte, Denmark. ngrp@steno.dk
Andreasen
Camilla H
CH
Andersen
Mette K
MK
Albrechtsen
Anders
A
Sandbaek
Annelli
A
Lauritzen
Torsten
T
Borch-Johnsen
Knut
K
Jørgensen
Torben
T
Schmitz
Ole
O
Hansen
Torben
T
Pedersen
Oluf
O
D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting / Q000097:blood*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics*; D009043:Motor Activity / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
D008076:Cholesterol, HDL; C504173:LIPC protein, human; D008049:Lipase