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Sources of variability in genetic association studies: Insights from the analysis of hepatic lipase (LIPC)
Author(s) -
Shohet Ralph V.,
Vega Gloria L.,
Bersot Thomas P.,
Mahley Robert W.,
Grundy Scott M.,
Guerra Rudy,
Cohen Jonathan C.
Publication year - 2002
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10079
Subject(s) - hepatic lipase , biology , linkage disequilibrium , genetic association , lipoprotein lipase , allele , medicine , population , genotype , genetics , endocrinology , triglyceride , single nucleotide polymorphism , gene , cholesterol , demography , adipose tissue , sociology
Abstract Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population‐specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype–phenotype association. We have examined two possible sources of variability in the association between the –514 polymorphism in hepatic lipase (LIPC) and plasma HDL‐C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the –514C allele was associated with a 10 mmol.hr –1 .l –1 increase in hepatic lipase activity in white American and Turkish men but only ∼5 mmol.hr –1 .l –1 in Chinese and African‐American men. Second, we tested the effects of a stanozolol‐induced increase in hepatic lipase activity on plasma HDL‐C concentrations in men with normal (< 150mg/dl) or elevated (150–300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL‐C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (‐1596insC, ‐2740A>G, and ‐2880G>C). Hum Mutat 19:536–542, 2002. © 2002 Wiley‐Liss, Inc.