Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).

Hum Mutat. 2002 May;19(5):536-42.

Sources of variability in genetic association studies: insights from the analysis
of hepatic lipase (LIPC).

Shohet RV, Vega GL, Bersot TP, Mahley RW, Grundy SM, Guerra R, Cohen JC.

Internal Medicine, University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas, USA.

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 approximately 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). Copyright 2002
Wiley-Liss, Inc.