Localization of genes for V+LDL plasma cholesterol levels on two diets in the opossum Monodelphis domestica

Madhuri Jasti,Kory C. Douglas,Candace M. Kammerer,David L. Rainwater,Paul B. Samollow,John L. VandeBerg,Nicolas Gouin,Prasanth Ganta,Amy S. Dressen

doi:10.1194/jlr.m005686

Abstract

Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.

Highlights

Plasma cholesterol levels among individuals vary considerably in response to diet
We previously reported evidence that plasma levels of HDL cholesterol and V+LDL cholesterol on the basal and HCHF diets are under the control of quantitative trait loci (QTLs) that account for a large proportion of the variation in HDL and V+LDL cholesterol in our population of animals [13]
Mean (±SD) HDL and V+LDL cholesterol levels were 1.29 ± 0.23 mmol/l and 0.5 ± 0.19 mmol/l, respectively; whereas after 8 weeks on the HCHF diet, they increased to 1.83 ± 0.56 mmol/l and 11.11 ± 12.7 mmol/l, respectively (Table 1)

Summary

Introduction

Plasma cholesterol levels among individuals vary considerably in response to diet. the genes that influence this response are largely unknown. Org), as well as high-throughput genotyping methods, recent genome-wide association analyses of large studies comprising ‫ف‬20,000 individuals have revealed additional genes that influence plasma lipoprotein levels, especially plasma HDL and LDL cholesterol levels [e.g., [4, 5]]. Taken together, these common genetic variants only account for a small proportion of the known heritable variation in HDL and LDL plasma cholesterol levels, resulting in a phenomenon referred to as the “missing heritability” [6]. Journal of Lipid Research Volume 51, 2010 2929 by-diet effects on lipid levels have been performed [8], results have been inconsistent, most likely due to relatively small sample sizes or difficulties in measuring dietary components in human populations

Methods

Results

Conclusion