Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population

To investigate the dependence of HDL quantitative trait loci (QTL) on sex and diet, we generated a large intercross population of mice from parental strains SM/J and NZB/BlNJ. We measured HDL levels in progeny fed a chow diet and measured them again after 6, 12, and 16 weeks of feeding a high-fat, high-cholesterol diet. QTL analysis was performed on the 260 female and 253 male F 2 progeny. A total of 13 significant QTL were found. Four QTL were specific to female mice: Hdlq23 (Chr 6, 26 cM), Hdlq26 (Chr 10, 70 cM), Hdlq27 (Chr 15, 48 cM), and Hdlq32 (Chr 19, 40 cM). One significant QTL was specific to male mice: Hdlq29 (Chr 17, 36 cM). In addition, several QTL were found to have effects that were dependent on diet. Sexand diet-dependent effects were characterized using a linear model-based genome scan method that avoids the potential pitfalls of subdivided data analysis. The dependence of QTL effects on sex suggests an important role for the sex hormones in HDL regulation. We recommend that sex should be explicitly accounted for in future studies in the genetics of HDL regulation in both mice and humans. —Korstanje, R. , R. Li, T. Howard, P. Kelmenson, J. Marshall, B. Paigen, and G. Churchill. Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J. Lipid Res. 2004. 45: 881–888. Supplementary key words diet • high density lipoprotein • mice • sex In the past decades, much emphasis has been put on elevated LDL levels as a risk factor for atherosclerosis. Drugs that control LDL levels effectively reduce disease risk (1). More recently, researchers are investigating the possibility of reducing atherosclerosis risk by controlling HDL cholesterol levels (2, 3). HDL has a protective effect, and a growing body of evidence suggests that increasing its levels through therapeutic intervention can reduce atherosclerosis risk (4). In order to enable the development of drugs that increase HDL levels, a better understanding is needed of the mechanism of HDL regulation and the genes that are involved. Several genes involved in HDL metabolism have been identified (e.g., Apoa2 , Abca1 ) and have been shown to influence HDL levels when mutated. However, the regulation of HDL levels is complex and additional (unknown) genes are involved. One approach to identify genes involved in HDL regulation is using quantitative trait locus (QTL) analysis in animal models. By crossing inbred strains that significantly differ in HDL levels, and subsequently testing for association between HDL levels and genetic markers in the progeny, many QTL involved in HDL levels have been identified in human, mouse, rat, and rabbit (5–13). A recent review summarized the QTL for HDL that have been found in mouse and human (5). At least 12 murine QTL are located in regions homologous to human QTL, suggesting that the underlying candidate genes may be the same. Several QTL found in mice are found repeatedly in different crosses, suggesting that a limited set of important genes control HDL levels in the mouse. Despite the many studies involving HDL QTL in mice, not much attention has been paid to the differences that we observe between males and females and between different diets. Mouse inbred strains NZB/BlNJ (NZB) and SM/J (SM) differ in their HDL levels [3.63 and 1.42 mmol/l in females and 4.33 and 1.42 mmol/l in males, respectively, according to the Mouse Phenome Database (14)]. Previously, an intercross between these two strains identified a QTL on Chr 1 (92.3 cM) and two QTL, one each on Chr 5 at 62 cM and 72 cM (11). Another study using the same two strains, but in a backcross to NZB, conAbbreviations: apoB, apolipoprotein B; ER, estrogen receptors; QTL, quantitative trait locus; LDLR, LDL receptor; LOD, logarithm of the odds; PLTP, phospholipid transfer protein; SR-BI, scavenger receptor class B type I; VLDLR, VLDL receptor. 1 To whom correspondence should be addressed. e-mail: rkorstan@jax.org Manuscript received 3 November 2003 and in revised form 23 December 2003. Published, JLR Papers in Press, March 1, 2004. DOI 10.1194/jlr.M300460-JLR200 by gest, on July 9, 2018 w w w . j.org D ow nladed fom