Candidate genes for plasma triglyceride, FFA, and glucose revealed from an intercross between inbred mouse strains NZB/B1NJ and NZW/LacJ*

Abstract

To identify the genes controlling plasma concentrations of triglycerides (TGs), FFAs, and glucose, we carried out a quantitative trait loci (QTL) analysis of the closely related mouse strains New Zealand Black (NZB/ B1NJ) and New Zealand White (NZW/LacJ), which share 63% of their genomes. The NZB 3 NZW F 2 progeny were genotyped and phenotyped to detect QTL, and then comparative genomics, bioinformatics, and sequencing were used to narrow the QTL and reduce the number of candidate genes. Triglyceride concentrations were linked to loci on chromosomes (Chr) 4, 7, 8, 10, and 18. FFA concentrations were affected by a significant locus on Chr 4, a suggestive locus on Chr 16, and two interacting loci on Chr 2 and 15. Plasma glucose concentrations were affected by QTL on Chr 2,4,7,8,10,15,17,and 18. Comparative genomics narrowed the QTL by 31% to 86%; haplotype analysis was usually able to further narrow it by 80%. We suggest several candidate genes: Gba2 on Chr 4, Irs2 on Chr 8, and Ppargc1b on Chr 18 for TG; A2bp1 on Chr 16 for FFA; and G6pc2 on Chr 2 and Timp3 on Chr 10 for glucose. During lipolysis, triglycerides (TGs) are broken down into FFAs and glycerol by the lipolytic enzymes (1). Several lines of evidence have shown the association of plasma FFA with the development of insulin resistance and type 2 diabetes (2). First, elevated FFA could alter glucose metabolism by affecting access to insulin-sensitive cells (adipose and muscle), as well as by reducing glucose transport into muscle (3). Second, chronically elevated FFA may also impair insulin secretory function through toxic effects on pancreatic b-cells, as predicted by the "lipotoxicity hypothesis" (4). Finally, increased flux of FFA into the liver, particularly from lipolysis of visceral adipose depots, may lead to excessive endogenous glucose production (5).The levels of plasma lipids and glucose are partially genetically determined, and these determinants involve multiple genes (6, 7). Because of inherent difficulties in carrying out linkage analyses for complex traits in humans, inbred strains of mice have been used as a powerful tool for identifying quantitative trait loci (QTL) that contribute to variations in circulating levels of lipids and glucose (7-9). Studies in mice not only have revealed a large number of QTL that regulate lipid levels but also have shown that there is a high degree of concordance with human QTL that regulate the same traits (7). However, only a few QTL genes that regulate lipids or glucose have so far been identified.Usually one chooses to intercross mouse strains that maximize the difference in both phenotype and genotype. However, the advent of thousands of single-nucleotide polymorphisms (SNPs) has enhanced the ability to genotypically distinguish even closely related strains. By intercrossing closely related strains that nevertheless differ in phenotype, one might enhance the probability of finding QTL and even causative genes, because the complexity of the system is reduced. For this reason, we crossed the clos...

Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes

“…These two strains are alike for 63.2% of their genome ( 17 ). At the Hdlq1 QTL, the SNP pattern surrounding the locus and the QTL gene Scarb1 is identical between NZB and NZW; at the Hdlq8 QTL, the SNP pattern is different.…”

Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice

“…rqtl.rog). As described previously (6,8), a three-step QTL analysis was conducted to search first for main effects, second for pair-wise gene interactions, and finally to integrate all main and interacting QTL phenotype associations into a multiple regression. In single locus scans, the sex was first included as an additive covariate in the genome scan to account for overall differences in phenotypes between the sexes.…”

“…A genome wide scan using 508 single-nucleotide polymorphisms (SNPs) identified 19 QTL, 2 of which were male specific and 2 were female specific. Using comparative genomics and haplotype analysis, we narrowed QTL on chromosomes 3,5,8,17, and 18 to 0.5, 6.3, 2.6, 1.1, and 0.6 Mb, respectively. These data will serve as a reference for any effort to test the impact of candidate genes on HDL using a knockout strategy.-Su, Z., X. Wang, S-W. Tsaih, A. Zhang, A. Cox, S. Sheehan, and B. Paigen.…”

Confirmation of Diabetes-Related Quantitative Trait Loci Derived from SM/J and A/J Mice by Using Congenic Strains Fed a High-Carbohydrate or High-Fat Diet

“…Nidd2, a QTL for free-fed blood glucose concentrations, was mapped at D18Mit60 (32.6 Mb) using (NZOϫ NON)F2 mice (16) fed an HC diet similar to that used in the present study, i.e., a diet containing 51.5% carbohydrates, 4.5% fat, and 21% protein. Bglu10, another QTL for blood glucose concentrations, was mapped at 33 Mb using (NZBϫNZW)F2 mice (17) fed an atherogenic diet. At present, it remains unclear whether or not these phenotypes are induced by a distinct diabetogenic gene.…”