Genetic linkage of hyperglycemia and dyslipidemia in an intercross between BALB/cJ and SM/J Apoe-deficient mouse strains

Abstract

BackgroundIndividuals with dyslipidemia often develop type 2 diabetes, and diabetic patients often have dyslipidemia. It remains to be determined whether there are genetic connections between the 2 disorders.MethodsA female F2 cohort, generated from BALB/cJ (BALB) and SM/J (SM) Apoe-deficient (Apoe−/−) strains, was started on a Western diet at 6 weeks of age and maintained on the diet for 12 weeks. Fasting plasma glucose and lipid levels were measured before and after 12 weeks of Western diet. 144 genetic markers across the entire genome were used for quantitative trait locus (QTL) analysis.ResultsOne significant QTL on chromosome 9, named Bglu17 [26.4 cM, logarithm of odds ratio (LOD): 5.4], and 3 suggestive QTLs were identified for fasting glucose levels. The suggestive QTL near the proximal end of chromosome 9 (2.4 cM, LOD: 3.12) was replicated at both time points and named Bglu16. Bglu17 coincided with a significant QTL for HDL (high-density lipoprotein) and a suggestive QTL for non-HDL cholesterol levels. Plasma glucose levels were inversely correlated with HDL but positively correlated with non-HDL cholesterol levels in F2 mice on either chow or Western diet. A significant correlation between fasting glucose and triglyceride levels was also observed on the Western diet. Haplotype analysis revealed that “lipid genes” Sik3, Apoa1, and Apoc3 were probable candidates for Bglu17.ConclusionsWe have identified multiple QTLs for fasting glucose and lipid levels. The colocalization of QTLs for both phenotypes and the sharing of potential candidate genes demonstrate genetic connections between dyslipidemia and type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0292-y) contains supplementary material, which is available to authorized users.

Mapping and Congenic Dissection of Genetic Loci Contributing to Hyperglycemia and Dyslipidemia in Mice

“…Among them, Ubash3b , Phldb1 , Sorl1 , Sik3 , and Apoa1 have been shown to be associated with variations in total, HDL cholesterol or triglyceride levels in humans ( http://www.ebi.ac.uk/gwas/home ). Linkage close to this locus has also been detected in a female intercross derived from BALB and SM Apoe -/- mice but BALB alleles were associated with to reduced HDL levels [ 42 ]. The opposite allelic effect on HDL in the male vs. female crosses suggests that two or more genes in this region contributed to the trait.…”

Genetic analysis of a mouse cross implicates an anti-inflammatory gene in control of atherosclerosis susceptibility

“…QTL analysis was performed using J/qtl and Map Manager QTX software as previously reported (Grainger et al 2016)(Shi et al 2016),(Wang et al 2015). LOD threshold values for significant and suggestive linkage were determined through 1000 permutations of the achieved data, which are provided in supplementary materials.…”

Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice

“…The creation of a female F 2 cohort from the two Apoe –/– strains was recently described [12]. The animals were weaned at 3 weeks of age, and at 6 weeks of age switched onto a Western diet.…”

“…F 2 mice were genotyped using the Illumina LD linkage panel, as reported [12]. Microsatellite markers were typed by PCR for regions of chromosome 8 that were not covered by informative SNP markers.…”

“…QTL analysis was performed using J/qtl and MapManager QTX software, as reported [12]. LOD threshold values were determined from 1000 permutations of the observed data, which are provided in Data-in-Brief.…”