title: High-resolution genetic mapping in the diversity outbred mouse population identifies Apobec1 as a candidate gene for atherosclerosis.
abstract: Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia that renders them useful in dissecting the genetic architecture of these complex diseases. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets. An alternative approach is the use of multiparental outbred lines for genetic mapping, such as the Diversity Outbred (DO) mouse panel, which can be more informative than traditional two-parent crosses and can aid in the identification of causal genes and variants associated with QTL. We fed 292 female DO mice either a high-fat, cholesterol-containing (HFCA) diet, to induce atherosclerosis, or a low-fat, high-protein diet for 18 wk and measured plasma lipid levels before and after diet treatment. We measured markers of atherosclerosis in the mice fed the HFCA diet. The mice were genotyped on a medium-density single-nucleotide polymorphism array and founder haplotypes were reconstructed using a hidden Markov model. The reconstructed haplotypes were then used to perform linkage mapping of atherosclerotic lesion size as well as plasma total cholesterol, triglycerides, insulin, and glucose. Among our highly significant QTL we detected a ~100 kb QTL interval for atherosclerosis on Chromosome 6, as well as a 1.4 Mb QTL interval on Chromosome 9 for triglyceride levels at baseline and a coincident 22.2 Mb QTL interval on Chromosome 9 for total cholesterol after dietary treatment. One candidate gene within the Chromosome 6 peak region associated with atherosclerosis is Apobec1, the apolipoprotein B (ApoB) mRNA-editing enzyme, which plays a role in the regulation of ApoB, a critical component of low-density lipoprotein, by editing ApoB mRNA. This study demonstrates the value of the DO population to improve mapping resolution and to aid in the identification of potential therapeutic targets for cardiovascular disease. Using a DO mouse population fed an HFCA diet, we were able to identify an A/J-specific isoform of Apobec1 that contributes to atherosclerosis.
authors.affiliation: Department of Genetics, University of North Carolina Chapel Hill, North Carolina 27599.
authors.forename: Tangi L
authors.initials: TL
authors.lastname: Smallwood
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gatti
authors.affiliation: Nutrition Research Institute, University of North Carolina Kannapolis, North Carolina 28081.
authors.forename: Pamela
authors.initials: P
authors.lastname: Quizon
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington Connecticut 06030.
authors.forename: George M
authors.initials: GM
authors.lastname: Weinstock
authors.affiliation: Department of Genetics, University of North Carolina Chapel Hill, North Carolina 27599.
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Jung
authors.affiliation: Department of Nutrition, University of North Carolina Chapel Hill, North Carolina 27599.
authors.forename: Liyang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Genetics, University of North Carolina Chapel Hill, North Carolina 27599.
authors.forename: Kunjie
authors.initials: K
authors.lastname: Hua
authors.affiliation: Department of Genetics, University of North Carolina Chapel Hill, North Carolina 27599 Department of Nutrition, University of North Carolina Chapel Hill, North Carolina 27599.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pomp
authors.affiliation: Department of Genetics, University of North Carolina Chapel Hill, North Carolina 27599 Nutrition Research Institute, University of North Carolina Kannapolis, North Carolina 28081 Department of Nutrition, University of North Carolina Chapel Hill, North Carolina 27599 bennettb@email.unc.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D002874:Chromosome Mapping; D003564:Cytidine Deaminase / Q000235:genetics*; D059305:Diet, High-Fat; D005260:Female; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D007328:Insulin / Q000097:blood; D008390:Markov Chains; D051379:Mice; D008815:Mice, Inbred Strains; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020033:Protein Isoforms; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase
keywords: MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); atherosclerosis; lipoproteins; multiparental models; multiparental populations; quantitative trait loci