title: Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice.
abstract: BACKGROUND
  Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
  
  
  RESULTS
  In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains Apoa2 gene. Sequencing analysis revealed polymorphisms of Apoa2 in TH mice, suggesting Apoa2 as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs.
  
  
  CONCLUSIONS
  We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in Apoa2 gene are suggested to be responsible for the Chr 1 QTL linked to hypercholesterolemia and hypertriglyceridemia. Further, genetical genomic analysis led to potential candidate genes for the QTLs.
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C, Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Taryn P
authors.initials: TP
authors.lastname: Stewart
authors.forename: Hyoung Yon
authors.initials: HY
authors.lastname: Kim
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Saxton
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics; D001483:Base Sequence; D001786:Blood Glucose / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D016678:Genome / Q000235:genetics*; D055106:Genome-Wide Association Study; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000150:complications / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
chemical_list: D016633:Apolipoprotein A-II; D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; D002784:Cholesterol