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

ABSTRACT: Nearly all genetic crosses generated from Apoe-/- or Lldlr-/- mice for genetic analysis of atherosclerosis have used C57BL/6 J (B6) mice as one parental strain, thus limiting their mapping power and coverage of allelic diversity. SM/J-Apoe -/- and BALB/cJ-Apoe -/- mice differ significantly in atherosclerosis susceptibility. 224 male F2 mice were generated from the two Apoe -/- strains to perform quantitative trait locus (QTL) analysis of atherosclerosis. F2 mice were fed 5 weeks of Western diet and analyzed for atherosclerotic lesions in the aortic root. Genome-wide scans with 144 informative SNP markers identified a significant locus near 20.2 Mb on chromosome 10 (LOD score: 6.03), named Ath48, and a suggestive locus near 49.5 Mb on chromosome 9 (LOD: 2.29; Ath29) affecting atherosclerotic lesion sizes. Using bioinformatics tools, we prioritized 12 candidate genes for Ath48. Of them, Tnfaip3, an anti-inflammatory gene, is located precisely underneath the linkage peak and contains two non-synonymous SNPs leading to conservative amino acid substitutions. Thus, this study demonstrates the power of forward genetics involving the use of a different susceptible strain and bioinformatics tools in finding atherosclerosis susceptibility genes.

SUBMITTER: Garrett NE

PROVIDER: S-EPMC5374004 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Garrett Norman E NE Grainger Andrew T AT Li Jing J Chen Mei-Hua MH Shi Weibin W

Mammalian genome : official journal of the International Mammalian Genome Society 20170123 3-4

Nearly all genetic crosses generated from Apoe-/- or Lldlr-/- mice for genetic analysis of atherosclerosis have used C57BL/6 J (B6) mice as one parental strain, thus limiting their mapping power and coverage of allelic diversity. SM/J-Apoe -/- and BALB/cJ-Apoe -/- mice differ significantly in atherosclerosis susceptibility. 224 male F2 mice were generated from the two Apoe -/- strains to perform quantitative trait locus (QTL) anal ...[more]

PMID: 28116503

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Project description:ObjectivesCytokines and related molecules in immune-response pathways seem important in deciding the outcome of the host-pathogen interactions towards different polar forms in leprosy. We studied the role of significant and functionally important single-nucleotide polymorphisms (SNPs) in these genes, published independently from our research group, through combined interaction with an additional analysis of the in silico network outcome, to understand how these impact the susceptibility towards the disease, leprosy.DesignThe study was designed to assess an overall combined contribution of significantly associated individual SNPs to reflect on epistatic interactions and their outcome in the form of the disease, leprosy. Furthermore, in silico approach was adopted to carry out protein-protein interaction study between PARK2 and proinflammatory/anti-inflammatory cytokines.SettingPopulation-based case-control study involved the data of North India. Protein-protein interaction networks were constructed using cytoscape.ParticipantsStudy included the data available from 2305 Northern Indians samples (829 patients with leprosy; 1476 healthy controls), generated by our research group.Primary and secondary outcome measuresFor genotype interaction analysis, all possible genotype combinations between selected SNPs were used as an independent variable, using binary logistic regression with the forward likelihood ratio method, keeping the gender as a covariate.ResultsInteraction analysis between PARK2 and significant SNPs of anti-inflammatory/proinflammatory cytokine genes, including BAT1 to BTNL2-DR spanning the HLA (6p21.3) region in a case-control comparison, showed that the combined analysis of: (1) PARK2, tumour necrosis factor (TNF), BTNL2-DR, interleukin (IL)-10, IL-6 and TGFBR2 increased the risk towards leprosy (OR=2.54); (2) PARK2, BAT1, NFKBIL1, LTA, TNF-LTB, IL12B and IL10RB provided increased protection (OR=0.26) in comparison with their individual contribution.ConclusionsEpistatic SNP-SNP interactions involving PARK2 and cytokine genes provide an additive risk towards leprosy susceptibility. Furthermore, in silico protein-protein interaction of PARK2 and important proinflammatory/anti-inflammatory molecules indicate that PARK2 is central to immune regulation, regulating the production of different cytokines on infection.

Dataset Information

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

Publications

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

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