Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice

Alkaissi, Hammoudi; Ekstrand, Jimmy; Jawad, Aksa; Nielsen, Jesper Bo; Havarinasab, Said; Söderkvist, Peter; Hultman, Per

doi:10.1289/ehp.1409284

Cited by 8 publications

(4 citation statements)

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“…For each sample, 20 ng of genomic DNA was mixed with the Extract-N-Amp PCR reaction mix (Sigma-Aldrich), and 30 cycles of amplification were performed in a thermal cycler (Thermo Fisher), with a temperature profile as follows: denaturation at 94°C for 30 s, annealing at 61°C for 60 s, and extension at 72 C for 90 s. PCR products were run on 4% agarose gel for 1.5 hours at 70 Volts. Haplotypes were identified by comparing the genotypes of F2 mice with the genotypes of A.SW and B10.S mice [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

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Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development

et al. 2018

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Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9, Il6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, Il6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkb1 (produced in most immune cells) as key regulators of ANoA development in HgIA.

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Section: Methodsmentioning

confidence: 99%

“…The geometric means of Gapdh and Ppia in each group were used as endogenous controls. The results are presented as relative transcription levels determined by the comparative 2 –ΔΔCt method [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development

et al. 2018

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“…These tandem repeats are found throughout the genome composed of di-, tri-, tetra-or bigger repeats (Fig 2). Genes are co-segregated with the highly polymorphic microsatellites, which make them useful markers for mapping studies [38][39][40][41]. SNPs occur naturally in the human population and is a variation of a single nucleotide replaced with different nucleotide.…”

Section: Genome Wide Association Studymentioning

confidence: 99%

“…Alkaissi et al 2016 discovered Pprc1 as key regulator in the excretion of Hg from the kidney by GWAS and fine mapping on QTL. Pprc1 and two genes Nrf1 and Nrf2coactivated by Pprc1 had significantly lower gene expression in the strain that accumulated more Hg in the kidney[38].Elucidate genomic factors responsible for differences in mercury induced autoimmunity (HgIA) and excretion of mercury (Hg) from the body.Phenotype and genotype data is required in order to perform a GWAS. The main phenotypic data were autoimmune parameters triggered by Hg in a F2 mouse generation by crossing two susceptible strains A.SW (H-2 s ) and B10.S (H-2 s ).…”

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Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity

Alkaissi¹

2018

Linköping University Medical Dissertations

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BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well-established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg. OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion. METHODS: MHC II (H-2 s) mice were paired (A.SW x B10.S) to achieve F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Petra Cassel, thank you for being there whenever I needed help. I know that there were many things that had nothing to do with you, but you still helped me and I appreciate that a lot. I sit in the corridor were no one else sits (except for when Said and students were there). So you and Camilla Janefjord were my daily colleagues I met every day and more or less the first that I said hi/good morning to. In some way, when I think of AIR, I actually think of you. You are the ones that represents it, how does that feel? . Sandra Hellberg, You are a very smart and kind person. We have always bumped in to each other in different occasions: being host in PhD party or being base group tutors together. You always take initiativ...

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In silico mapping of quantitative trait loci (QTL) regulating the milk ionome in mice identifies a milk iron locus on chromosome 1

Hadsell

Rijnkels

et al. 2018

Mamm Genome

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The breast-feeding neonate depends on mother's milk for both macronutrients and micronutrients including minerals. The goals of the present study were to document the effects of genetic background in mice on milk concentrations of select minerals and to use genome-wide association study (GWAS) to identify quantitative trait loci (QTL) regulating milk mineral concentrations. Milk samples from lactating mice in each of 31 different inbred strains of the mouse diversity panel (MDP) were analyzed by inductively coupled plasma-optical emission spectroscopy to determine the concentrations of calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), sodium (Na), phosphorus (P), sulfur (S), and zinc (Zn). GWAS identified a single pleiotropic milk mineral concentration QTL (Mmcq) on chromosome 3 for Ca, Mg, and P. For the remaining minerals, six QTL were detected for Fe, four for K, three for Zn, and one for S. Intersecting the Mmcq with published chromatin immunoprecipitation sequence data identified 15 out of 4633 high-linkage disequilibrium single-nucleotide polymorphisms that resided in signal transducer and activation of transcription 5 (STAT5) binding regions. A milk Fe-associated locus (Mmcq9) on chromosome 1 contained an SNP that localized to a STAT5 binding region and intersected with a HOMER motif predicted to bind the transcriptional regulator E74-Like ETS transcription factor 5. This locus also contained the genes for solute carrier family (Slc) members Slc9a2, Slc9a4, Slc39a10, and Slc40a1. Expression analysis of these transporters supports the conclusion that Slc9a2 and Slc40a1 within the mammary gland could mediate the effect of Mmcq9 on milk Fe concentration.

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Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice

Cited by 8 publications

References 47 publications

Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development

Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development

Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity

In silico mapping of quantitative trait loci (QTL) regulating the milk ionome in mice identifies a milk iron locus on chromosome 1

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