Publications by authors named "William E Ollier"

132 Publications

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis.

Commun Biol 2021 03 26;4(1):419. Epub 2021 Mar 26.

Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.
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http://dx.doi.org/10.1038/s42003-021-01932-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997983PMC
March 2021

Antibodies against immunogenic epitopes with high sequence identity to SARS-CoV-2 in patients with autoimmune dermatomyositis.

Ann Rheum Dis 2020 10 22;79(10):1383-1386. Epub 2020 May 22.

Division of Population Health, Health Services Research and Primary Care, The University of Manchester, Manchester, Manchester, UK

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http://dx.doi.org/10.1136/annrheumdis-2020-217522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509518PMC
October 2020

Increasing incidence of adult idiopathic inflammatory myopathies in the City of Salford, UK: a 10-year epidemiological study.

Rheumatol Adv Pract 2018 17;2(2):rky035. Epub 2018 Sep 17.

Rheumatology Department, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford.

Objectives: The aim was to identify and characterize all incident adult cases of idiopathic inflammatory myopathies (IIM) between 1 January 2007 and 31 December 2016 in the City of Salford, UK.

Methods: Adults first diagnosed with IIM within the study period were identified by: a Salford Royal NHS Foundation Trust (SRFT) inpatient episode IIM-specific ICD-10 coding search; all new patient appointments to SRFT neuromuscular outpatient clinics; and all Salford residents enrolled within the UKMYONET study. All patients with definite IIM by the 2017 EULAR/ACR classification criteria were included, as were probable cases if consensus expert opinion agreed. Cases were excluded if <18 years of age at disease onset, if they did not meet probable criteria or when probable but expert opinion concluded a non-IIM diagnosis.

Results: The multimodal case ascertainment identified 1156 cases which, after review and application of exclusion criteria, resulted in 32 incident cases during the study period. Twenty-three of 32 were female, with a mean age of 58.1 years. The mean incidence of adult IIM was 17.6/1 000 000 person years, and higher for females than for males (25.2 10.0/1 000 000 person years, respectively). A significant incidence increase over time was apparent (13.6 21.4/1 000 000 person years;  = 0.032). Using EULAR/ACR classification criteria, the largest IIM subtype (21/32) was PM, followed by DM (8/32), IBM (2/32) and amyopathic DM (1/32). Expert opinion subtype differed from EULAR/ACR classification criteria in 19/32 cases.

Conclusion: The incidence of adult IIM in Salford is 17.6/1 000 000 person years, higher in females, and is increasing over time. Disagreement exists between EULAR/ACR-derived and expert opinion-derived IIM subtype assignments.
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http://dx.doi.org/10.1093/rap/rky035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649983PMC
September 2018

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.

Ann Rheum Dis 2019 07 28;78(7):996-1002. Epub 2019 May 28.

Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.

Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.

Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 and HLA-DRB1*03:01, p=3.25×10), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10) and position 9 of HLA-B (p=7.03×10). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.

Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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http://dx.doi.org/10.1136/annrheumdis-2019-215046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585280PMC
July 2019

The temporal relationship between cancer and adult onset anti-transcriptional intermediary factor 1 antibody-positive dermatomyositis.

Rheumatology (Oxford) 2019 04;58(4):650-655

Centre for Musculoskeletal Research, University of Manchester, Manchester.

Objectives: To characterize the 10 year relationship between anti-transcriptional intermediary factor 1 antibody (anti-TIF1-Ab) positivity and cancer onset in a large UK-based adult DM cohort.

Methods: Data from anti-TIF1-Ab-positive/-negative adults with verified diagnoses of DM from the UK Myositis Network register were analysed. Each patient was followed up until they developed cancer. Kaplan-Meier methods and Cox proportional hazard modelling were employed to estimate the cumulative cancer incidence.

Results: Data from 263 DM cases were analysed, with a total of 3252 person-years and a median 11 years of follow-up; 55 (21%) DM cases were anti-TIF1-Ab positive. After 10 years of follow-up, a higher proportion of anti-TIF1-Ab-positive cases developed cancer compared with anti-TIF1-Ab-negative cases: 38% vs 15% [hazard ratio 3.4 (95% CI 2.2, 5.4)]. All the detected malignancy cases in the anti-TIF1-Ab-positive cohort occurred between 3 years prior to and 2.5 years after DM onset. No cancer cases were detected within the following 7.5 years in this group, whereas cancers were detected during this period in the anti-TIF1-Ab-negative cases. Ovarian cancer was more common in the anti-TIF1-Ab-positive vs -negative cohort: 19% vs 2%, respectively (P < 0.05). No anti-TIF1-Ab-positive case <39 years of age developed cancer, compared with 21 (53%) of those ≥39 years of age.

Conclusion: Anti-TIF1-Ab-positive-associated malignancy occurs exclusively within the 3 year period on either side of DM onset, the risk being highest in those ≥39 years of age. Cancer types differ according to anti-TIF1-Ab status, and this may warrant specific cancer screening approaches.
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http://dx.doi.org/10.1093/rheumatology/key357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434375PMC
April 2019

High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case-control study.

Ann Rheum Dis 2018 07 7;77(7):981-987. Epub 2018 Feb 7.

Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

Objectives: Findings relating to dietary intake of n-3 polyunsaturated fatty acids (PUFA) and risk of rheumatoid arthritis (RA) are mixed. Erythrocyte membrane PUFA is an accurate objective biomarker of PUFA status; however, there are little data on erythrocyte membrane PUFA and risk of RA. The objective was therefore to compare erythrocyte membrane PUFA between pre-RA individuals and matched controls from a population-based sample, and specifically to test the hypothesis that higher levels of longer chain n-3 PUFA are associated with lower risk of RA.

Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) is a large European prospective cohort study of apparently healthy populations. We undertook a nested case-control study by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts in Italy and Spain. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Conditional logistic regression analysis was used to estimate associations of PUFA with the development of RA, adjusting for potential confounders including body mass index, waist circumference, education level, physical activity, smoking status and alcohol intake.

Results: The study analysed samples from 96 pre-RA subjects and 258 matched controls. In this analysis, the median time to diagnosis (defined as time between date of blood sample and date of diagnosis) was 6.71 years (range 0.8-15). A significant inverse association was observed with n-6 PUFA linoleic acid (LA) levels and pre-RA in the fully adjusted model (highest tertile: OR 0.29; 95% CI 0.12 to 0.75; P for trend 0.01). No association was observed with any individual n-3 PUFA, total n-3 PUFA or total n-3:n-6 ratio.

Conclusions: Erythrocyte levels of the n-6 PUFA LA were inversely associated with risk of RA, whereas no associations were observed for other n-6 or n-3 PUFA. Further work is warranted to replicate these findings and to investigate if lower LA levels are a bystander or contributor to the process of RA development.
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http://dx.doi.org/10.1136/annrheumdis-2017-212274DOI Listing
July 2018

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Nat Commun 2017 10 13;8(1):910. Epub 2017 Oct 13.

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
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http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

The EuroMyositis registry: an international collaborative tool to facilitate myositis research.

Ann Rheum Dis 2018 Jan 30;77(1):30-39. Epub 2017 Aug 30.

Department of Rheumatology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK.

Aims: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data.

Methods: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated.

Results: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%.

Conclusion: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.
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http://dx.doi.org/10.1136/annrheumdis-2017-211868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754739PMC
January 2018

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence.

Nat Genet 2017 Jul 22;49(7):1107-1112. Epub 2017 May 22.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, the Netherlands.

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (r = 0.89, LD score regression P = 5.4 × 10). These findings provide new insight into the genetic architecture of intelligence.
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http://dx.doi.org/10.1038/ng.3869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665562PMC
July 2017

Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum.

Arthritis Rheumatol 2017 05 4;69(5):1090-1099. Epub 2017 Apr 4.

Feinstein Institute for Medical Research, Manhasset, New York.

Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip.

Methods: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.

Results: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10 ). HLA imputation identified 3 independent associations (with HLA-DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti-cytosolic 5'-nucleotidase 1A-positive status was found independent of HLA-DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant.

Conclusion: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.
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http://dx.doi.org/10.1002/art.40045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516174PMC
May 2017

Systematic protein-protein interaction and pathway analyses in the idiopathic inflammatory myopathies.

Arthritis Res Ther 2016 07 7;18(1):156. Epub 2016 Jul 7.

Centre for Epidemiology, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Background: The idiopathic inflammatory myopathies (IIM) are autoimmune diseases characterised by acquired proximal muscle weakness, inflammatory cell infiltrates in muscle and myositis-specific/associated autoantibodies. It is unclear which pathways are involved in IIM, and the functional relationship between autoantibody targets has not been systematically explored. Protein-protein interaction and pathway analyses were conducted to identify pathways relevant to disease, using autoantibody targets and gene products of IIM-associated single nucleotide polymorphism (SNP) loci.

Methods: Protein-protein interactions were analysed using Disease Association Protein-Protein Link Evaluator (DAPPLE). Gene ontology and pathway analyses were conducted using Database for Annotation Visualisation and Integrated Discovery (DAVID) and Gene Relationships Across Implicated Loci (GRAIL). Analyses were undertaken including the targets of published autoantibodies, significant and suggestive SNPs from an IIM association study and autoantibody targets plus SNPs combined.

Results: The protein-protein interaction networks formed by autoantibody targets and associated SNPs showed significant direct and/or indirect connectivity (p < 0.05). Autoantibody targets plus associated SNPs combined resulted in more significant indirect and common interactor connectivity, suggesting autoantibody targets and proteins encoded by IIM-associated loci may be involved in common pathways. Tumour necrosis factor receptor-associated factor 6 (TRAF6) was identified as a hub protein, and UBE3B, HSPA1A, HSPA1B and PSMD3 also were identified as genes with significant connectivity. Pathway analysis identified that autoantibody targets and associated SNP regions are significantly interconnected (p < 0.01), and confirmed autoantibody target involvement in translational and post-translational processes. 'Ubiquitin' was the only keyword strongly linking significant genes across regions in all three GRAIL analyses of autoantibody targets and IIM-associated SNPs.

Conclusions: Autoantibody targets and IIM-associated loci show significant connectivity and inter-relatedness, and identify several key genes and pathways in IIM pathogenesis, possibly mediated via the ubiquitination pathway.
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http://dx.doi.org/10.1186/s13075-016-1061-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936183PMC
July 2016

Genome-wide association study identifies 74 loci associated with educational attainment.

Nature 2016 05 11;533(7604):539-42. Epub 2016 May 11.

Department of Neurology, General Hospital and Medical University Graz, Graz 8036, Austria.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups.

Ann Rheum Dis 2016 Aug 11;75(8):1558-66. Epub 2015 Sep 11.

Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

Objectives: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium.

Results: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM.

Conclusions: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
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http://dx.doi.org/10.1136/annrheumdis-2015-208119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300750PMC
August 2016

Breed differences in development of anti-insulin antibodies in diabetic dogs and investigation of the role of dog leukocyte antigen (DLA) genes.

Vet Immunol Immunopathol 2015 Oct 2;167(3-4):130-8. Epub 2015 Aug 2.

Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK. Electronic address:

Administration of insulin for treatment of diabetes mellitus in dogs can stimulate an immune response, with a proportion of animals developing anti-insulin antibodies (AIA). For an IgG antibody response to occur, this would require B cell presentation of insulin peptides by major histocompatibility complex (MHC) class II molecules, encoded by dog leukocyte antigen (DLA) genes, in order to receive T-cell help for class switching. DLA genes are highly polymorphic in the dog population and vary from breed to breed. The aim of the present study was to evaluate AIA reactivity in diabetic dogs of different breeds and to investigate whether DLA genes influence AIA status. Indirect ELISA was used to determine serological reactivity to insulin in diabetic dogs, treated with either a porcine or bovine insulin preparation. DLA haplotypes for diabetic dogs were determined by sequence-based typing of DLA-DRB1, -DQA1 and -DQB1 loci. Significantly greater insulin reactivity was seen in treated diabetic dogs (n=942) compared with non-diabetic dogs (n=100). Relatively few newly diagnosed diabetic dogs (3/109) were found to be AIA positive, although this provides evidence that insulin autoantibodies might be involved in the pathogenesis of the disease in some cases. Of the diabetic dogs treated with a bovine insulin preparation, 52.3% (182/348) were AIA positive, compared with 12.6% (75/594) of dogs treated with a porcine insulin preparation, suggesting that bovine insulin is more immunogenic. Breeds such as dachshund, Cairn terrier, miniature schnauzer and Tibetan terrier were more likely to develop AIA, whereas cocker spaniels were less likely to develop AIA, compared with crossbreed dogs. In diabetic dogs, DLA haplotype DRB1*0015--DQA1*006--DQB1*023 was associated with being AIA positive, whereas the haplotype DLA-DRB1*006--DQA1*005--DQB1*007 showed an association with being AIA negative. These research findings suggest that DLA genes influence AIA responses in treated diabetic dogs.
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http://dx.doi.org/10.1016/j.vetimm.2015.07.014DOI Listing
October 2015

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

PLoS One 2015 11;10(8):e0134720. Epub 2015 Aug 11.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds--the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134720PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532498PMC
May 2016

Restricted dog leucocyte antigen (DLA) class II haplotypes and genotypes in Beagles.

Vet J 2015 Mar 5;203(3):345-7. Epub 2015 Jan 5.

Department of Pathology and Pathogen Biology, Royal Veterinary College, North Mymms, Hertfordshire AL9 7TA, United Kingdom.

Beagles are commonly used in vaccine trials as part of the regulatory approval process. Genetic restriction within this breed and the impact this might have on vaccine responses are rarely considered. This study was designed to characterise diversity of dog leucocyte antigen (DLA) class II genes in a breeding colony of laboratory Beagles, whose offspring are used in vaccine studies. DLA haplotypes were determined by PCR and sequence-based typing from genomic DNA extracted from blood. Breeding colony Beagles had significantly different DLA haplotype frequencies in comparison with pet Beagles and both groups showed limited DLA diversity. Restricted DLA class II genetic variability within Beagles might result in selective antigen presentation and vaccine responses that are not necessarily representative of those seen in other dog breeds.
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http://dx.doi.org/10.1016/j.tvjl.2014.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366010PMC
March 2015

Genetic variation in inflammatory and bone turnover pathways and risk of osteolytic responses to prosthetic materials.

J Orthop Res 2015 Feb 16;33(2):193-8. Epub 2014 Nov 16.

Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom.

Wear particle-induced inflammatory bone loss (osteolysis) is the leading cause of total hip arthroplasty (THA) failure. Individual susceptibility to osteolysis is modulated by genetic variation. In this 2-stage case-control association study we examined whether variation within candidate genes in inflammatory and bone turnover signaling pathways associates with susceptibility to osteolysis and time to prosthesis failure. We examined two cohorts, comprising 758 (347 male) Caucasian subjects who had undergone THA with a metal on polyethylene bearing couple; 315 of whom had developed osteolysis. Key genes within inflammatory, bone resorption, and bone formation pathways were screened for common variants by pairwise-SNP tagging using a 2-stage association analysis approach. In the discovery cohort four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP (p < 0.05) were associated with osteolysis susceptibility. Two SNPs within LRP6, and one each within LRP5, NOD2, SOST, SQSTM1, TIRAP, and TRAM associated with time to implant failure (p < 0.05). Meta-analysis of the two cohorts identified four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP associated with osteolysis susceptibility (p < 0.05). Genetic variation within inflammatory signaling and bone turnover pathways may play a role in susceptibility to osteolysis.
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http://dx.doi.org/10.1002/jor.22755DOI Listing
February 2015

Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies.

Arthritis Rheumatol 2014 Apr;66(4):940-9

Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.

Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.

Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant.

Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.

Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
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http://dx.doi.org/10.1002/art.38300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660891PMC
April 2014

Variations in inflammation-related genes may be associated with childhood febrile seizure susceptibility.

Seizure 2014 Jun 18;23(6):457-61. Epub 2014 Mar 18.

Faculty of Life Sciences, University of Manchester, UK.

Purpose: To investigate whether genetic variants in inflammation-related genes are associated with increased risk of childhood-onset febrile seizures.

Method: Tagging single nucleotide polymorphisms (SNPs) from 19 inflammation-related candidate genes were identified and genotyped on the Sequenom platform in a sample of Caucasian childhood-onset febrile seizures cases (n=98) compared to ethnicity, age and gender matched febrile controls presenting without seizures (n=123). Tests for allelic association were carried out using PLINK. SNPs generating empirical P-values (P<0.05) were analysed in an expanded Caucasian control sample (n=2692) from the 1958 Birth Cohort.

Results: Six SNPs generated empirical pointwise significance values P<0.05 in the febrile seizures case-control analysis in the P2X7R (purinergic receptor P2X7), TLR4 (toll-like receptor 4), IL6R (interleukin 6 receptor) and PTGER3 (prostaglandin E receptor 3, subtype EP3) genes. The most significant result was for missense SNP rs208294 in P2X7R (P=0.009); this novel association was supported in the expanded case-control analysis using the 1958 Birth Cohort (pointwise P=0.009, OR=0.63, familywise P=0.039).

Conclusion: Genetic variants in inflammation-related genes, specifically purinergic receptor P2X7, may be involved in susceptibility to childhood-onset febrile seizures.
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http://dx.doi.org/10.1016/j.seizure.2014.03.006DOI Listing
June 2014

Genetic basis of cranial cruciate ligament rupture (CCLR) in dogs.

Connect Tissue Res 2014 Aug 25;55(4):275-81. Epub 2014 Apr 25.

Department of Infection Biology, Institute of Infection and Global Health, School of Veterinary Science, University of Liverpool , Liverpool , UK .

Cranial Cruciate Ligament rupture (CCLR) is one of the most common forms of lameness in dogs and is analogous to rupture of the anterior cruciate ligament in humans, for which it can serve as a model. As there is a strong breed-related predisposition to CCLR in dogs, a study was undertaken to consider putative genetic components in susceptible dog breeds. A candidate gene, single nucleotide polymorphism (SNP) genotyping approach using MALDI-TOF mass spectrometry (Sequenom Ltd) was designed to investigate several CCLR-susceptible dog breeds and identify CCLR-associated genes/gene regions that may confer susceptibility or resistance. A meta-analysis was performed using the breed case/control candidate gene data to identify SNP associations that were common to the whole cohort of susceptible dogs. We identified SNPs in key genes involved in ligament strength, stability and extracellular matrix formation (COL5A1, COL5A2, COL1A1, COL3A1, COL11A1, COL24A1, FBN1, LOX, LTBP2) which were significantly associated with CCLR susceptibility across the dog breeds used in this study. These SNPs could have an involvement in CCLR due to a detrimental effect on ligament structure and strength. This is the first published candidate gene study that has revealed significant genetic associations with canine CCLR.
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http://dx.doi.org/10.3109/03008207.2014.910199DOI Listing
August 2014

Genetics of canine anal furunculosis in the German shepherd dog.

Immunogenetics 2014 May 14;66(5):311-24. Epub 2014 Mar 14.

Centre for Integrated Genomic Medical Research (CIGMR), Institute of Population Health, Faculty of Medical and Human Sciences, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK,

Canine anal furunculosis (AF) is characterised by ulceration and fistulation of perianal tissue and is a disease that particularly affects German shepherd dogs (GSDs). There are some similarities between AF and perianal Crohn's disease (CD) in man. An immune-mediated aetiopathogenesis for AF has been suggested due to tissue pathology, a major histocompatibility complex (MHC) association and clinical response to ciclosporin. Genome-wide association studies (GWAS) can be conducted in dogs with fewer markers and individuals than would be required in a human study. A discovery GWAS was performed on 21 affected and 25 control GSDs from the UK. No SNPs reached genome-wide significance levels at this stage. However, 127 nominally associated SNPs were genotyped in further 76 cases and 191 controls from the UK and Finland. Sequencing of these regions was undertaken to discover novel genetic variation. Association testing of these variants in the UK and Finnish cohorts revealed nine significantly associated SNPs, six of which cause non-synonymous changes in protein sequence. The ADAMTS16 and CTNND2 gene regions were most significantly associated with disease. Members of the butyrophilin protein family, important in intestinal inflammatory regulation, were also associated with disease, but their independence from the MHC region remains to be established. The CTNND2 gene region is also interesting as this locus was implicated in human ulcerative colitis and CD, albeit at a different candidate gene: DAP. We suggest that this represents a common association between inflammatory bowel disease-related conditions in both species and believe that future studies will strengthen this link.
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http://dx.doi.org/10.1007/s00251-014-0766-5DOI Listing
May 2014

Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes.

Ann Clin Biochem 2014 Jul 30;51(Pt 4):468-75. Epub 2013 Sep 30.

Vascular Research Group, The University of Manchester, Manchester, UK.

Introduction: Associations of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) with cardiovascular risk have been inadequately studied. We hypothesized that IGF-II and IGFBP-2 associate with longitudinal trends in lipid profiles in type 2 diabetes patients.

Subjects And Methods: Four hundred and eighty nine subjects with type 2 diabetes (age 27-87 years) from the Salford Diabetes Cohort were studied. Longitudinal clinical information was extracted for an eight-year period (2002-2009) from an integrated electronic dataset of primary care and hospital data.

Results: There were 294 male subjects and mean age was 62.9 years. At baseline, IGF-II concentration was 602 ng/mL. HDL cholesterol at baseline was associated with log-IGF-II concentration in a model adjusted for age, gender, baseline body-mass index (BMI), estimated glomerular filtration rate (eGFR) and lipid-lowering therapy. IGFBP-1 and IGFBP-2 were associated with high HDL-cholesterol. A higher circulating IGF-II concentration at baseline was also associated with longitudinal increase in HDL-cholesterol in mixed-effects regression analyses independent of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, age, gender, eGFR, BMI and lipid-lowering therapy. Log-transformed baseline concentrations of IGFBP-1 and IGFBP-2 were also associated with longitudinal elevation in HDL-cholesterol. No association was observed for IGF-II or IGFBP-2 with longitudinal LDL cholesterol trends.

Conclusion: Our analyses based on 'real world' data demonstrate that higher baseline IGF-II and IGFBP-2 predict increased HDL concentration over time, implicating IGF-II in modulation of circulating HDL-cholesterol concentrations.
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http://dx.doi.org/10.1177/0004563213499145DOI Listing
July 2014

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders.

Arthritis Rheum 2013 Dec;65(12):3239-47

National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland.

Objective: To identify new genetic associations with juvenile and adult dermatomyositis (DM).

Methods: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.

Results: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM.

Conclusion: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1002/art.38137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934004PMC
December 2013

IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes.

Endocr Connect 2012 Nov 24;1(2):95-102. Epub 2012 Oct 24.

Vascular Research Group The University of Manchester Manchester, M13 9PT UK.

Objective: Insulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.

Design And Methods: IGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.

Results: High IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (β=-0.02, (95% confidence interval -0.03 to -0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.

Conclusion: This study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.
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http://dx.doi.org/10.1530/EC-12-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681324PMC
November 2012

Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs.

PLoS One 2013 14;8(2):e56490. Epub 2013 Feb 14.

Centre for Integrated Genomic Medical Research (CIGMR), Institute of Population Health, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom.

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056490PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572995PMC
August 2013

Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation.

BMC Genomics 2013 Feb 26;14:127. Epub 2013 Feb 26.

Gastrointestinal Sciences, Institute of Inflammation and Repair, Faculty of Medicine and Human Sciences, University of Manchester, 4.004 AV Hill Building, Oxford Road, Manchester M13 9PT, UK.

Background: Genetic susceptibility to colonic inflammation is poorly defined at the gene level. Although Genome Wide Association studies (GWAS) have identified loci in the human genome which confer susceptibility to Inflammatory Bowel Disease (Crohn's and Ulcerative Colitis), it is not clear if precise loci exist which confer susceptibility to inflammation at specific locations within the gut e.g. small versus large intestine. Susceptibility loci for colitis in particular have been defined in the mouse, although specific candidate genes have not been identified to date. We have previously shown that infection with Trichuris muris (T. muris) induces chronic colitis in susceptible mouse strains with clinical, histological, and immunological homology to human colonic Crohn's disease. We performed an integrative analysis of colitis susceptibility, using an F2 inter-cross of resistant (BALB/c) and susceptible (AKR) mice following T. muris infection. Quantitative Trait Loci (QTL), polymorphic and expression data were analysed alongside in silico workflow analyses to discover novel candidate genes central to the development and biology of chronic colitis.

Results: 7 autosomal QTL regions were associated with the establishment of chronic colitis following infection. 144 QTL genes had parental strain SNPs and significant gene expression changes in chronic colitis (expression fold-change ≥ +/-1.4). The T. muris QTL on chromosome 3 (Tm3) mapped to published QTL in 3 unrelated experimental models of colitis and contained 33 significantly transcribed polymorphic genes. Phenotypic pathway analysis, text mining and time-course qPCR replication highlighted several potential cis-QTL candidate genes in colitis susceptibility, including FcgR1, Ptpn22, RORc, and Vav3.

Conclusion: Genetic susceptibility to induced colonic mucosal inflammation in the mouse is conserved at Tm3 and overlays Cdcs1.1. Genes central to the maintenance of intestinal homeostasis reside within this locus, implicating several candidates in susceptibility to colonic inflammation. Combined methodology incorporating genetic, transcriptional and pathway data allowed identification of biologically relevant candidate genes, with Vav3 newly implicated as a colitis susceptibility gene of functional relevance.
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http://dx.doi.org/10.1186/1471-2164-14-127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621453PMC
February 2013

MHC class II association study in eight breeds of dog with hypoadrenocorticism.

Immunogenetics 2013 Apr 29;65(4):291-7. Epub 2013 Jan 29.

Centre for Integrated Genomic Medical Research (CIGMR), School of Medicine, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison's disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.
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http://dx.doi.org/10.1007/s00251-013-0680-2DOI Listing
April 2013
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