School of Biomedical Sciences - Research Publications

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    Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
    Binder, MD ; Fox, AD ; Merlo, D ; Johnson, LJ ; Giuffrida, L ; Calvert, SE ; Akkermann, R ; Ma, GZM ; Perera, AA ; Gresle, MM ; Laverick, L ; Foo, G ; Fabis-Pedrini, MJ ; Spelman, T ; Jordan, MA ; Baxter, AG ; Foote, S ; Butzkueven, H ; Kilpatrick, TJ ; Field, J ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2016-03)
    Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
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    Variants of ST8SIA1 Are Associated with Risk of Developing Multiple Sclerosis
    Husain, S ; Yildirim-Toruner, C ; Rubio, JP ; Field, J ; Schwalb, M ; Cook, S ; Devoto, M ; Vitale, E ; Reitsma, PH (PUBLIC LIBRARY SCIENCE, 2008-07-09)
    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.
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    Prednisolone promotes remission and gastric mucosal regeneration in experimental autoimmune gastritis
    Biondo, M ; Field, J ; Toh, B-H ; Alderuccio, F (WILEY, 2006-07)
    A cardinal feature of organ-specific autoimmunity is destructive pathology in the target organ. In human and experimental models of autoimmune gastritis, mononuclear cell infiltration and cellular destruction in the gastric mucosa are disease hallmarks. Strategies to cure autoimmune disease must not only establish immunological tolerance to autoantigen, but also rid the organ of pathogenic autoreactive cells. The present study has assessed the effect of prednisolone treatment in clearing the inflammatory infiltrate in experimental autoimmune gastritis and in preventing disease relapse in athymic compared with euthymic mice. Experimental autoimmune gastritis was induced by neonatal thymectomy or by transgenic expression of GM-CSF (PC-GMCSF mice). Groups of mice were treated with prednisolone (10 mg/kg per day) for 10 weeks or with prednisolone for 10 weeks followed by 10 weeks without prednisolone. Stomachs were examined for gross morphological changes, and by histology and immunohistochemistry for composition of inflammatory infiltrate and gastric mucosal integrity. Autoantibody to gastric H+/K+ ATPase was determined by ELISA. Prednisolone promoted remission of gastritis in both mouse models of experimental autoimmune gastritis, evident by reduction in stomach size, clearing of gastric inflammatory infiltrate, and regeneration of the gastric mucosa. Prednisolone withdrawal resulted in disease relapse in all PC-GMCSF mice, whereas approximately 40% of neonatal thymectomy mice retained normal stomach morphology and remained free of gastric pathology. It is concluded that prednisolone promotes remission and gastric mucosal regeneration in experimental autoimmune gastritis. Prolonged remission of autoimmune gastritis in some athymic mice suggests a role for the thymus in disease relapse.
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    Chemokine receptor CCR5 is not required for development of experimental autoimmune gastritis
    Field, J ; Marshall, ACJ ; Hertzog, PJ ; Wells, TN ; Alderuccio, F ; Toh, BH (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2003-11)
    Experimental autoimmune gastritis (EAG) is a model of human autoimmune gastritis, the underlying cause of pernicious anaemia. It is characterised by gastric mononuclear cell infiltrates, destruction of parietal and zymogenic cells, and autoantibodies to parietal cell-associated H(+)/K(+) ATPase. Here, we have investigated the role of CCR5 in the development of EAG. We found that the development of EAG was not prevented in CCR5-deficient mice. Using reverse-transcriptase analysis of stomachs from normal and gastritic mice we found no difference in expression of CCR5 and its chemokine ligands MIP-1alpha, MIP-1beta, and RANTES. We also found that the CCR5 antagonist met-RANTES failed to prevent the development of EAG induced by neonatal thymectomy. These observations suggest that the CC chemokine receptor CCR5 is not essential for development of EAG.
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    Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects
    Lill, CM ; Liu, T ; Schjeide, B-MM ; Roehr, JT ; Akkad, DA ; Damotte, V ; Alcina, A ; Ortiz, MA ; Arroyo, R ; Lopez de lapuente, A ; Blaschke, P ; Winkelmann, A ; Gerdes, L-A ; Luessi, F ; Fernadez, O ; Izquierdo, G ; Antigueedad, A ; Hoffjan, S ; Cournu-Rebeix, I ; Gromoeller, S ; Faber, H ; Liebsch, M ; Meissner, E ; Chanvillard, C ; Touze, E ; Pico, F ; Corcia, P ; Doerner, T ; Steinhagen-Thiessen, E ; Baeckman, L ; Heekeren, HR ; Li, S-C ; Lindenberger, U ; Chan, A ; Hartung, H-P ; Aktas, O ; Lohse, P ; Kuempfel, T ; Kubisch, C ; Epplen, JT ; Zettl, UK ; Fontaine, B ; Vandenbroeck, K ; Matesanz, F ; Urcelay, E ; Bertram, L ; Zipp, F (BMJ PUBLISHING GROUP, 2012-09)
    BACKGROUND: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. METHODS: We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. RESULTS: Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). CONCLUSION: Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
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    Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis
    Lee, SH ; Harold, D ; Nyholt, DR ; Goddard, ME ; Zondervan, KT ; Williams, J ; Montgomery, GW ; Wray, NR ; Visscher, PM (OXFORD UNIV PRESS, 2013-02-15)
    Common diseases such as endometriosis (ED), Alzheimer's disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.
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    Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips
    Ritchie, ME ; Liu, R ; Carvalho, BS ; Irizarry, RA (BMC, 2011-03-08)
    BACKGROUND: Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. RESULTS: In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. CONCLUSIONS: CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended.
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    Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients
    Jensen, CJ ; Stankovich, J ; Van der Walt, A ; Bahlo, M ; Taylor, BV ; van der Mei, IAF ; Foote, SJ ; Kilpatrick, TJ ; Johnson, LJ ; Wilkins, E ; Field, J ; Danoy, P ; Brown, MA ; Rubio, JP ; Butzkueven, H ; Kleinschnitz, C (PUBLIC LIBRARY SCIENCE, 2010-04-02)
    Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13-14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.
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    Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
    Bahlo, M ; Booth, DR ; Broadley, SA ; Brown, MA ; Foote, SJ ; Griffiths, LR ; Kilpatrick, TJ ; Lechner-Scott, J ; Moscato, P ; Perreau, VM ; Rubio, JP ; Scott, RJ ; Stankovich, J ; Stewart, GJ ; Taylor, BV ; Wiley, J ; Clarke, G ; Cox, MB ; Csurhes, PA ; Danoy, P ; Drysdale, K ; Field, J ; Foote, SJ ; Greer, JM ; Guru, P ; Hadler, J ; McMorran, BJ ; Jensen, CJ ; Johnson, LJ ; McCallum, R ; Merriman, M ; Merriman, T ; Pryce, K ; Tajouri, L ; Wilkins, EJ ; Browning, BL ; Browning, SR ; Perera, D ; Butzkueven, H ; Carroll, WM ; Chapman, C ; Kermode, AG ; Marriott, M ; Mason, D ; Heard, RN ; Pender, MP ; Slee, M ; Tubridy, N ; Willoughby, E (NATURE PUBLISHING GROUP, 2009-07)
    To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
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    A Polymorphism in the HLA-DPB1 Gene Is Associated with Susceptibility to Multiple Sclerosis
    Field, J ; Browning, SR ; Johnson, LJ ; Danoy, P ; Varney, MD ; Tait, BD ; Gandhi, KS ; Charlesworth, JC ; Heard, RN ; Stewart, GJ ; Kilpatrick, TJ ; Foote, SJ ; Bahlo, M ; Butzkueven, H ; Wiley, J ; Booth, DR ; Taylor, BV ; Brown, MA ; Rubio, JP ; Stankovich, J ; Andreu, AL (PUBLIC LIBRARY SCIENCE, 2010-10-26)
    We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.