Melbourne Medical School Collected Works - Research Publications

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Start date: 2010 × End date: 2010 × Author: Bahlo, Melanie ×

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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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    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.