Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in australians

The Howard Florey Institute, Melbourne, Victoria, Australia.
Genes and immunity (Impact Factor: 2.91). 10/2008; 9(7):624-30. DOI: 10.1038/gene.2008.59
Source: PubMed


A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.

Download full-text


Available from: Melanie Bahlo, Mar 12, 2014
  • Source
    • "Subsequent studies identified CD2 and CD58 as being involved in the E-rosette phenomenon [151]. Interestingly, CD58 has recently been identified as a susceptibility gene for MS [152, 153]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Central nervous system (CNS) myelin, the likely major target of autoimmune attack in multiple sclerosis (MS), contains a number of unique components that are potential targets of the attack. Two classes of molecules that are greatly enriched in CNS myelin compared to other parts of the body are certain types of proteolipids and glycolipids. Due to the hydrophobic nature of both of these classes of molecules, they present challenges for use in immunological assays and have therefore been somewhat neglected in studies of T-cell reactivity in MS compared to more soluble molecules such as the myelin basic proteins and the extracellular domain of myelin oligodendrocyte glycoprotein. This review firstly looks at the makeup of CNS myelin, with an emphasis on proteolipids and glycolipids. Next, a retrospective of what is known of T-cell reactivity directed against proteolipids and glycolipids in patients with MS is presented, and the implications of the findings are discussed. Finally, this review considers the question of what would be required to prove a definite role for autoreactivity against proteolipids and glycolipids in the pathogenesis of MS.
    Full-text · Article · Nov 2013
  • Source
    • "Our findings in this Western Australian MS cohort suggest that the effects of non-HLA genes on disease risk may also be gender-specific. However, no such interactions were detected between CLEC-16A, IL2RA, CD58, or HLA-DRB1*15 and gender in another Australian patient cohort from Victoria (Rubio et al., 2008). It is acknowledged that, due to the relatively small sample size, our results must be considered as preliminary and need to be replicated in independent patient cohorts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes (IL7R, IL2RA, CLEC-16A, TYK2, CD58, IRF5, STAT3, CTLA-4, APOE, ICAM-1) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R, TYK2, IRF5 and APOE have modifying effects on MS susceptibility. We also found evidence of interactive protective effects between polymorphisms in the IL7R/CD58, CLEC-16A/CTLA-4, and TYK2/IRF5 genes, which in some instances are restricted within HLA- or gender-defined groups.
    Full-text · Article · May 2013 · Journal of neuroimmunology
  • Source
    • "Finally, after the genotyping of hundreds of thousands of single nucleotide polymorphisms (SNPs) in many thousands of MS patients and controls, we are beginning to establish a network of loci outside of the HLA region involved in determining MS susceptibility.[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17] It is worth considering that even the most strongly associated of these with MS is still a significantly weaker determinant of MS susceptibility than HLA alleles. For some of these loci, functional studies have been undertaken.[11], "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is a complex neurological disorder. Its aetiology involves both environmental and genetic factors. Recent genome-wide association studies have identified a number of single nucleotide polymorphisms (SNPs) associated with susceptibility to (MS). We investigated whether these genetic variations were associated with alteration in gene expression. We used a database of mRNA expression and genetic variation derived from immortalised peripheral lymphocytes to investigate polymorphisms associated with MS for correlation with gene expression. Several SNPs were found to be associated with changes in expression: in particular two with HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB4 and HLA-DRB5, one with ZFP57, one with CD58, two with IL7 and FAM164A, and one with FAM119B, TSFM and KUB3. We found minimal cross-over with a recent whole genome expression study in MS patients. We have shown that many susceptibility loci in MS are associated with changes in gene expression using an unbiased expression database. Several of these findings suggest novel gene candidates underlying the effects of MS-associated genetic variation.
    Full-text · Article · Apr 2010 · PLoS ONE
Show more