Abstract
In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.
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Acknowledgements
Our thanks go to the people with MS and their families who have shown tremendous enthusiasm towards our research. J.P.R. and M.B. are supported by the National Health and Medical Research Council of Australia (NHMRC). T.J.K., S.J.F. and T.P.S. are fellows of the NHMRC. We are grateful to John Carey and Josephine Baker for assistance with recruitment of the Victorian MS cohort. We also thank the Menzies Centre for Population Health Research for assisting with recruitment of the Tasmanian cohort. All genotyping was conducted at the Australian Genome Research Facility. Work contained in this manuscript was supported by project grant funding from: NHMRC (App. ID 257518), MS Australia, The National MS Society (USA) and The Cooperative Research Centre (CRC) for the Discovery of Genes for Common Human Diseases (Genes-CRC). The Genes-CRC was established and is supported by the Australian Government’s Co-operative Research Centre’s Scheme.
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Electronic database information: URLs for the data in this article are as follows:
Division of Genetics and Bioinformatics, WEHI, (http://bioinf.wehi.edu.au) for LINKPREP and HAPLO.PL
Australian Genome Research Facility, http://www.agrf.org.au for genotyping
University of California Santa Cruz Human Genome Project working draft, http://genome.ucsc.edu/
UniSTS at National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/genome/sts/
Genome Database, http://www.gdb.org/ for genomic information and primer sequences
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/OMIM/ for MS and HH information
Australian Bureau of Statistics, http://www.abs.gov.au/ for 2001 census data
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Rubio, J.P., Bahlo, M., Tubridy, N. et al. Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis. Hum Genet 114, 573–580 (2004). https://doi.org/10.1007/s00439-004-1095-9
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DOI: https://doi.org/10.1007/s00439-004-1095-9