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Investigation of promoter HLA-DRB1 polymorphism in relation to a putative VDRE motif: HLA-DRB1 allele associations and influence on risk of multiple sclerosis

Castley, A., Tschochner, M., James, I., Kermode, A., Carroll, W., Sayer, D., Christiansen, F., Witt, C. and Nolan, D. (2011) Investigation of promoter HLA-DRB1 polymorphism in relation to a putative VDRE motif: HLA-DRB1 allele associations and influence on risk of multiple sclerosis. In: 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, 19 – 22 October 2011, Amsterdam, Netherlands.

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Background: The identification of a vitamin D response element (VDRE) in the HLA-DRB1 promoter region, and demonstration of reduced gene expression in response to vitamin D stimulus in the presence of HLA-DRB1*15:01 allele-associated VDRE variant [PLoS Genet. 2009;5:e1000369], has provided an attractive explanation for the combined effects of Class II HLA carriage and vitamin D exposure as risk factors for multiple sclerosis.

Goals: To further delineate genetic variation in the promoter region VDRE among a broad range of HLA-DRB1 alleles that are highly represented in Caucasian populations, and to assess its potential impact on MS disease risk.

Methods: We utilised DNA extracted from 32 cell lines to obtain sequence data for 17 homozygous DRB1 alleles including 8 major Caucasian MHC ancestral haplotyopes, and 53 heterozygote MS cohort samples selected to obtain sequence data for 20 DRB1 alleles. HLA-DRB1 promoter genotyping was performed by PCR and DNA sequencing (RPH), and analysed using ASSIGN V4.0.1.36 (Conexio Genomics). The influence of VDRE variation on risk of MS was then assessed in the context of HLA-DRB1 allelic associations among 350 Western Australian cohort cases and 498 controls using multivariable logistic regression analysis.

Results: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the “non-responder” GGGTGGAGGGGTTCA sequence, while the alternative “responder” GGGTGGAGAGGGGT-CA sequence was associated only with HLA-DRB1*04, *07 and *09 alleles. Analysis of the broader promoter region identified sequence identity between HLA-DRB1*15:01, 01:01, and 16:01, with minor variation outside of the VDRE motif producing seven extended HLA-DRB1 promoter sequence variants. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04/07/09 allele dose (p= 5 x 10-10). On the other hand, the risk of MS associated with HLA-DRB1*15:01 could not be readily explained in terms of VDRE variation, although reduced vitamin D responsiveness of the HLA-DRB1 promoter in this instance may contribute to HLA-associated risk.

Discussion: A broad range of HLA-DRB1 alleles, including HLA-DRB1*15:01, are associated with a promoter VDRE motif that is relatively resistant to vitamin D stimulus. The less frequent “responsive” VDRE motif associated with HLA-DRB1*04/*07/*09 alleles is associated with significantly reduced risk of MS, potentially consistent with a “gain of VDRE response” effect.

Item Type: Conference Item
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Sage Publications
Copyright: © SAGE Publications
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