1. ¹Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
2. ²Laboratory of Molecular Medicine and Biotechnology, Don C Gnocchi Foundation IRCCS, S Maria Nascente, Milan, Italy
3. ³Unit of Medical Statistics and Cancer Epidemiology, Department of Medical Sciences, University of Eastern Piedmont and Ospedale Maggiore, Novara, Italy
4. ⁴Department of Biomedical Sciences and Technology, University of Milan, Milan, Italy
5. ⁵Department of Neurology, Ospedale Maggiore, Novara, Italy
6. ⁶Multiple Sclerosis Unit, Don C Gnocchi Foundation ONLUS, IRCCS, Milan, Italy
7. ⁷Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
8. ⁸Neurology and Center for Experimental Neurological Therapy (CENTERS), Universitá La Sapienza, Roma, Italy
9. ⁹Department of Neurological Sciences, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
10. ¹⁰Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy

Correspondence: Dr S D'Alfonso, Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Via Solaroli 17, Novara 28100, Italy. E-mail: dalfonso@med.unipmn.it

Received 2 July 2007; Revised 27 August 2007; Accepted 31 August 2007; Published online 11 October 2007.

Abstract

Several studies suggest that the histocompatibility complex (HLA) class I region harbours genes modulating multiple sclerosis (MS) susceptibility independently from the effect of class II alleles. A candidate gene in this region is MOG, encoding the myelin oligodendrocyte glycoprotein. A significant association with the missense variation V142L (rs2857766) was previously reported in a small sample of 50 Italian MS patients. We confirmed this result in two independent Italian sample sets consisting of 878 MS patients and 890 matched controls (P=6.6 10^-4) and 246 trio families (P=1.5 10^-3). The comparison of genotype frequencies suggested a dominant-protective effect of L142. In the combined sample sets L142 conferred an odds ratio (OR)=0.70 (95% confidence interval (CI): 0.60–0.82) that remained similar after accounting for HLA-DRB1^*15 carrier status. The association with MOG V142L was still significant after conditioning for all DRB1 alleles (P=0.035). Eleven additional single nucleotide polymorphisms in the MOG gene (namely -1077T/C, -910T/C, -875A/G, -93T/C, S5S, Indel L22, V145I, +814C/T, +900A/G, +1024A/T, +1059C/T), two microsatellites in the MOG 5' flanking (MOGCA) and 3' untranslated (MOGTAAA) regions and four microsatellites in the HLA-class I region, from HLA-B to HFE, (namely MIB, D6S265, D6S1683 and D6S2239) were tested by transmission disequilibrium test in 199 trio families. None of these polymorphisms or of their haplotypic combinations showed a significant transmission distortion, in the absence of V142L. In conclusion, MOG V142L, or an untested variant in tight-linkage disequilibrium with it, is an independent MS susceptibility-modulating factor in the HLA class I region.