HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Abstract

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR ¼ 0.61; 95% confidence intervals, CI ¼ 0.51-0.72, Po10 À9 ), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI ¼ 0.13-0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI ¼ 0.58-0.83) with a significant (P ¼ 4.94 Â 10 À5 ) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR ¼ 3.89, P ¼ 0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively.

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

“…This opposite behavior has been observed for other HLA alleles, for example, associated with MS susceptibility and belonging to different ancestral HLA haplotypes. 24 It is worth noting that HLA A*32 and DRB1*1501 are part of the HLA-A19 haplotype (with the closely linked alleles HLA A*29, A*30 and A*33) that was found significantly under-transmitted in MS patients. 25 Although with caution owing to the exploratory nature of our analysis and without the support of functional studies, we hypothesized that the observed HLA DRB1*1501 modulation of the effect of several HLA alleles might suggest epistatic models of allele interactions.…”

The Role of HLA in MS Susceptibility and Phenotype

“…Recently, particular attention has been on the protective effects of some of the class I HLA molecules. HLA-A*02 has been reported to confer protection against MS in multiple casecontrol studies (Bettencourt et al 2012;Bergamaschi et al 2010Bergamaschi et al , 2011Brynedal et al 2007;Burfoot et al 2008;Link et al 2010;Rubio et al 2002;Sawcer et al 2011;Silva et al 2009). However, a protective effect of HLA-A*02 was not observed in studies investigating transmission of HLA in MS families (Chao et al 2007), and recent reports suggest that HLA-A*02 might only exert protective effects in the absence of HLA-DRB1*15:01 (Link et al 2012).…”

The Role of Environment and Lifestyle in Determining the Risk of Multiple Sclerosis

“…Genetic susceptibility to MS is mainly located within the MHC region (Ascherio and Munger 2007a;Brynedal et al 2007;Gale and Martyn 1995;Lincoln et al 2005), but several other non-MHC genetic loci have been observed to confer a less pronounced influence on MS risk (Bergamaschi et al 2010;Burfoot et al 2008).…”

“…As in most autoimmune/inflammatory disorders, the strongest genetic associations with MS are located within the human leukocyte antigen (HLA) complex. The class II allele HLA-DRB1*15 increases the risk of developing MS in almost all populations, with an odds ratio (OR) around 3 (Lincoln et al 2005), whereas the class I allele HLA-A*02 has a protective effect with an OR of approximately 0.7 (Bergamaschi et al 2010;Brynedal et al 2007;Burfoot et al 2008). Over recent years, genome-wide association studies (GWAS) have identified a large number of genetic regions outside the HLA complex that influence disease susceptibility.…”