Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis

Abstract

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…Variation in the MHC, specifically the HLA-DRB1*15 haplotype, is the strongest known genetic factor for MS, and results from multiple studies support this association. 32,33 The complex contribution from this region, however, is estimated to account for only a portion of the risk for the disease. On the basis of these results, it is clear that common (frequency 45 to 10%) non-MHC MS susceptibility alleles confer quite modest risk (odd ratios o2), and are difficult to detect using linkage studies.…”

“…20 The diagnostic criteria, ascertainment protocols and clinical and demographic characteristics of these populations are described in more detail elsewhere. 31,32,36,45 The EDSS 46 was used in conjunction with disease duration to define very mild or severe forms of MS as a secondary phenotype for analysis, as previously described. 32 Disease duration was measured as the number of years between the year of onset of first symptom and year of last exam with EDSS assessment; in most cases this is at the entry of the study, given the cross-sectional nature of these datasets.…”

Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

“…The strongest susceptibility signal maps to the HLA-DRB1 gene in the class II region of the major histocompatibility complex (MHC) (Barcellos et al, 2006;Yeo et al, 2007). Recently, the two largest genome-wide association studies (GWAS) of MS genetics confirmed HLA as the major MS susceptibility locus and provided unequivocal evidence for the association of additional 110 non-MHC "candidate" genetic variants conferring susceptibility to the disease (IMSGC, 2011;IMSGC, 2013).…”

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

“…The risk haplotype that has been identified for the Caucasian populations is HLA DRB1*1501-DQB1*0602 (also known as DR15 haplotype) in the HLA-class II region. In the Italian 3 as well as in other European populations, [4][5][6] DR15 confers an odds ratio (OR) of about 3.…”