Suppressor Alleles in Multiple Sclerosis: Inheritance and Interactions

Abstract

Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility.

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“…The D6S1610*05‐DRB1*04 haplotype was shared in 5/6 cases and DRB1*04 was observed in 6/7 cases once the 7th affected Hutterite was tissue‐typed. The single non‐DRB1*04 bearing Hutterite was DRB1*08/15; a genotype that confers a relative risk of RR = 4.3 and is second only to DRB1*15/15 in MS risk [Ramagopalan et al, 2007]. While we did not have an appropriate control population, in the literature DRB1*04 has an allele frequency of 0.192 [Weitkamp and Ober, 1999] and this is significantly different than the 0.50 (7/14) allele frequency we observe in our sample ( P = 0.014).…”