Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

Background: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated. Objectives: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS. Methods: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals. Results: HLA-DRB1*15:01:01:01SG (OR = 3.20, p < 2.2E-16), HLA-DRB5*01:01:01 (OR = 2.96, p < 2.2E-16), and HLA-DRB5*01:01:01v1_STR1 (OR = 8.18, p = 4.3E-05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01 similar to HLA-DQA1*01:02:01:01SG similar to HLA-DRB1*15:01:01:01SG similar to HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01 similar to HLA-DQA1*01:02:01:01SG similar to HLA-DRB1*15:01:01:01SG similar to HLA-DRB5*01:01:01v1_STR1 (OR = 3.19, p < 2.2E-16; OR = 9.30, p = 9.7E-05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01 similar to HLA-DQA1*03:03:01:01 similar to HLA-DRB1*04:01:01:01SG similar to HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01 similar to HLA-DQA1*03:01:01 similar to HLA-DRB1*04:01:01:01SG similar to HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR = 1.66, p = 4.9E-03). Conclusion: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.