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. (May 2019)

• Record Type: Journal Article
• Authors: Creary, Lisa E; Mallempati, Kalyan C; Gangavarapu, Sridevi; Caillier, Stacy J; Oksenberg, Jorge R; Fernández-Viňa, Marcelo A
• Is Part Of: Multiple sclerosis. Volume 25:Number 6(2019)
• Page Start: 772
• Page End: 782
• Publication Date: 2019-05
• Subjects: Human leukocyte antigen DRB1 -- haplotype -- European-Americans -- next-generation sequencing -- multiple sclerosis -- susceptibility -- protection; Central nervous system -- Diseases -- Periodicals; Myelin sheath -- Diseases -- Periodicals; Inflammation -- Periodicals; Multiple sclerosis -- Periodicals; Central Nervous System Diseases -- Periodicals; Demyelinating Diseases -- Periodicals; Inflammation -- Periodicals; Multiple Sclerosis -- Periodicals; Système nerveux central -- Maladies -- Périodiques; Gaine de myéline -- Maladies -- Périodiques; Inflammation (Pathologie) -- Périodiques; Sclérose en plaques -- Périodiques; Electronic journals; 616.834005
• DOI: 10.1177/1352458518770019
• Languages: English
• ISSNs: 1352-4585

Abstract

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 ~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~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~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~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.