Dataset Information

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

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.

SUBMITTER: Creary LE

PROVIDER: S-EPMC6365219 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

Creary Lisa E LE Mallempati Kalyan C KC Gangavarapu Sridevi S Caillier Stacy J SJ Oksenberg Jorge R JR Fernández-Viňa Marcelo A MA

Multiple sclerosis (Houndmills, Basingstoke, England) 20180423 6

<h4>Background</h4>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.<h4>Objectives</h4>To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with ...[more]

PMID: 29683085

Similar Datasets

Project description:In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.

Dataset Information

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

Background

Objectives

Methods

Results

Conclusion

Publications

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Objectives

Methods

Results

Conclusion

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

Deconstruction of HLA-DRB104:01:01 and HLA-DRB115:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.