Contributions
Abstract: P443
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 14 Genetics/Epigenetics
Background: The strongest disease association signal genome-wide in MS maps within the major histocompatibility complex (MHC). This multi-genic and multi-allelic association has been observed across all populations studied, but has not been fully decoded yet. The lower linkage disequilibrium in African Americans compared to Europeans provides an opportunity to further fine-map this key disease risk locus and better describe the allelic heterogeneity driving susceptibility.
Goals: Fine-map HLA in an African American MS cohort.
Methods: 1,305 African American MS cases and 1,155 controls were genotyped on the custom MS Chip. The MHC region is densely covered with ~7,000 SNPs allowing for a deep analysis of the locus and robust imputation of classical HLA alleles. 651 samples with existing two-field HLA-A, B, C, DRB1 and DQB1 genotyping were used to train HLA imputation models for the remaining 1,809 individuals. HLA association with MS was tested using a logistic regression model, and SNPs outside classical HLA loci were examined to fine-map extended HLA haplotypes. We used data from the 1KG RNA-seq project to assess allelic-specific expression variance.
Results: We replicated the association of A*02:01 (p=1.7x10-4, OR=0.71) and DRB1*15:01 (p=1.2x10-4, OR=1.84). We also identified a previously unrecognized class I protective allele B*53:01 (p=8.5x10-4, OR=0.7), a private African allele. Despite differing in a single amino acid at position 30 with DRB1*15:01, the African DRB1*15:03 allele is not associated with MS in this dataset. Interestingly, 15:01 or 15:03 were found to segregate exclusively with a seven SNPs haplotype, and it includes rs8084 [A/C], a splice acceptor variant for HLA-DRA. Alternative splicing has been previously shown to result in expression of a short (-25 amino acids) DRA transcript. Our analysis of the 1KG RNA-seq dataset shows significantly higher relative abundance of the short transcript associated with the DRB1*15:01-linked SNP (A) (p=2.8x10-11).
Conclusions: We identified a new class I protective allele, B*53:01, which is found at high frequency in African but not European populations. We show that a DRB1*15:01-linked SNP leads to expression of an alternative DRA transcript with a predicted functional protein and important implications for the HLA class II heterodimer in MS susceptibility. Analysis of public tissue specific protein databases suggests the alternate transcript may be preferentially expressed in the brain.
Disclosure:
V. Damotte has nothing to disclose
N. Isobe has nothing to disclose
S. Caillier has nothing to disclose
M. K. Misra has nothing to disclose
A. Santaniello has nothing to disclose
J. McCauley has nothing to disclose
S. L. Hauser serves on the Scientific Advisory Boards for Annexon, Symbiotix, Bionure, Neurona, and Molecular Stethoscope. Dr. Hauser also has received travel reimbursement and writing assistance from F. Hoffman-La Roche Ltd. for CD20-related meetings and presentations.
J. Oksenberg has nothing to disclose
J. Hollenbach has nothing to disclose
Abstract: P443
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 14 Genetics/Epigenetics
Background: The strongest disease association signal genome-wide in MS maps within the major histocompatibility complex (MHC). This multi-genic and multi-allelic association has been observed across all populations studied, but has not been fully decoded yet. The lower linkage disequilibrium in African Americans compared to Europeans provides an opportunity to further fine-map this key disease risk locus and better describe the allelic heterogeneity driving susceptibility.
Goals: Fine-map HLA in an African American MS cohort.
Methods: 1,305 African American MS cases and 1,155 controls were genotyped on the custom MS Chip. The MHC region is densely covered with ~7,000 SNPs allowing for a deep analysis of the locus and robust imputation of classical HLA alleles. 651 samples with existing two-field HLA-A, B, C, DRB1 and DQB1 genotyping were used to train HLA imputation models for the remaining 1,809 individuals. HLA association with MS was tested using a logistic regression model, and SNPs outside classical HLA loci were examined to fine-map extended HLA haplotypes. We used data from the 1KG RNA-seq project to assess allelic-specific expression variance.
Results: We replicated the association of A*02:01 (p=1.7x10-4, OR=0.71) and DRB1*15:01 (p=1.2x10-4, OR=1.84). We also identified a previously unrecognized class I protective allele B*53:01 (p=8.5x10-4, OR=0.7), a private African allele. Despite differing in a single amino acid at position 30 with DRB1*15:01, the African DRB1*15:03 allele is not associated with MS in this dataset. Interestingly, 15:01 or 15:03 were found to segregate exclusively with a seven SNPs haplotype, and it includes rs8084 [A/C], a splice acceptor variant for HLA-DRA. Alternative splicing has been previously shown to result in expression of a short (-25 amino acids) DRA transcript. Our analysis of the 1KG RNA-seq dataset shows significantly higher relative abundance of the short transcript associated with the DRB1*15:01-linked SNP (A) (p=2.8x10-11).
Conclusions: We identified a new class I protective allele, B*53:01, which is found at high frequency in African but not European populations. We show that a DRB1*15:01-linked SNP leads to expression of an alternative DRA transcript with a predicted functional protein and important implications for the HLA class II heterodimer in MS susceptibility. Analysis of public tissue specific protein databases suggests the alternate transcript may be preferentially expressed in the brain.
Disclosure:
V. Damotte has nothing to disclose
N. Isobe has nothing to disclose
S. Caillier has nothing to disclose
M. K. Misra has nothing to disclose
A. Santaniello has nothing to disclose
J. McCauley has nothing to disclose
S. L. Hauser serves on the Scientific Advisory Boards for Annexon, Symbiotix, Bionure, Neurona, and Molecular Stethoscope. Dr. Hauser also has received travel reimbursement and writing assistance from F. Hoffman-La Roche Ltd. for CD20-related meetings and presentations.
J. Oksenberg has nothing to disclose
J. Hollenbach has nothing to disclose