High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis

Mack, Steven J.; Udell, Julia; Cohen, Franziska; Osoegawa, Kazutoyo; Hawbecker, Sharon K.; Noonan, David; Ladner, Martha; Goodridge, Damian; Trachtenberg, Elizabeth; Oksenberg, Jorge R.; Erlich, Henry A.

doi:10.1038/s41435-017-0006-8

Cited by 15 publications

(18 citation statements)

References 87 publications

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“…Of the significantly associated HLA haplotypes and alleles reported by Mack, et al . in Europeans, three were nominally associated with MS in at least one admixed population in this study[18]. In particular, the HLA-DRB1*03 : 01 and HLA-A*02 : 01 alleles in African Americans exhibited similar ORs and direction of effect (Table 5).…”

Section: Discussionmentioning

confidence: 61%

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

et al. 2019

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Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

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Section: Discussionmentioning

confidence: 61%

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

et al. 2019

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“… c Associated with Lupus erythematosus (Miyagawa et al, 1997 ). d Associated with central nervous system demyelination and autoimmune disease (Dyment et al, 2005 ; Kaushansky and Ben-Nun, 2014 ; Mack et al, 2019 ) . e Associated with celiac disease (Selleski et al, 2018 ; Farina et al, 2019 ) .…”

Section: Resultsmentioning

confidence: 99%

Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg

et al. 2021

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Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although <1% of cases develop severe neurological manifestations such as inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) like acute disseminated encephalomyelitis (ADEM) and extensive transverse myelitis. Genetic factors associated with host response and disease severity are still poorly understood. In this study, we performed whole-exome sequencing (WES) to identify HLA alleles, genes and cellular pathways associated with CNS IDD clinical phenotype outcomes following CHIKV infection. The cohort includes 345 patients of which 160 were confirmed for CHIKV. Six cases presented neurological manifestation mimetizing CNS IDD. WES data analysis was performed for 12 patients, including the CNS IDD cases and 6 CHIKV patients without any neurological manifestation. We identified 29 candidate genes harboring rare, pathogenic, or probably pathogenic variants in all exomes analyzed. HLA alleles were also determined and patients who developed CNS IDD shared a common signature with diseases such as Multiple sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD). When these genes were included in Gene Ontology analyses, pathways associated with CNS IDD syndromes were retrieved, suggesting that CHIKV-induced CNS outcomesmay share a genetic background with other neurological disorders. To our knowledge, this study was the first genome-wide investigation of genetic risk factors for CNS phenotypes in CHIKV infection. Our data suggest that HLA-DRB1 alleles associated with demyelinating diseases may also confer risk of CNS IDD outcomes in patients with CHIKV infection.

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“…Studies have shown that HLA plays an important role in almost all immune-related diseases, including MS. HLA is divided into HLA-I, -II, and -III regions, of which I and II are the most polymorphic regions in the human genome, which can lead to different combinations of genotypes or haplotypes. Class I contains HLA-expressing A, B, C, and other major sites, and class II mainly includes 3 sub-zones: DP, DQ, and DR [45–47]. Since the 1970s, HLA loci have been reported to be associated with MS [48], and the relationship between HLA genes and MS susceptibility has been increasingly studied.…”

Section: Genetics and Smoking-induced Msmentioning

confidence: 99%

Correlation Between Smoking and Passive Smoking with Multiple Sclerosis and the Underlying Molecular Mechanisms

Wang

Xie

et al. 2019

Med Sci Monit

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Multiple sclerosis (MS) is a chronic immune-mediated disease of the spinal cord and brain. Many studies have shown that smoking and passive smoking are key environmental risk factors for MS.Here, we provide an overview of the human leukocyte antigen (HLA) gene studies on smoking and MS risk, and we discuss recent studies on between epigenetics and smoking-induced MS. In addition, in this review we also summarize current research advances in biological pathways and smoking-induced MS.This review provides an overview of studies on the association between smoking, passive smoking, and MS susceptibility, and the underlying molecular mechanism.

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High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis

Cited by 15 publications

References 87 publications

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg

Correlation Between Smoking and Passive Smoking with Multiple Sclerosis and the Underlying Molecular Mechanisms

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