In:
Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-5-25)
Kurzfassung:
Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p & lt; 2.20e-16; mTDT: p =1.61e-07; CC: p & lt; 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.
Materialart:
Online-Ressource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2021.644838
DOI:
10.3389/fimmu.2021.644838.s001
DOI:
10.3389/fimmu.2021.644838.s002
DOI:
10.3389/fimmu.2021.644838.s003
DOI:
10.3389/fimmu.2021.644838.s004
DOI:
10.3389/fimmu.2021.644838.s005
DOI:
10.3389/fimmu.2021.644838.s006
DOI:
10.3389/fimmu.2021.644838.s007
DOI:
10.3389/fimmu.2021.644838.s008
DOI:
10.3389/fimmu.2021.644838.s009
DOI:
10.3389/fimmu.2021.644838.s010
DOI:
10.3389/fimmu.2021.644838.s011
DOI:
10.3389/fimmu.2021.644838.s012
DOI:
10.3389/fimmu.2021.644838.s013
DOI:
10.3389/fimmu.2021.644838.s014
Sprache:
Unbekannt
Verlag:
Frontiers Media SA
Publikationsdatum:
2021
ZDB Id:
2606827-8
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