High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility.

Autor:	Osoegawa K; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States., Creary LE; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States.; Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States., Montero-Martín G; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States.; Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States., Mallempati KC; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States., Gangavarapu S; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States., Caillier SJ; Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Santaniello A; Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Isobe N; Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Hollenbach JA; Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Hauser SL; Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Oksenberg JR; Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Fernández-Viňa MA; Histocompatibility & Immunogenetics Laboratory, Stanford Blood Center, Palo Alto, CA, United States.; Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 May 25; Vol. 12, pp. 644838. Date of Electronic Publication: 2021 May 25 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.644838
Abstrakt:	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 < 2.20e-16; mTDT: p =1.61e-07; CC: p < 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Osoegawa, Creary, Montero-Martín, Mallempati, Gangavarapu, Caillier, Santaniello, Isobe, Hollenbach, Hauser, Oksenberg and Fernández-Viňa.)
Databáze:	MEDLINE
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