AUTHOR=Osoegawa Kazutoyo , Creary Lisa E. , Montero-Martín Gonzalo , Mallempati Kalyan C. , Gangavarapu Sridevi , Caillier Stacy J. , Santaniello Adam , Isobe Noriko , Hollenbach Jill A. , Hauser Stephen L. , Oksenberg Jorge R. , Fernández-Viňa Marcelo A. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.644838

DOI=10.3389/fimmu.2021.644838

ISSN=1664-3224

ABSTRACT=Multiple sclerosis (MS) shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes from 477 MS patients and their 954 unaffected parents using NGS typing system. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using transmission disequilibrium test (TDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and a cohort of healthy unrelated ethnically matched controls. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (TDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (TDT: 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 significantly high protection (TDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 and DQB1*03:03, 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 and the alleles B*27:05 and B*38:01 showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of various haplotype segments, 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.