Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF
Ai YakuYuki IshikawaTakeshi IwasakiRyosuke HiwaKeitaro MatsuoHiroh SajiKimiko YurugiYasuo MiuraMoritoshi FuruHiromu ItoTakao FujiiTaira MaekawaMotomu HashimotoKoichiro OhmuraTsuneyo MimoriChikashi Terao
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Abstract Objective HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. Methods We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. Results We found both IgG-RF(+) and IgG-RF(–) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (–) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(–) subset. We confirmed that these associations were irrespective of ACPA presence. Conclusion We found a unique genetic architecture for IgG-RF(–) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.Keywords:
Rheumatoid factor
Genetic architecture
HLA-DRB1
Abstract In this study, polymerase chain reaction‐sequence‐specific oligonucleotide prode (SSOP) typing results for the human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1, DQA1, DQB1, and DPB1) loci in 264 individuals of the Han ethnic group from the Canton region of southern China are presented. The data are examined at the allele, genotype, and haplotype level. Common alleles at each of the loci are in keeping with those observed in similar populations, while the high‐resolution typing methods used give additional details about allele frequency distributions not shown in previous studies. Twenty distinct alleles are seen at HLA‐A in this population. The locus is dominated by the A*1101 allele, which is found here at a frequency of 0.266. The next three most common alleles, A*2402, A*3303, and A*0203, are each seen at frequencies of greater than 10%, and together, these four alleles account for roughly two‐thirds of the total for HLA‐A in this population. Fifty alleles are observed for HLA‐B, 21 of which are singleton copies. The most common HLA‐B alleles are B*4001 ( f = 0.144), B*4601 ( f = 0.119), B*5801 ( f = 0.089), B*1301 ( f = 0.068), B*1502 ( f = 0.073), and B*3802 ( f = 0.070). At the HLA‐C locus, there are a total of 20 alleles. Four alleles (Cw*0702, Cw*0102, Cw*0801, and Cw*0304) are found at frequencies of greater than 10%, and together, these alleles comprise over 60% of the total. Overall, the class II loci are somewhat less diverse than class I. Twenty‐eight distinct alleles are seen at DRB1, and the most common three, DRB1*0901, *1202, and *1501, are each seen at frequencies of greater than 10%. The DR4 lineage also shows extensive expansion in this population, with seven subtypes, representing one quarter of the diversity at this locus. Eight alleles are observed at DQA1; DQA1*0301 and 0102 are the most common alleles, with frequencies over 20%. The DQB1 locus is dominated by four alleles of the 03 lineage, which make up nearly half of the total. The two most common DQB1 alleles in this population are DQB1*0301 ( f = 0.242) and DQB1*0303 ( f = 0.15). Eighteen alleles are observed at DPB1; DPB1*0501 is the most common allele, with a frequency of 37%. The class I allele frequency distributions, expressed in terms of Watterson’s (homozygosity) F ‐statistic, are all within expectations under neutrality, while there is evidence for balancing selection at DRB1, DQA1, and DQB1. Departures from Hardy–Weinberg expectations are observed for HLA‐C and DRB1 in this population. Strong individual haplotypic associations are seen for all pairs of loci, and many of these occur at frequencies greater than 5%. In the class I region, several examples of HLA‐B and ‐C loci in complete or near complete linkage disequilibrium (LD) are present, and the two most common, B*4601‐Cw*0102 and B*5801‐Cw*0302 account for more than 20% of the B‐C haplotypes. Similarly, at class II, nearly all of the most common DR‐DQ haplotypes are in nearly complete LD. The most common DRB1‐DQB1 haplotypes are DRB1*0901‐DQB1*0303 ( f = 0.144) and DRB1*1202‐DQB1*0301 ( f = 0.131). The most common four locus class I and class II combined haplotypes are A*3303‐B*5801‐DRB1*0301‐DPB1*0401 ( f = 0.028) and A*0207‐B*4601‐DRB1*0901‐DPB1*0501 ( f = 0.026). The presentation of complete DNA typing for the class I loci and haplotype analysis in a large sample such as this can provide insights into the population history of the region and give useful data for HLA matching in transplantation and disease association studies in the Chinese population.
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Linkage Disequilibrium
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Next generation sequencing characterizes HLA diversity in a registry population from the Netherlands
Next generation DNA sequencing is used to determine the HLA-A, -B, -C, -DRB1, -DRB3/4/5, and -DQB1 assignments of 1009 unrelated volunteers for the unrelated donor registry in The Netherlands. The analysis characterizes all HLA exons and introns for class I alleles; at least exons 2 to 3 for HLA-DRB1; and exons 2 to 6 for HLA-DQB1. Of the distinct alleles present, there are 229 class I and 71 class II; 36 of these alleles are novel. The majority (approximately 98%) of the cumulative allele frequency at each locus is contributed by alleles that appear three or more times. Alleles encoding protein variation outside of the antigen recognition domains are 0.6% of the class I assignments and 5.3% of the class II assignments.
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Serology-based tests for tuberculosis (TB) diagnosis, though rapid, efficient and easily implemented, have so far shown unsatisfactory levels of sensitivity and specificity, probably due to variations of the antibody response in TB patients. The number and types of seropositive antigens vary from individual to individual. The person-to-person variations of antigen recognition may be linked to genetic polymorphisms of the human leukocyte antigen (HLA) class II alleles. In the present study, we find that there is a significant increase in the frequency of HLA-DRB1*14 (P = 2.5×10-4) among subjects with high antibody response levels compared to those with low antibody levels. HLA-DRB1*15, the most frequent allelic group in the studied active TB population, positively correlates with subjects with low antibody response levels rather than subjects with high antibody response levels (P = 0.005), which indicates the loss of relevant antigens for screening of patients with this allelic group. The potential association between HLA-DRB1 allelic group and individual antigens implies that TB diagnostic yield could be improved by the addition of antigens screened at the proteome scale in infected subjects from the HLA-DRB1*15 allelic group.
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Summary Type 1 diabetes (T1D) is an autoimmune disease with a strong human leucocyte antigen (HLA) class II association. Depending on geographic locations, the disease-associated HLA class II alleles vary. We evaluated the β cell-specific autoimmunity reflected in autoantibodies directed to the smaller isoform of glutamate decarboxylase (GAD65) in Japanese and Swedish T1D patients. GAD65Ab epitope specificities were assessed using GAD65-specific recombinant Fab. GAD65Ab epitope specificities did not differ between Swedish and Japanese patients. Only recognition of the MICA-4-defined middle epitope was significantly stronger in the Japanese T1D patient group compared to the Swedish T1D patients (P = 0·001). Binding to the b96·11-defined middle epitope was substantial in both groups and showed significant associations with high-risk HLA class II haplotypes. In the Japanese T1D group the association was with haplotype DRB1*0802-DQB1*0302 (P = 0·0008), while in the Swedish T1D patients binding to the b96·11-defined epitope as associated with the presence of high-risk HLA genotypes DR3-DQB1*0201 and/or DR4-DQB1*0302 (P = 0·02). A significant association between reduction in binding in the presence of recombinant Fab (rFab) DPD and high-risk allele DQB1*0201 was found (P = 0·008) in the Swedish T1D patients only. We hypothesize that epitope-specific autoantibodies effect the peptide presentation on HLA class II molecules by modulating antigen uptake and processing. Molecular modelling of the high-risk HLA class II molecules will be necessary to test whether these different molecules present similar peptide-binding specificities.
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Two human leukocyte antigen (HLA)-DRB1 (HLA-DRB1*1376 and -DRB1*1465) and one HLA-A (HLA-A*2471) novel alleles have been identified in individuals from the Brazilian Bone Marrow Donor Registry. DNA sequencing of exon 2 for HLA-DRB1 alleles showed two and five nucleotide substitutions in -DRB1*1376 and -DRB1*1465, compared with closely related alleles, respectively. These substitutions result in a change of amino acid residues in HLA-DRB1*1376 at position 74 (Arg --> Glu) and in -DRB*1465 at positions 47 (Tyr --> Phe), 57 (Asp --> Ser) and 74 (Glu --> Ala). On the other hand, sequence analysis of exons 2 and 3 for HLA-A*2471 showed a single substitution, leading to a single amino acid change at position 151 (His --> Arg). These three novel alleles may have originated from other HLA alleles by gene conversion. However, it is also possible that HLA-A*2471 has evolved from one of the alleles of the HLA-A*2402 group through a point mutation.
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