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1.
Am J Hum Genet ; 105(3): 616-624, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474319

RESUMO

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10-17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

2.
Nat Commun ; 10(1): 3685, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31417091

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity. Several AIS susceptibility loci have been identified; however, they could explain only a small proportion of AIS heritability. To identify additional AIS susceptibility loci, we conduct a meta-analysis of the three genome-wide association studies consisting of 79,211 Japanese individuals. We identify 20 loci significantly associated with AIS, including 14 previously not reported loci. These loci explain 4.6% of the phenotypic variance of AIS. We find 21 cis-expression quantitative trait loci-associated genes in seven of the fourteen loci. By a female meta-analysis, we identify additional three significant loci. We also find significant genetic correlations of AIS with body mass index and uric acid. The cell-type specificity analyses show the significant heritability enrichment for AIS in multiple cell-type groups, suggesting the heterogeneity of etiology and pathogenesis of AIS. Our findings provide insights into etiology and pathogenesis of AIS.

3.
Ann Rheum Dis ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427439

RESUMO

OBJECTS: Although the association of cigarette smoking (CS) with susceptibility to rheumatoid arthritis (RA) has been established, the impact of CS on anticitrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) levels in RA has yet been clear, especially in relation to shared epitope (SE) alleles. METHODS: A total of 6239 subjects, the largest Asian study ever, from two independent Japanese cohorts were enrolled. Precise smoking histories, levels of ACPA and RF, and HLA-DRB1 allele status were withdrawn from databases. Associations between CS and high ACPA or RF levels, defined by the top quartiles, were evaluated. The effect of HLA-DRB1 alleles on the association was further investigated. RESULTS: CS at RA onset conferred the risks of high levels of both antibodies, especially RF (OR 2.06, p=7.4×10-14; ACPA, OR 1.29, p=0.012), suggesting that RF level is more sensitive to CS than ACPA level. The patients who had quitted CS before RA onset showed a trend of decreased risks of developing high levels of ACPA or RF, and the risks steadily decreased according to the cessation years. The association of CS with high ACPA level was observed only in subjects carrying SE alleles, while the association of high RF level was observed regardless of SE. CONCLUSIONS: CS confers the risks of high autoantibody levels in RA in different manners; CS interacts with SE alleles on ACPA level, while CS impacts on RF level despite SE allele. These data suggest novel distinct production mechanisms of RF and ACPA.

4.
Front Immunol ; 10: 1066, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164884

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component. We recently identified a novel SLE susceptibility locus near RASGRP1, which governs the ERK/MAPK kinase cascade and B-/T-cell differentiation and development. However, precise causal RASGRP1 functional variant(s) and their mechanisms of action in SLE pathogenesis remain undefined. Our goal was to fine-map this locus, prioritize genetic variants likely to be functional, experimentally validate their biochemical mechanisms, and determine the contribution of these SNPs to SLE risk. We performed a meta-analysis across six Asian and European cohorts (9,529 cases; 22,462 controls), followed by in silico bioinformatic and epigenetic analyses to prioritize potentially functional SNPs. We experimentally validated the functional significance and mechanism of action of three SNPs in cultured T-cells. Meta-analysis identified 18 genome-wide significant (p < 5 × 10-8) SNPs, mostly concentrated in two haplotype blocks, one intronic and the other intergenic. Epigenetic fine-mapping, allelic, eQTL, and imbalance analyses predicted three transcriptional regulatory regions with four SNPs (rs7170151, rs11631591-rs7173565, and rs9920715) prioritized for functional validation. Luciferase reporter assays indicated significant allele-specific enhancer activity for intronic rs7170151 and rs11631591-rs7173565 in T-lymphoid (Jurkat) cells, but not in HEK293 cells. Following up with EMSA, mass spectrometry, and ChIP-qPCR, we detected allele-dependent interactions between heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and rs11631591. Furthermore, inhibition of hnRNP-K in Jurkat and primary T-cells downregulated RASGRP1 and ERK/MAPK signaling. Comprehensive association, bioinformatics, and epigenetic analyses yielded putative functional variants of RASGRP1, which were experimentally validated. Notably, intronic variant (rs11631591) is located in a cell type-specific enhancer sequence, where its risk allele binds to the hnRNP-K protein and modulates RASGRP1 expression in Jurkat and primary T-cells. As risk allele dosage of rs11631591 correlates with increased RASGRP1 expression and ERK activity, we suggest that this SNP may underlie SLE risk at this locus.

5.
Genome Biol ; 20(1): 117, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159850

RESUMO

BACKGROUND: Structural variations (SVs) or copy number variations (CNVs) greatly impact the functions of the genes encoded in the genome and are responsible for diverse human diseases. Although a number of existing SV detection algorithms can detect many types of SVs using whole genome sequencing (WGS) data, no single algorithm can call every type of SVs with high precision and high recall. RESULTS: We comprehensively evaluate the performance of 69 existing SV detection algorithms using multiple simulated and real WGS datasets. The results highlight a subset of algorithms that accurately call SVs depending on specific types and size ranges of the SVs and that accurately determine breakpoints, sizes, and genotypes of the SVs. We enumerate potential good algorithms for each SV category, among which GRIDSS, Lumpy, SVseq2, SoftSV, Manta, and Wham are better algorithms in deletion or duplication categories. To improve the accuracy of SV calling, we systematically evaluate the accuracy of overlapping calls between possible combinations of algorithms for every type and size range of SVs. The results demonstrate that both the precision and recall for overlapping calls vary depending on the combinations of specific algorithms rather than the combinations of methods used in the algorithms. CONCLUSION: These results suggest that careful selection of the algorithms for each type and size range of SVs is required for accurate calling of SVs. The selection of specific pairs of algorithms for overlapping calls promises to effectively improve the SV detection accuracy.


Assuntos
Variação Estrutural do Genoma , Genômica/métodos , Sequenciamento Completo do Genoma , Algoritmos , Humanos
6.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
7.
Mod Rheumatol ; : 1-7, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31104539

RESUMO

IgG4-related disease (IgG4-RD) is an emerging concept of a novel clinical entity, characterized by the swelling of the affected organs, increase in serum total IgG and IgG4 levels, infiltration of plasmacyte and eosinophil, fibrosis of the affected lesions and good response to corticosteroid. IgG4-RD includes diseases with organ-specific fibrosis and infiltration of IgG4-positive plasmacyte, previously known as type 1 autoimmune pancreatitis (AIP), Mikulicz's disease and others. Although the precise mechanisms of the pathogenesis of IgG4-RD are not yet understood, some studies have suggested genetic components contributing to the onset of IgG4-RD or its subgroup. The recent emergence of the concept of IgG4-RD has made it difficult to conduct genetic analyses of IgG4-RD as a whole. When the analyses are restricted to the various subgroups of IgG4-RD, they require a large number of DNA samples from patients satisfying IgG4-RD diagnostic criteria not completely overlapping the criteria in type 1 AIP, Mikulicz's disease and others. Not only HLA but also non-HLA genes have been described as IgG4-RD risk genes, particularly in type 1 AIP. In this mini-review article, we will explore previous studies analyzing genetic associations with IgG4-RD and its subgroups, and discuss the future direction of the research addressing the existing problems.

8.
PLoS Genet ; 15(4): e1008092, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31022184

RESUMO

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.

9.
J Am Soc Nephrol ; 30(5): 855-864, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30975718

RESUMO

BACKGROUND: A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. METHODS: To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. RESULTS: The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). CONCLUSIONS: Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30803720

RESUMO

BACKGROUND: It has been well known that TNF-α inhibitor (TNFi) treatment for patients with rheumatoid arthritis (RA) is associated with anti-nuclear antibody (ANA) development. We previously reported that ANA development was associated with poor outcomes of infliximab (IFX) treatment (1). However, no replication studies have been reported to date. In addition, whether the findings are true to general biological disease-modifying anti-rheumatic drugs (bDMARDs) is uncertain. METHODS: To evaluate an association between treatment response and ANA development during bDMARDs treatment in RA and to analyze correlates of ANA development, Japanese RA patients treated with (n = 657) or without (n = 211) bDMARDs as a first line bDMARD were enrolled from a single center cohort. ANA was measured by an indirect immunofluorescence assay at multiple time points of treatment. We analyzed associations between ANA development and insufficient response to treatment. Correlates of ANA development were also analyzed. RESULTS: ANA development (≥2 times baseline levels) at 3 months and at 6-12 months after bDMARDs initiation were significantly associated with insufficient response at 3-12 months (odds ratio (OR)=3.51, p = 0.020) and at 12-24 months (OR = 3.16, p = 0.038), respectively. The associations remained significant after conditioning on the use of each bDMARD. The use of IFX (OR = 6.24, p < 0.001) was a risk for ANA development, and other TNFi showed the same tends as infliximab. On the other hand, non-TNFi bDMARDs were not associated with ANA development. CONCLUSIONS: ANA development could be a marker of poor treatment response in RA patients undergoing bDMARDs treatment. Undefined factors might influence ANA development and subsequent poor bDMARDs outcome in RA.

11.
Ann Rheum Dis ; 78(4): 509-518, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30679154

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice. METHODS: We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant. RESULTS: We found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10-11 and 3.7×10-8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody. CONCLUSIONS:  We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30498034

RESUMO

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

13.
Nucleic Acids Res ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407537

RESUMO

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

15.
Mod Rheumatol ; : 1-7, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092163

RESUMO

OBJECTIVES: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients. METHODS: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses. RESULTS: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia. CONCLUSION: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.

16.
Mod Rheumatol ; 28(5): 766-769, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29651889

RESUMO

Rare autoimmune diseases are difficult to conduct researches in spite of present era with advanced scientific progress. Research using genetic approach is a promising way since genetic findings implicate causality of diseases. Still, there are multiple obstacles preventing genetic studies of rare diseases. Here, we list up the problems and propose solutions for them with detailed examples. The biggest problem is that it is difficult to collect a substantial number of DNA samples from patients with rare diseases. We propose to collaborate not only with academic institutions and hospitals but with patients' groups. Detailed examples include studies about Takayasu arteritis (TAK), relapsing polychondritis, and systemic sclerosis. In TAK, we identified IL12B, a key gene which seems to play a central role in the disease. After getting evidence of IL12p40 encoded by IL12B as a possible therapeutic target by showing similarities of the genetic background between TAK and ulcerative colitis, we performed a pilot clinical study of ustekinumab, a monoclonal antibody against IL12p40 for patients with refractory TAK and obtained good response. This is a good example of how genetic findings in a rare disease lead to development of new therapeutic option.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Doenças Autoimunes/tratamento farmacológico , Estudo de Associação Genômica Ampla/métodos , Humanos , Terapia de Alvo Molecular/métodos , Variantes Farmacogenômicos , Doenças Raras/tratamento farmacológico , Doenças Raras/genética
17.
J Rheumatol ; 45(4): 470-480, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29419463

RESUMO

OBJECTIVE: HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF. METHODS: A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions. RESULTS: RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10-5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10-5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70). CONCLUSION: The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.

18.
J Med Genet ; 54(12): 853-858, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29025870

RESUMO

BACKGROUND: HLA-DRB1 is the strongest susceptibility gene to rheumatoid arthritis (RA). HLA-DRB1 alleles showed significant non-additive and interactive effects on susceptibility to RA in the European population, but these effects on RA susceptibility should vary between populations due to the difference in allelic distribution. Furthermore, non-additive or interactive effects on the phenotypes of RA are not fully known. We evaluated the non-additive and interactive effects of HLA-DRB1 alleles on RA susceptibility and anticitrullinated protein/peptide antibody (ACPA) levels in Japanese patients. METHODS: A total of 5581 ACPA(+) RA and 19 170 controls were genotyped or imputed for HLA-DRB1 alleles. Logistic regression analysis was performed for both allelic non-additive effects and interactive effects of allelic combinations. The significant levels were set by Bonferroni's correction. A total of 4371 ACPA(+) RA were analysed for ACPA levels. RESULTS: We obtained evidence of non-additive and interactive effects of HLA-DRB1 on ACPA(+) RA susceptibility (p=2.5×10-5 and 1.5×10-17, respectively). Multiple HLA-DRB1 alleles including HLA-DRB1*04:05, the most common susceptibility allele in the Japanese, showed significant non-additive effects (p≤0.0043). We identified multiple allelic combinations with significant interactive effects including a common combination with the European population as well as novel combinations. Additional variance of ACPA(+) RA susceptibility could be explained substantially by heterozygote dominance or interactive effects. We did not find evidence of non-additive and interactive effects on levels of ACPA. CONCLUSION: HLA allelic non-additive and interactive effects on ACPA(+) RA susceptibility were observed in the Japanese population. The allelic non-additive and interactive effects depend on allelic distribution in populations.


Assuntos
Alelos , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/etiologia , Autoanticorpos/imunologia , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Substituição de Aminoácidos , Autoantígenos/imunologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Japão/epidemiologia , Masculino , Vigilância da População
19.
Arthritis Res Ther ; 19(1): 197, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28874185

RESUMO

BACKGROUND: A previous study revealed the association between susceptibility to Takayasu arteritis (TAK) and a single nucleotide polymorphism (SNP) rs6871626 located in IL12B, which encodes interleukin (IL)-12p40, a common component of IL-12p70 and IL-23. We investigated the expression of these cytokines in patients with TAK, stratifying them into those with or without the risk allele at the rs6871626 SNP. METHODS: Plasma levels of IL-12p40, IL-12p70, and IL-23 were quantified in 44 patients with TAK and 19 healthy controls (HCs) by enzyme-linked immunosorbent assays. Monocytes were obtained from 20 patients with TAK and 14 HCs, treated with interferon-γ (IFN-γ) and lipopolysaccharide, and then supernatant cytokines were quantified. In addition, the ratio of IFN-γ+ or IL-17A+ cells to CD4+ T cells was measured by flow cytometric analysis of peripheral blood mononuclear cells. RESULTS: The levels of plasma IL-12p40, plasma IL-12p70, and supernatant IL-12p70 were significantly higher in patients with TAK than in HCs, whereas there were no significant differences in the levels of plasma IL-23, supernatant IL-23, or supernatant IL-12p40. The levels of plasma IL-12p70, supernatant IL-12p40, and supernatant IL-12p70 were significantly higher in patients with the risk allele than in those without. The ratio of CD4+IFN-γ+ cells was significantly higher in patients with the risk allele, whereas CD4+IL-17A+ cells showed no differences. CONCLUSIONS: The rs6871626 SNP in IL12B may influence the increased expression of IL-12p40 and IL-12p70. These enhanced cytokines might play roles in the pathophysiology of TAK.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Subunidade p40 da Interleucina-12/genética , Interleucina-12/genética , Arterite de Takayasu/genética , Adulto , Biomarcadores/sangue , Feminino , Humanos , Interleucina-12/sangue , Subunidade p40 da Interleucina-12/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Arterite de Takayasu/sangue , Arterite de Takayasu/fisiopatologia
20.
Sci Rep ; 7(1): 6911, 2017 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-28761166

RESUMO

Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9,575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3,353 RA patients and confirmed the findings. ACA was also associated with Raynaud's phenomenon (p = 6.8 × 10-11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.

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