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Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.

ABSTRACT: Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual's underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.

SUBMITTER: Hanson AL

PROVIDER: S-EPMC9214260 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionHuman leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications.MethodsWe included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population.ResultsOur study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and -DRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients.ConclusionThis is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical presentations as well as different autoantibody profiles in Mexicans.

Project description:Natural killer (NK) cells are key participants in the innate immune response. Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of NK cells through the recognition of human leukocyte antigen (HLA) class I molecules. We investigated the impact of KIR/HLA combinations on susceptibility and long-term clinical outcome in Japanese patients with type 1 autoimmune hepatitis (AIH). Methods:A total of 154 cases of AIH were recruited at Shinshu University Hospital between 1974 and 2018. KIR genes and HLA class I and II alleles were genotyped in all patients along with 201 healthy individuals. Associations between KIR/HLA pairs and clinical outcomes (liver decompensation and liver-related death) were evaluated using the Cox proportional hazards model with stepwise method. Results:After a median follow-up period of 11.1 years, 12% of patients experienced liver decompensation and 8% died from liver disease. KIR3DL1/HLA-B Bw4-80Ile (p = 0.0062) and the HLA-DRB1*04:05-DQB1*04:01 haplotype (p ?0.001) were significantly associated with AIH. Conversely, significant protective associations were found for KIR3DL1/HLA-B Bw4-80Thr (p = 0.0092) and KIR2DL1/HLA-C2 (p = 0.0025). The KIR3DL1/HLA-B Bw4-positive phenotype was strongly associated with a favorable clinical outcome (liver decompensation: hazard ratio [HR] 0.37, p = 0.037; liver-related death: HR 0.26, p = 0.038). Cirrhosis was detected in 16 (10%) patients at diagnosis and was significantly related to poor survival (HR 17.87, p ?0.001) and progression to liver decompensation (HR 9.00, p ?0.001). Conclusions:This study revealed the impact of specific KIR/HLA pairs in AIH susceptibility and progression in Japanese patients. KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis at diagnosis are at high risk of adverse outcomes and require careful surveillance. Lay summary:Autoimmune hepatitis (AIH) is a disease of the liver that can present in acute or chronic hepatitis. We examined whether KIR/HLA pairs were associated with AIH susceptibility or disease progression. KIR3DL1/HLA-B Bw4 was a novel KIR/HLA pair related to a favorable clinical outcome, while cirrhosis at the initial diagnosis was a risk factor for poor prognosis. Thus, frequent and careful surveillance is advised for KIR3DL1/HLA-B Bw4-negative patients with AIH and cirrhosis.

Project description: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.

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Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.

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