High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis

2011 ◽  
Vol 70 (4) ◽  
pp. 690-694 ◽  
Author(s):  
Proton Rahman ◽  
Nicole M Roslin ◽  
Fawnda J Pellett ◽  
Mathieu Lemire ◽  
Celia M T Greenwood ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Psoriatic Arthritis ◽  
Genetic Locus ◽  
Ring Finger ◽  
Primary Objective ◽  
Nucleotide Polymorphisms ◽  
Major Histocompatibility ◽  
Hla Alleles ◽  
Familial Predisposition ◽  
Histocompatibility Complex

ObjectivePsoriatic arthritis (PsA) has a clear familial predisposition, the major histocompatibility complex (MHC) region being the strongest genetic locus. The study primary objective was to identify single nucleotide polymorphisms (SNPs) independent of known human leucocyte antigen (HLA) alleles within the MHC region that are associated with PsA using a high-density SNP map.MethodIn all, 914 samples were assessed, including 427 PsA cases from 2 well established PsA cohorts and 487 controls from Canada. The genotype data consisted of 2521 SNPs from 2 Illumina Goldengate MHC panels, spanning 4.9 Mb of chromosome 6 with an average spacing of 2 kb. Classical HLA alleles were genotyped in all subjects using sequence-specific oligonucleotide probes or sequence-specific primers. A conditioning approach was used to distinguish between new associations and those in linkage disequilibrium (LD) with known HLA alleles.ResultsUnconditional association analysis revealed 43 markers with p<7.26×10−5 (calculated experiment-wide significance threshold). In the conditional analysis, 10 SNPs showed statistically significant association at a threshold of p<7.26×10−5. Seven SNPs were in strong LD in the study data (pairwise r2 >0.77 in the controls) reflecting one association signal. These SNPs spanned a 1.6 Mb region. SNP rs1150735 is 1.5 kb upstream from ring finger protein 39 (RNF39). RNF39 SNPs have been associated with HIV1 disease progression and set point CD4 T cell count.ConclusionFour new loci for either psoriasis or PsA in the MHC region that are independent of known HLA alleles have been identified. The effect size of these variants is modest. Replication of these variants in multiple larger populations is necessary.

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1633-1640 ◽  
Author(s):  
Fay J. Hosking ◽  
Stephen Leslie ◽  
Alexander Dilthey ◽  
Loukas Moutsianas ◽  
Yufei Wang ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Genomic Region ◽  
Nucleotide Polymorphisms ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Hla Dqa1

Abstract A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.

scholarly journals Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

2021 ◽  
pp. annrheumdis-2021-219884
Author(s):  
Marialbert Acosta-Herrera ◽  
Martin Kerick ◽  
Elena Lopéz-Isac ◽  
Shervin Assassi ◽  
Lorenzo Beretta ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Systemic Sclerosis ◽  
Genome Wide Association Study ◽  
Genetic Effect ◽  
Nucleotide Polymorphisms ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Genome Wide ◽  
Novel Association ◽  
Hla Dqa1

ObjectiveThe greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.Methods9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).ResultsSequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation.ConclusionsThis study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.

scholarly journals Genetic variation in the Major Histocompatibility Complex and association with depression

2018 ◽  
Author(s):  
Kylie P Glanville ◽  
Jonathan R I Coleman ◽  
Ken B Hanscombe ◽  
Jack Euesden ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Major Histocompatibility Complex ◽  
Autoimmune Diseases ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Major Histocompatibility ◽  
Hla Alleles ◽  
Histocompatibility Complex ◽  
Mental Health Questionnaire ◽  
Risk For Depression

AbstractBackgroundThe prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. In this study we tested whether genetic variation in the Major Histocompatibility Complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.MethodWe fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB samples, applying both a conservative region-wide significance threshold (3.9-e6) and a candidate threshold (1.6e-4).ResultsNo HLA alleles or C4 haplotypes were associated with depression at the conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression.DiscussionWe found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC.

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