Clinical Role of Human Leukocyte Antigen in Health and Disease

Mosaad, Youssef M.

doi:10.1111/sji.12329

Cited by 149 publications

(128 citation statements)

References 172 publications

(236 reference statements)

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“…Diseases such as autoimmune, inflammatory and malignant diseases are significantly more common among individuals carrying particular HLA alleles. 10 Many of the genes in the MHC region are hypermutable, which is fundamental for their function. This is particularly relevant for HLA genes involved in the induction and regulation of the immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Variants in this region may account for 30%-50% of genetic T1D risk. 10 In addition to HLA genes, numerous other genes in the MHC region, such as TNF, MICA, MICB and MOG, also have apparent immunological roles. [11][12][13] The potential importance of this genetic locus in disease aetiology is also highlighted by the significant proportion of conditions that are genetically mapped to these genes despite occupying a small proportion (only 0.1%) of the human genome.…”

Section: Introductionmentioning

confidence: 99%

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Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Liu

Mayer

et al. 2016

J Med Genet

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Background Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the etiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. Methods In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥ 0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. Results Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (e.g. psoriasis, ankylosing spondylitis, type I diabetes, and celiac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with 8 diseases not previously assessed by GWAS (e.g., lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16,484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic etiologies. Conclusions These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterizing cross-phenotype associations, and further emphasizes the importance of the MHC region in human health and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Liu

Mayer

et al. 2016

J Med Genet

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“…Moreover, when strictly considering cis-relationships between SNPs via the relatedness matrix K cis , LT-MAPIT was able to detect more marginal signal than LT-PLINK in both RA and T1D (again see Table S9). These results are unsurprising since it is well known that the MHC region holds significant clinical relevance in complex traits and diseases with respect to infection, inflammation, autoimmunity, and transplant medicine [110,111]. Since this region has also been consistently implicated by other epistatic analyses, we focus our search for significant pairwise interactions to these two phenotypic traits (see the second half of Table S9 for results pertaining to the other five traits).…”

Section: Practical Application To Wtccc Datamentioning

confidence: 97%

Genome-wide Marginal Epistatic Association Mapping in Case-Control Studies

Crawford

Zhou

2018

Preprint

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Epistasis, commonly defined as the interaction between genetic loci, is an important contributor to the genetic architecture underlying many complex traits and common diseases. Most existing epistatic mapping methods in genome-wide association studies explicitly search over all pairwise or higher-order interactions. However, due to the potentially large search space and the resulting multiple testing burden, these conventional approaches often suffer from heavy computational cost and low statistical power. A recently proposed attractive alternative for mapping epistasis focuses instead on detecting marginal epistasis, which is defined as the combined pairwise interaction effects between a given variant and all other variants. By searching for marginal epistatic effects, one can identify genetic variants that are involved in epistasis without the need to identify the exact partners with which the variants interact -thus, potentially alleviating much of the statistical and computational burden associated with conventional epistatic mapping procedures. However, previous marginal epistatic mapping methods are based on quantitative trait models. As we will show here, these lack statistical power in case-control studies. Here, we develop a liability threshold mixed model that extends marginal epistatic mapping to case-control studies. Our method properly accounts for case-control ascertainment and the binary nature of casecontrol data. We refer to this method as the liability threshold marginal epistasis test (LT-MAPIT). With simulations, we illustrate the benefits of LT-MAPIT in terms of providing effective type I error control, and being more powerful than both existing marginal epistatic mapping methods and conventional explicit search-based approaches in case-control data. We finally apply LT-MAPIT to identify both marginal and pairwise epistasis in seven complex diseases from the Wellcome Trust Case Control Consortium (WTCCC) 1 study.

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“…The immune system is one of the most complex networks in living organisms and consists of billions of cells that differ greatly in phenotype, function, origin and spatial distribution across various tissues. Regulation of the immune system in health and disease is still incompletely understood and many layers of complexity influence the system, including genetics [1,2], environmental factors [3,4], infections [5][6][7], hormonal balance [8,9], the microbiome [10][11][12][13], and ageing [14][15][16]. Many diseases are linked to an imbalanced or uncontrolled immune response toward pathogenic [17][18][19] or endogenous antigens, the latter resulting in autoimmune disease [20].…”

Section: Introductionmentioning

confidence: 99%

High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis

et al. 2019

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Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high‐dimensional single‐cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems‐wide analyses of immune cell frequencies and cell type‐specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK‐cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK‐cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.

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Clinical Role of Human Leukocyte Antigen in Health and Disease

Cited by 149 publications

References 172 publications

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Genome-wide Marginal Epistatic Association Mapping in Case-Control Studies

High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis

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