Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Seldin, Michael F.; Alkhairy, Omar K.; Lee, Annette T.; Lamb, Janine A.; Sussman, Jon; Pirskanen-Matell, R.; Piehl, Fredrik; Verschuuren, Jan J.; Kostera‐Pruszczyk, Anna; Szczudlik, Piotr; McKee, David; Maniaol, Angelina; Harbo, Hanne F.; Lie, Benedicte A.; Melms, Arthur; Garchon, Henri Jean; Willcox, Nicholas; Gregersen, Peter K.; Hammarström, Lennart

doi:10.2119/molmed.2015.00232

Cited by 61 publications

(74 citation statements)

References 65 publications

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“…Another GWAS showed three distinct and largely independent association peaks for LOMG corresponding to MHC class II, HLA-A and MHC class III SNPs, while imputation of HLA alleles showed a protective effect of DQA1*05:01. 133 Additional studies have sought to elucidate an association of HLA with specific subtypes of MG. Four studies found an association of DQ5 with the specific subgroup of muscle-specific kinase (MuSK) antibody-positive (Ab + ) MG patients. [134][135][136][137] A Turkish study also found that DRB1*14 and DRB1*16 were associated with this specific subgroup, 136 whereas in a Serbian cohort, DRB1*13 seems to be completely absent in this specific patient population.…”

Section: Hla and Myasthenia Gravismentioning

confidence: 99%

The immunogenetics of neurological disease

2017

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Summary Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.

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Section: Hla and Myasthenia Gravismentioning

confidence: 99%

The immunogenetics of neurological disease

2017

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“…The fifth immune-related SNP, rs9267650 at 6p21.3 (P ¼ 1.1 Â 10 À 8 , OR ¼ 1.17, logistic regression), lies 0.5 kb downstream of NEU1, which encodes a lysosomal enzyme implicated in many diverse processes, including activation of TLRs 25 , wound healing 26,27 and suppression of ovarian carcinoma 28 . Finally, rs11993814 at 8q21.13 (P ¼ 1.1 Â 10 À 12 , OR¼ 0.91, logistic regression), located 9 kb upstream of ZBTB10, is an eQTL in two tissues and is in LD with rs6998967 (r 2 ¼ 0.6, D 0 ¼ 1.0), associated with late-onset myasthenia gravis 29 . ZBTB10 encodes a zinc finger transcription factor involved in regulating the expression of Interleukin-10 through suppression of Sp1 [29][30][31] .…”

Section: Discussionmentioning

confidence: 99%

069 Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma

Chahal

Ransohoff

et al. 2016

Journal of Investigative Dermatology

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Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a twostage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (Po5 Â 10 À 8 , logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.

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“…Here, we focus on early‐onset MG (EOMG), the MG subset of TFH‐associated, anti‐AChR + , nonthymomatous MG . EOMG is mainly a disease of women (female:male ratio 2–3:1) between 18 and 50 or even 60 years of age; is strongly associated with a distinct genetic risk profile that overlaps only slightly with that of late‐onset MG (LOMG); and is commonly associated with other autoimmune diseases (such as thyroiditis) . Additional autoantibodies to MuSK, titin, and ryanodine receptor (RYR) are very rare.…”

mentioning

confidence: 99%

“…2 A peculiarity of the subgroup of MG patients with anti-AChR autoantibodies is the association with various thymic alterations that segregate with typical age, gender, and genetic biases and comprise (1) thymic lymphofollicular hyperplasia (TFH), (2) thymoma, and (3) thymic atrophy. 3,4 Here, we focus on early-onset MG (EOMG), the MG subset of TFH-associated, anti-AChR + , nonthymomatous MG. 5 EOMG is mainly a disease of women (female:male ratio 2-3:1) between 18 and 50 or even 60 years of age; is strongly associated with a distinct genetic risk profile that overlaps only slightly with that of late-onset MG (LOMG); [6][7][8] and is commonly associated with other autoimmune diseases (such as thyroiditis). 9 Additional autoantibodies to MuSK, titin, and ryanodine receptor (RYR) are very rare.…”

mentioning

confidence: 99%

“…10,12 doi: 10.1111/nyas.13563 Notably, the age range of EOMG overlaps with that of the thymic atrophy-associated MG subset (i.e., LOMG) that can start at age 50 but is more common in men after age 60. 5,8,13 Since the MGTX trial accepted anti-AChR + , nonthymomatous MG patients up to the age of 63 years, 14 it is likely that some MGTX patients belonged to the LOMG subset.…”

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confidence: 99%

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Challenging the current model of early‐onset myasthenia gravis pathogenesis in the light of the MGTX trial and histological heterogeneity of thymectomy specimens

Weis

Schalke

Ströbel

et al. 2018

Annals of the New York Academy of Sciences

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The MGTX trial provided evidence that, in general, thymectomy is beneficial in adult patients up to 60 years of age with anti-acetylcholine receptor-positive, nonthymomatous myasthenia gravis (MG). This finding supports the long-held view that the pathogenesis of this type of MG (early-onset MG (EOMG)) starts inside the thymus, results in the long-term intrathymic recruitment of autoantibody-producing B cells and plasma cells, and eventually spreads to the peripheral immune system. However, observed clinical responses to treatment in the MGTX trial were diverse. This might be due to heterogeneous epidemiological and genetic features of EOMG patients and variable durations of corticosteroid treatment before surgery, including a paucity of patients that were corticosteroid naive. Furthermore, the observed histological heterogeneity suggests that a single pathogenetic model may not fully reflect the spectrum of events that modify the course of EOMG. Here, we describe the morphology of the normal and MG-associated thymus, how to evaluate morphological changes, and the current pathogenetic model of EOMG and discuss how it could be refined by integrating MGTX-derived histological findings in thymectomy specimens and associated clinical observations.

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Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Cited by 61 publications

References 65 publications

The immunogenetics of neurological disease

The immunogenetics of neurological disease

069 Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma

Challenging the current model of early‐onset myasthenia gravis pathogenesis in the light of the MGTX trial and histological heterogeneity of thymectomy specimens

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