scholarly journals Somatic Mutations and Autoimmunity

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2056
Author(s):  
Maha Alriyami ◽  
Constantin Polychronakos
Keyword(s):  
Risk Factors ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Somatic Mutations ◽  
De Novo ◽  
Malignant Diseases ◽  
Underlying Causes ◽  
Novel Concept ◽  
Inherited Mutations ◽  
Reactive Lymphocytes

Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in Western countries develops some form of autoimmunity, yet its underlying causes, although intensively studied, are still not fully known, and no curative therapies exist. It is well established that autoimmune diseases have common mechanisms and are caused by both genetic and non-genetic risk factors. One novel risk factor that can contribute to autoimmunity is somatic mutations, in a role parallel to their role in cancer. Somatic mutations are stochastic, de novo, non-inherited mutations. In this hypothesis, the persistent proliferation of self-reactive lymphocytes (that is usually hindered by a series of checkpoints) is permitted, due to somatic mutations in these expanding cells, allowing them to bypass multiple regulatory checkpoints, causing autoimmunity. This novel concept of the contribution of these mutations in non-malignant diseases has recently started to be explored. It proposes a novel paradigm for autoimmunity etiology and could be the missing piece of the autoimmunity puzzle.

scholarly journals Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Blood ◽  
2020 ◽  
Vol 136 (1) ◽  
pp. 24-35 ◽  
Author(s):  
Anna L. Brown ◽  
Christopher N. Hahn ◽  
Hamish S. Scott
Keyword(s):  
Somatic Mutations ◽  
De Novo ◽  
Laboratory Data ◽  
Germline Mutations ◽  
Model Systems ◽  
World Health ◽  
Patient Groups ◽  
Health Organization ◽  
Inherited Mutations

Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

Genetic risk factors for autoimmune diseases

1999 ◽  
Vol 20 (1) ◽  
pp. 10-12 ◽  
Author(s):  
T.E.W Feltkamp ◽  
Lucien A Aarden ◽  
Cees J Lucas ◽  
Cor L Verweij ◽  
René R.P de Vries
Keyword(s):  
Risk Factors ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Genetic Risk Factors

Genetic risk factors for pathogenic IgG4 autoantibodies: a systematic review and meta-analysis of HLA class II associations in patients with IgG4 autoimmune diseases

2021 ◽  
Author(s):  
Anja Panhuber ◽  
Giovanni Lamorte ◽  
Veronica Bruno ◽  
Hakan Cetin ◽  
Wolfgang Bauer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Pemphigus Vulgaris ◽  
Genetic Risk Factors ◽  
Case Control Studies ◽  
Leukocyte Antigen

Abstract Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case-control studies on IgG4-AID based on MOOSE and HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44-5.9; p < 0.00001; A: OR 2.54; 95% CI 1.82-3.55; p < 0.00001) and HLA-DRB1*14 (G: OR 4.31; 95% CI 2.82-6.59; p < 0.00001; A: OR 4.78; 95% CI 3.52-6.49; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (OR 6.3; 95% CI 3.28-12.09; p < 0.00001 / OR 4.98; 95% CI 3.8-6.53; p < 0.00001) were increased while HLA-DRB1*13 (G: OR 0.48; 95% CI 0.34-0.68; p < 0.0001; A: OR 0.46; 95% CI 0.34-0.62; p < 0.00001) was decreased in IgG4-AID patients. In conclusion, the HLA-DQB1*05 , HLA-DRB1*14 alleles and the HLA-DQB1*05-DRB1*14 haplotype could be genetic risk factors that predispose for the production of pathogenic IgG4 autoantibodies and the HLA-DRB1*13 allele may protect from IgG4 autoimmunity.

scholarly journals Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes

2019 ◽  
Author(s):  
Pamela Feliciano ◽  
Xueya Zhou ◽  
Irina Astrovskaya ◽  
Tychele N. Turner ◽  
Tianyun Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Exome Sequencing ◽  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Genetic Risk Factors ◽  
Autism Spectrum ◽  
Whole Exome ◽  
Statistical Support ◽  
Complete Set

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. Additionally, we identified variants that are possibly associated with autism in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.2 provides statistical support for 34 ASD risk genes with at least one damaging variant identified in SPARK. Nine of these genes (BRSK2, DPP6, EGR3, FEZF2, ITSN1, KDM1B, NR4A2, PAX5 and RALGAPB) are newly emerging genes in autism, of which BRSK2 has the strongest statistical support as a risk gene for autism (TADA q-value = 0.0015). Future studies leveraging the thousands of individuals with ASD that have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate autism research that incorporates genetic etiology.

1655-P: Genetic Risk Factors for Incident Cardiovascular Disease in Type 2 Diabetes Patients

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1655-P
Author(s):  
SOO HEON KWAK ◽  
JOSEP M. MERCADER ◽  
AARON LEONG ◽  
BIANCA PORNEALA ◽  
PEITAO WU ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Incident Cardiovascular Disease ◽  
Diabetes Patients

107-OR: Novel Genetic Risk Factors Influence Islet Autoimmunity Progression

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 107-OR
Author(s):  
SUNA ONENGUT-GUMUSCU ◽  
UMA DEVI PAILA ◽  
WEI-MIN CHEN ◽  
AAKROSH RATAN ◽  
ZHENNAN ZHU ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Islet Autoimmunity
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