scholarly journals Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly

2020 ◽  
Author(s):  
Mingi Hong ◽  
Annabel Christ ◽  
Anna Christa ◽  
Thomas E. Willnow ◽  
Robert S. Krauss
Keyword(s):  
Alcohol Exposure ◽  
Environment Interaction ◽  
Nodal Signaling ◽  
Fetal Alcohol Exposure ◽  
Fetal Alcohol ◽  
Multifactorial Model ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Hh Signaling

AbstractHoloprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal, not HH, signaling is the point of synergistic interaction between Cdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of Cdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on downstream HH signaling during midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.

scholarly journals Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mingi Hong ◽  
Annabel Christ ◽  
Anna Christa ◽  
Thomas E Willnow ◽  
Robert S Krauss
Keyword(s):  
Birth Defect ◽  
Alcohol Exposure ◽  
Environment Interaction ◽  
Nodal Signaling ◽  
Fetal Alcohol Exposure ◽  
Fetal Alcohol ◽  
Multifactorial Model ◽  
Gene Environment Interaction ◽  
Gene Environment

Holoprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, Cdon mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal signaling is a major point of synergistic interaction between Cdon mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of Cdon mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.

scholarly journals Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis

2018 ◽  
Vol 115 (18) ◽  
pp. 4755-4760 ◽  
Author(s):  
Jiaqi Fu ◽  
Sarah V. Nogueira ◽  
Vincent van Drongelen ◽  
Patrick Coit ◽  
Song Ling ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Genetic Risk ◽  
Shared Epitope ◽  
Environmental Pollutants ◽  
Autoimmune Arthritis ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Aryl Hydrocarbon ◽  
Gene Environment

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene–environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants.

Gene-environment Interaction on the Risk of Type 2 Diabetes Among Ethnic Minority Populations Living in Europe and North America: A Systematic Review

2020 ◽  
Vol 16 (5) ◽  
pp. 457-470 ◽  
Author(s):  
Mohammad H. Zafarmand ◽  
Parvin Tajik ◽  
René Spijker ◽  
Charles Agyemang
Keyword(s):  
Type 2 Diabetes ◽  
North America ◽  
Ethnic Minority ◽  
Ethnic Minorities ◽  
Minority Groups ◽  
Environment Interaction ◽  
Ethnic Minority Groups ◽  
Gene Environment Interaction ◽  
Gene Environment

Background: The body of evidence on gene-environment interaction (GEI) related to type 2 diabetes (T2D) has grown in the recent years. However, most studies on GEI have sought to explain variation within individuals of European ancestry and results among ethnic minority groups are inconclusive. Objective: To investigate any interaction between a gene and an environmental factor in relation to T2D among ethnic minority groups living in Europe and North America. Methods: We systematically searched Medline and EMBASE databases for the published literature in English up to 25th March 2019. The screening, data extraction and quality assessment were performed by reviewers independently. Results: 1068 studies identified through our search, of which nine cohorts of six studies evaluating several different GEIs were included. The mean follow-up time in the included studies ranged from 5 to 25.7 years. Most studies were relatively small scale and few provided replication data. All studies included in the review included ethnic minorities from North America (Native-Americans, African- Americans, and Aboriginal Canadian), none of the studies in Europe assessed GEI in relation to T2D incident in ethnic minorities. The only significant GEI among ethnic minorities was HNF1A rs137853240 and smoking on T2D incident among Native-Canadians (Pinteraction = 0.006). Conclusion: There is a need for more studies on GEI among ethnicities, broadening the spectrum of ethnic minority groups being investigated, performing more discovery using genome-wide approaches, larger sample sizes for these studies by collaborating efforts such as the InterConnect approach, and developing a more standardized method of reporting GEI studies are discussed.

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