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      Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

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          Abstract

          Background

          Twin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes ( PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM.

          Methods

          We carried out whole exome sequencing ( WES) of genomic DNA from neonates born of African‐American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies ( N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes. Targeted genotyping of mutations in the candidates discovered by WES was conducted on an additional 188 PPROM cases and 175 controls.

          Results

          We identified rare heterozygous nonsense and frameshift mutations in several of the candidate genes, including CARD6, CARD8, DEFB1, FUT2, MBL2, NLP10, NLRP12, and NOD2 . We discovered that some mutations ( CARD6, DEFB1, FUT2, MBL2, NLRP10, NOD2 ) were present only in PPROM cases.

          Conclusions

          We conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in African‐Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.

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          Most cited references 64

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          Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

           S Almer,  S Lesage,  J Hugot (2001)
          Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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            NOD1 and NOD2: signaling, host defense, and inflammatory disease.

            The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.
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              Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight.

              Little is known about genetic susceptibility to cigarette smoke in relation to adverse pregnancy outcomes. To investigate whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1. Case-control study conducted in 1998-2000 among 741 mothers (174 ever smokers and 567 never smokers) who delivered singleton live births at Boston Medical Center. A total of 207 cases were preterm or low-birth-weight infants and 534 were non-low-birth-weight, full-term infants (control). Birth weight, gestation, fetal growth by smoking status and CYP1A1 MspI (AA vs Aa and aa, where Aa and aa were combined because of small numbers of aa and similar results), and GSTT1 (present vs absent) genotypes. Without consideration of genotype, continuous maternal smoking during pregnancy was associated with a mean reduction of 377 g (SE, 89 g) in birth weight (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.7). When CYP1A1 genotype was considered, the estimated reduction in birth weight was 252 g (SE, 111 g) for the AA genotype group (n = 75; OR, 1.3; 95% CI, 0.6-2.6), but was 520 g (SE, 124 g) for the Aa/aa genotype group (n = 43 for Aa, n = 6 for aa; OR, 3.2; 95% CI, 1.6-6.4). When GSTT1 genotype was considered, the estimated reduction in birth weight was 285 g (SE, 99 g) (OR, 1.7; 95% CI, 0.9-3.2) and 642 g (SE, 154 g) (OR, 3.5; 95% CI, 1.5-8.3) for the present and absent genotype groups, respectively. When both CYP1A1 and GSTT1 genotypes were considered, the greatest reduction in birth weight was found among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes (-1285 g; SE, 234 g; P<.001). Among never smokers, genotype did not independently confer an adverse effect. A similar pattern emerged in analyses stratified by maternal ethnicity and in analyses for gestation. In our study, maternal CYP1A1 and GSTT1 genotypes modified the association between maternal cigarette smoking and infant birth weight, suggesting an interaction between metabolic genes and cigarette smoking.
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                Author and article information

                Contributors
                jerome.strauss@vcuhealth.org
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                23 August 2017
                November 2017
                : 5
                : 6 ( doiID: 10.1002/mgg3.2017.5.issue-6 )
                : 720-729
                Affiliations
                [ 1 ] Department of Human and Molecular Genetics Virginia Commonwealth University Richmond Virginia
                [ 2 ] Department of Obstetrics and Gynecology Virginia Commonwealth University Richmond Virginia
                [ 3 ] Department of Anthropology Pennsylvania State University University Park Pennsylvania
                [ 4 ] Department of Microbiology and Immunology Virginia Commonwealth University Richmond Virginia
                [ 5 ] Perinatology Research Branch Eunice Kennedy Shriver National Institute for Child Health and Human Development NIH Detroit Michigan
                [ 6 ] Department of Obstetrics and Gynecology University of Michigan Ann Arbor Michigan
                [ 7 ] Department of Epidemiology and Biostatistics Michigan State University East Lansing Michigan
                [ 8 ] Center for Molecular Medicine and Genetics Wayne State University Detroit Michigan
                Author notes
                [* ] Correspondence

                Jerome F. Strauss III, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, 11‐029 Sanger Hall, 1101 East Marshall Street, Richmond, VA 23298. Tel: 804 828 5598; Fax: 804 828 5076; E‐mail: jerome.strauss@ 123456vcuhealth.org

                Article
                MGG3330
                10.1002/mgg3.330
                5702565
                29178652
                © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 0, Tables: 3, Pages: 10, Words: 7472
                Product
                Funding
                Funded by: National Institute on Minority Health and Health Disparities
                Award ID: MD002256
                Funded by: Eunice Kennedy Shriver National Institute of Child Health and Human Development
                Award ID: HD073555
                Award ID: HSN275201300006c
                Funded by: National Institutes of Health
                Award ID: R01 HD073555
                Award ID: P60 MD002256
                Funded by: National Institutes of Health, Department of Health and Human Services (NICHD/NIH)
                Award ID: HSN275201300006C
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                mgg3330
                November 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.6.1 mode:remove_FC converted:26.11.2017

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