Unique variation in genetic selection among Black North American women and its potential influence on pregnancy outcome

Jaffe, Shirlee; Normand, Neil; Jayaram, Aswathi; Orfanelli, Theofano; Doulaveris, Georgios; Passos, Mariana; Kanninen, Tomi T.; Bongiovanni, Ann Marie; Linhares, Iara M.

doi:10.1016/j.mehy.2013.08.015

Cited by 28 publications

(22 citation statements)

References 30 publications

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“…Polymorphisms in the MBL2 gene are more frequent in African-Americans and multiple studies have suggested an association between MBL2 genetic variants that result in diminished MBL2 protein levels and preterm birth, and conditions commonly found in preterm pregnancies including chorioamnionitis (Annells et al 2004(Annells et al , 2005Gibson et al 2011;Jaffe et al 2013;Capece et al 2014;Nedovic et al 2014). Our discovery of a nonsense mutations that significantly truncates the MBL2 protein is thus consistent with the notion that loss of this antimicrobial protein increases risk of prematurity.…”

Section: Discussionsupporting

confidence: 83%

“…Mutations in genes encoding host defense mechanisms against microbes had been anticipated based on studies documenting differential expression of the proteins in fetal membranes associated with labor with ruptured and nonruptured membranes (Erez et al 2009) Notable in this regard are the rare heterozygous damaging mutations in DEFB1, FUT2 and MBL2 that were found only in PPROM cases. Variation in these genes have been previously associated with increased risk of infection and in some cases preterm birth (Annells et al 2005;Gibson et al 2011;Jaffe et al 2013).…”

Section: Discussionmentioning

confidence: 99%

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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)

Modi

Teves

Pearson

et al. 2017

Molec Gen & Gen Med

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BackgroundTwin 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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

Modi

Teves

Pearson

et al. 2017

Molec Gen & Gen Med

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“…For example, genes inherited from different ascendants may exhibit variations in the extent of a pro-inflammatory immune response to factors present in a given environment. Thus, genetic variations in populations due to differences in ancestral evolution may have a selective positive or negative influence on health depending on present exposures that may be very different from the ancestral environment (Jaffe et al 2013). Clearly, there is a complex interplay between genetics and environment that should be considered in determining prevention and treatment strategies for multifactorial diseases.…”

Section: Discussionmentioning

confidence: 99%

Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry

et al. 2016

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Ancestry information can be useful in investigations of diseases with a genetic or infectious background. As the Brazilian population is highly admixed physical traits tend to be poor indicators of ancestry. The assessment of ancestry by ancestry informative markers (AIMs) can exclude the subjectivity of self-declared ethnicity and reported family origin. We aimed to evaluate the reliability of self-reported ethnicity or reported family origin as indicators of genomic ancestry in a female population from the Southeast of Brazil. Two cohorts were included: 404 women asked to self-report their ethnicity (Pop1) and 234 women asked to report their family's origin (Pop2). Identification of AIMs was performed using a panel of 61 markers and results were plotted against parental populations-Amerindian, Western European and Sub-Saharan African-using Structure v2.3.4. In Pop1 57.4 % of women self-reported as white, 34.6 % as brown and 8.0 % as black. Median global European, Amerindian and African contributions were 66.8, 12.6 and 16.6 %. In Pop2, 66.4 % of women declared European origin, 23.9 % African origin and 26.9 % Amerindian. Median global European, Amerindian and African contributions were 80.8, 7.3 and 7.6 %, respectively. Only 31.0 and 21.0 % of the global variation in African and European contributions, respectively, could be explained by self-reported ethnicity and reported family origin only accounted for 20.0 and 5.0 % of the variations observed in African and European ancestries, respectively. Amerindian ancestry did not influence self-reported ethnicity or declared family origin. Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry in these Brazilian populations.

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“…However, the dominance of inherited genetic alterations that were best suited to survival in an ancient microbe‐prevalent milieu may not always be optimal based on differences in rates of exposure to infectious agents in the 21st century. Reports of elevated rates of pregnancy complications including preterm birth when women move from their ancestral environment to a new country may be explained by this less than ideal capacity for tolerance when confronted with a radically different microbial environment.…”

Section: Immune Tolerance To Microorganismsmentioning

confidence: 99%

Microorganisms in the Female Genital Tract during Pregnancy: Tolerance versus Pathogenesis

Ramos

Kanninen

Sisti

et al. 2014

American J Rep Immunol

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Microorganisms in the pregnant female genital tract are not always associated with pathology. The factors that influence the maternal response to microorganisms remain ill defined. We review the state of knowledge of microbe-host interactions in gestational tissues and highlight mechanisms that promote tolerance or pathogenesis. Tolerance to microorganisms is promoted during pregnancy by several mechanisms including upregulation of anti-inflammatory mediators, induction of endotoxin tolerance, and possibly by regulation of autophagy. Conversely, an altered vaginal microbiota or a pre-existing viral presence may result in induction of excessive inflammation and preterm labor. Although infections play a prevalent role in preterm birth, microbes are present in gestational tissues of women with healthy outcomes and may provide beneficial functions. The complex interactions between different microbial species and the maternal immune system during gestation remain incompletely elucidated.

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Unique variation in genetic selection among Black North American women and its potential influence on pregnancy outcome

Cited by 28 publications

References 30 publications

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

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

Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry

Microorganisms in the Female Genital Tract during Pregnancy: Tolerance versus Pathogenesis

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