Preterm birth in African Americans is associated with infection and inflammatory response gene variants
Dr John T. Macdonald Foundation Department of Human Genetics and Miami Institute of Human Genomics, University of Miami, Miami, FL, USA. American journal of obstetrics and gynecology
(Impact Factor: 4.7).
11/2008; 200(2):209.e1-27. DOI: 10.1016/j.ajog.2008.08.051
The objective of the study was to study the genetic risk factors of spontaneous preterm birth (PTB) in African Americans.
Case-control analyses were performed using maternal and fetal deoxyribonucleic acid from 279 African American birth events (82 PTB and 197 term) and 1432 single-nucleotide polymorphisms from 130 candidate genes. Single-locus association and haplotype analyses were performed.
The most significant associations were in the maternal interleukin (IL)-15 (rs10833, allele P = 2.91 x 10(-4), genotype P = 2.00 x 10(-3)) gene and the fetal IL-2 receptor B (IL-2RB) (rs84460, allele P = 1.37 x 10(-4), genotype P = 6.29 x 10(-4)) gene. The best models for these markers were additive (rs10833, odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14-0.62; P = 1.0 x 10(-3); rs84460, OR, 2.32; 95% CI, 1.47-3.67; P < 1.0 x 10(-3)). The largest number of significant associations was found in genes related to infection and inflammation. There were overall a larger number of significant associations in infants than in mothers.
These results support a strong role for genes involved in infection and inflammation in the pathogenesis of PTB, particularly IL-12 and IL-12RB, and indicate that in African Americans there may be complementarity of maternal and fetal genetic risks for PTB.
Available from: Balázs Börzsönyi
- "Several epidemiological studies revealed the importance of genetic factors in the background of preterm deliveries  . Among these, some studies point to the role of genes involved in cholesterol metabolism , infection and inflammation  . "
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During pregnancy, 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is involved in the development of the placental barrier, and its main function is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids. We compared human placental gene expression patterns of 11β-HSD2 from pregnancies that ended with preterm delivery versus full term pregnancies as controls.
We used real-time PCR to assess the placental gene expression patterns of 11β-HSD2 in 104 preterm and 140 full term pregnancies (control group) at the time of delivery.
In the preterm delivery group, the proportion of smokers was 26.9%, significantly higher than in the control group. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. The 11β-HSD2 gene was underexpressed in the preterm delivery group compared to normal pregnancy between 28 and 36 gestational weeks, but unchanged between 24 and 28 weeks. There was no fetal gender effect on 11β-HSD2 gene expression.
The reduced activity of the 11β-HSD2 gene seen in the preterm delivery group may impair fetal defences against maternal glucocorticoid exposure. In cases of impending premature delivery, glucocorticoid effects, potentially including postnatal neurological abnormalities and growth restriction, may be worsened by prophylactic steroids given to accelerate fetal lung maturity. The impairment in fetal defences against maternal glucocorticoids due to reduced 11β-HSD2 enzyme activity appears to begin after gestational week 28.
European journal of obstetrics, gynecology, and reproductive biology 09/2012; 165(2). DOI:10.1016/j.ejogrb.2012.08.009 · 1.70 Impact Factor
Available from: Leticia Reyes
- "For example, there are racial disparities in the inflammatory response associated with PTL such as over production of IL-6 and IL-8 in Caucasian women versus an increase in IL-1β and TNF-α in African American women , . These differences have been found to correlate with variations in single nucleotide polymorphisms (SNP) that are associated with each race , . Polymorphism in the promoter region of TNF-α gene has been documented to be risk factor for PTL in the presence of bacterial vaginosis . "
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ABSTRACT: Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P<0.02). C57BL/6 infected animals predominantly exhibited mild to moderate chorioamnionitis (P<0.0001), and a significant reduction in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 compared to sham controls (P<0.02). Conversely, severe protracted chorioamnionitis with cellular necrosis was the predominant lesion phenotype in BALB/c mice, which also exhibited a significant increase in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 (P<0.01). Fetal pathology in BALB/c was multi-organ and included brain, lung, heart, liver, and intestine, whereas fetal pathology in C57BL/6 was only detected in the liver and intestines. These results confirm that the host genetic background is a major determinant in ureaplasmal induced chorioamnionitis with fetal infection and fetal inflammatory response.
PLoS ONE 08/2012; 7(8):e44047. DOI:10.1371/journal.pone.0044047 · 3.23 Impact Factor
Available from: Stephanie M Fullerton
- "Genetic research exploring determinants of preterm birth in African American women has identified several polymorphisms associated with increased risk, including variants in a currently undefined susceptibility locus on chromosome 7 , tumor necrosis factor alpha (TNF-α) and tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2) , cytokines and cytokine-related genes , and in genes involved in infection and inflammation, including interleukin (IL)-12 and IL-12RB. Though these observed genetic associations have been modest and for the most part unreplicated , they suggest that genetic variation contributing to variation in inflammation, maternal/fetal stress, uterine distension, decidual hemorrhage, and/or enzymatic metabolism may contribute to risk of preterm birth . "
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ABSTRACT: The existence of pronounced differences in health outcomes between US populations is a problem of moral significance and public health urgency. Pursuing research on genetic contributors to such disparities, despite striking data on the fundamental role of social factors, has been controversial. Still, advances in genomic science are providing an understanding of disease biology at a level of precision not previously possible. The potential for genomic strategies to help in addressing population-level disparities therefore needs to be carefully evaluated. Using 3 examples from current research, we argue that the best way to maximize the benefits of population-based genomic investigations, and mitigate potential harms, is to direct research away from the identification of genetic causes of disparities and instead focus on applying genomic methodologies to the development of clinical and public health tools with the potential to ameliorate healthcare inequities, direct population-level health interventions or inform public policy. Such a transformation will require close collaboration between transdisciplinary teams and community members as well as a reorientation of current research objectives to better align genomic discovery efforts with public health priorities and well-recognized barriers to fair health care delivery.
Public Health Genomics 04/2012; 15(3-4):156-63. DOI:10.1159/000334717 · 2.21 Impact Factor
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