Dataset Information

Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study.

ABSTRACT:

Background

Despite having the highest number of preterm births globally, no genomic study on preterm birth was previously published from India or other South-Asian countries.

Methods

We conducted a genome-wide association (GWA) study of spontaneous preterm birth (sPTB) on 6211 women from India. We used a novel resampling procedure to identify the associated single nucleotide polymorphisms (SNPs) followed by haplotype association analysis and imputation.

Findings

We found that 512 maternal SNPs were associated with sPTB (p < 2.51e-3), of which minor allele at 19 SNPs (after Bonferroni correction) had increased genotype relative risk. Haplotypes containing six of the 19 SNPs (rs13011430, rs8179838, rs2327290, rs4798499, rs7629800, and rs13180906) were associated with sPTB (p < 9.9e-4; Bonferroni adjusted p-value <0.05). After imputation in regions around the 19 SNPs, 15 imputed SNPs were found to be associated with sPTB (Bonferroni adjusted p-value <0.05). One of these imputed SNPs, rs35760881, and three other SNPs (rs17307697, rs4308815, and rs10983507) were also reported to be associated with sPTB in women belonging to European ancestry. Moreover, we found that GG genotype at rs1152954, one of the associated SNPs, enhanced risk of sPTB and reduced telomere length.

Interpretation

This is the first study from South Asia on the genome-wide identification of maternal SNPs associated with sPTB. These SNPs are known to alter the expression of genes associated with major pathways in sPTB viz. inflammation, apoptosis, cervical ripening, telomere maintenance, selenocysteine biosynthesis, myometrial contraction, and innate immunity. From a public health perspective, the trans-ethnic association of four SNPs identified in our study may help to stratify women with risk of sPTB in most populations.

Funding

Department of Biotechnology (India), Grand Challenges India - All Children Thriving Program and Biotechnology Industry Research Assistance Council (BIRAC).

SUBMITTER: Bhattacharjee E

PROVIDER: S-EPMC10363490 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study.

Bhattacharjee Esha E Thiruvengadam Ramachandran R Ayushi Das Chitrarpita C Wadhwa Nitya N Natchu Uma Chandra Mouli UCM Kshetrapal Pallavi P Bhatnagar Shinjini S Majumder Partha Pratim PP Maitra Arindam A

The Lancet regional health. Southeast Asia 20230418

<h4>Background</h4>Despite having the highest number of preterm births globally, no genomic study on preterm birth was previously published from India or other South-Asian countries.<h4>Methods</h4>We conducted a genome-wide association (GWA) study of spontaneous preterm birth (sPTB) on 6211 women from India. We used a novel resampling procedure to identify the associated single nucleotide polymorphisms (SNPs) followed by haplotype association analysis and imputation.<h4>Findings</h4>We found th ...[more]

PMID: 37492417

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Project description:ObjectivesTo assess the psychological well-being of pregnant women at increased risk of spontaneous preterm birth, and the impact of care from a preterm birth clinic.DesignSingle-centre longitudinal cohort study over 1 year, 2018-2019.SettingTertiary maternity hospital in Auckland, New Zealand.ParticipantsPregnant women at increased risk of spontaneous preterm birth receiving care in a preterm birth clinic.InterventionParticipants completed three sets of questionnaires (State-Trait Anxiety Inventory, Edinburgh Postnatal Depression Scale, and 36-Item Short Form Survey)-prior to their first, after their second, and after their last clinic appointments. Study-specific questionnaires explored pregnancy-related anxiety and perceptions of care.Primary and secondary outcome measuresThe primary outcome was the mean State-Anxiety score. Secondary outcomes included depression and quality of life measures.Results73/97 (75.3%) eligible women participated; 41.1% had a previous preterm birth, 31.5% a second trimester loss and 28.8% cervical surgery; 20.6% had a prior mental health condition. 63/73 (86.3%) women completed all questionnaires. The adjusted mean state-anxiety score was 39.0 at baseline, which decreased to 36.5 after the second visit (difference -2.5, 95% CI -5.5 to 0.5, p=0.1) and to 32.6 after the last visit (difference -3.9 from second visit, 95% CI -6.4 to -1.5, p=0.002). Rates of anxiety (state-anxiety score >40) and depression (Edinburgh Postnatal Depression Scale score >12) were 38.4%, 34.8%, 19.0% and 13.7%, 8.7%, 9.5% respectively, at the same time periods. Perceptions of care were favourable; 88.9% stated the preterm birth clinic made them significantly or somewhat less anxious and 87.3% wanted to be seen again in a future pregnancy.ConclusionsWomen at increased risk of spontaneous preterm birth have high levels of anxiety. Psychological well-being improved during the second trimester; women perceived that preterm birth clinic care reduced pregnancy-related anxiety. These findings support the ongoing use and development of preterm birth clinics.

Project description:BackgroundPreterm delivery is a leading cause of neonatal mortality and morbidity. History of spontaneous preterm birth is the greatest risk factor for another preterm delivery. So, every effort should be made to prevent the recurrence of preterm delivery in this vulnerable group. This study aimed to evaluate the predictive ability of the anterior uterocervical angle and cervical length in preterm birth.Patients and methodsThis was a prospective cohort study that included 70 patients with a history of spontaneous preterm birth. Ultrasound measurements of cervical length and anterior uterocervical angle were set to be measured for each patient at three visits; first between 16 0/7 and 24 0/7 weeks, second between 24 1/7 and 32 0/7 weeks, and the third was between 32 1/7 and 36 6/7 weeks. The correlation between both measures and the prediction of preterm birth among study participants was the primary outcome of the study. Neonatal outcome among the study patients was a secondary measure of outcome.ResultsThe incidence of preterm birth among study participants was 31.41%. Cervical length and uterocervical angle showed progressive decrease and increase respectively throughout pregnancy. At the 2nd visit, the two measures were significantly different between those who delivered at term and those with preterm delivery with the cervical length being significantly shorter in the preterm arm (3.0 ± 0.49 versus 3.38 ± 0.36, p < 0.001) and uterocervical angle being significantly bigger among the same arm (110.1 ± 18.48 versus 84.42 ± 12.24, p < 0.001). A uterocervical angle > 89.8° at the second visit predicted preterm birth with 81.8% sensitivity and 70.8% specificity while cervical length ≤ 3.22 cm at the second visit predicted preterm birth with 68.1% sensitivity and 62.5% specificity. Multivariant logistic regression analysis showed that uterocervical angle > 89.8° at the second visit increased the odds ratio for preterm birth by 9.ConclusionUterocervical angle can be a useful ultrasound marker for the prediction of preterm birth among high risk patients. A cutoff value of 89.8° can be used as a threshold above which prophylactic measures such as cervical cerclage or progesterone therapy can be provided.Trial registrationNCT05632003 (First posted date: 30/11/2022).

Project description:BackgroundA processed diet, high in fat and low in fiber, is associated with differences in the gut microbiota and adverse health outcomes in humans; however, little is known about the diet-microbiota relation and its impact on pregnancy. Spontaneous preterm birth (SPTB), a pregnancy outcome with serious short- and long-term consequences, occurs more frequently in black and in obese women in the United States.ObjectivesIn a prospective, case-control sample matched for race and obesity (cases = 16, controls = 32), we compared the fecal gut microbiota, fecal and plasma metabolites, and diet in the late second trimester. We hypothesized that a Western diet would be associated with reduced microbiota richness and a metabolic signature predicting incidence of SPTB.MethodsThe fecal microbiota was characterized by 16S-tagged sequencing and untargeted metabolomics was used to analyze both plasma and fecal metabolites. Wilcoxon's rank-sum test was used for the comparison of microbiota genera, α-diversity, fecal and plasma metabolites, and dietary variables between term and SPTB. β-Diversity was analyzed using permutational multivariate ANOVA, and metabolite associations were assessed by module analysis.ResultsA decrease in α-diversity was strongly associated with the development of SPTB, especially in the taxonomic class of Betaproteobacteria. Of 824 fecal metabolites, 22 metabolites (mostly lipids) differed between cases and controls (P < 0.01), with greater DHA (22:6n-3) and EPA (20:5n-3) in cases [false discovery rate (FDR) < 0.2]. The most significant fecal metabolite module (FDR-adjusted P = 0.008) was dominated by DHA and EPA. Dietary saturated fat (primarily palmitate) intake was greater in cases (31.38 ± 7.37 compared with 26.08 ± 8.62 g, P = 0.045) and was positively correlated with fecal DHA and EPA (P < 0.05).ConclusionsReduced α-diversity of the gut microbiota and higher excretion of omega-3 (n-3) fatty acids in stool may provide a novel biomarker signature predicting SPTB in women with a low-fiber, high-fat diet. Further investigation of these markers in a larger sample is needed for validation.

Project description:BackgroundPreterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery.ObjectiveThe objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women.Study designThis is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term.ResultsOf the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term.ConclusionWe identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.

Dataset Information

Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study.

Background

Methods

Findings

Interpretation

Funding

Publications

Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study.

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