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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

ABSTRACT: Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P < 0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10(-219)). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.

SUBMITTER: Falah N

PROVIDER: S-EPMC3864772 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

Falah Nadia N McElroy Jude J Snegovskikh Victoria V Lockwood Charles J CJ Norwitz Errol E Murray Jeffey C JC Kuczynski Edward E Menon Ramkumar R Teramo Kari K Muglia Louis J LJ Morgan Thomas T

Human genetics 20120913 1

Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female coho ...[more]

PMID: 22972380

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Project description:BackgroundPreterm birth (PTB),2 defined as birth at gestational age <37 weeks, is a major public health concern. Infants born prematurely, comprising of about 10% of the US newborns, have elevated risks of neonatal mortality and a wide array of health problems. Although numerous clinical, genetic, environmental and socioeconomic factors have been implicated in PTB, very few studies investigate the impacts of multiple pollutants and social factors on PTB using large scale datasets.ObjectivesTo evaluate association between environmental and socioeconomic factors and PTB in California.MethodsWe linked the birth cohort file maintained by the California Office of Statewide Health Planning and Development from 2009 to 2012 years across 1.8 million births and the CalEnviroScreen 3.0 dataset from California Communities Environmental Health Screening Tool at the census tract level for 56 California counties. CalEnviroScreen contains 7 exposure and 5 environmental effects variables that constitute the Pollution Burden variable, and 5 socioeconomic variables. We evaluated relationships between environmental exposures and the risk of PTB using hierarchical clustering analyses and GIS-based visualization. We also used logistic regression to evaluate the relationship between specific pollutant and exposure indicators and PTB, accounted for socio-demographic determinants such as maternal race/ethnicity, maternal age, maternal education and payment of delivery costs.ResultsThere exists geographic variability in PTB for groups of counties with similar environmental and social exposure profiles. We found an association between Pollution Burden, particulate matter ≤2.5 μm (PM2.5), and Drinking Water Scores and PTB (adjusted odds ratios were 1.03 (95% Confidence Interval (CI): 1.01, 1.04), 1.03 (95% CI: 1.02,1.04), and 1.04 (95% CI: 1.03,1.05), respectively). Additional findings suggest that certain drinking water contaminants such as arsenic and nitrate are associated with PTB in California.ConclusionsCalEnviroScreen data combined with birth records offer great opportunity for revealing novel exposures and evaluating cumulative exposures related to PTB by providing useful environmental and social information. Certain drinking water contaminants such as arsenic and nitrate are potentially associated with PTB in California and should be investigated further. Small association signals may involve sizeable population impacts.

Project description:Background:Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4-15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population. Methods:We analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes. Results:In both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight. Conclusion:From these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.

Project description:BACKGROUND:Globally, about 15 million neonates are born preterm and about 85% of global preterm birth occurs in Asia and Africa regions. We aimed to estimate the incidence and risk factors for preterm birth in a rural Bangladeshi cohort. METHODS:Between June 2007 and September 2009, community health workers prospectively collected data from 32,126 mother-live-born baby pairs on household socio-demographic status, pregnancy history, antenatal care seeking and newborn gestational age determined by recall of date of last menstrual period. RESULTS:Among all live births, 22.3% were delivered prior to 37 weeks of gestation (i.e. preterm); of which 12.3% were born at 35-36 weeks of gestation (late preterm), 7.1% were born at 32-34 weeks (moderate preterm), and 2.9% were born at 28-31 weeks of gestation (very preterm). Overall, the majority of preterm births (55.1%) were late preterm. Risk of preterm birth was lower among women with primary or higher level of education (RR: 0.92; 95% CI: 0.88, 0.97), women who sought antenatal care at least once during the index pregnancy (RR: 0.86; 95% CI: 0.83, 0.90), and women who had completed all birth preparedness steps (RR: 0.32; 95% CI: 0.30, 0.34). In contrast, risk of preterm birth was higher among women with a history of child death (RR: 1.05; 95% CI: 1.01, 1.10), who had mid-upper arm circumference (MUAC) ?250 mm, indicative of under nutrition (for women having MUAC <214 mm the risk was higher; RR: 1.26; 95% CI: 1.17, 1.35), who reported an antenatal complication (RR: 1.32; 95% CI: 1.14, 1.53), and who received iron-folic acid supplementation for 2-6 months during the index pregnancy (RR: 1.33; 95% CI: 1.24, 1.44). CONCLUSIONS:In resource poor settings with high burden of preterm birth, alike Bangladesh, preterm birth risk could be reduced by close monitoring and/or frequent follow-up of women with history of child death and antenatal complications, by encouraging women to seek antenatal care from qualified providers, to adopt birth preparedness planning and to maintain good nutritional status. Additional research is needed to further explore the associations of antenatal iron supplementation and maternal nutritional status on preterm birth.

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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

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