Torque Teno Virus (TTV) in Renal Transplant Recipients: Species Diversity and Variability.

Torque Teno Virus (TTV) is a nonpathogenic and ubiquitous ssDNA virus, a member of the Anelloviridae family. TTV has been postulated as a biomarker in transplant patients. This study aimed to determine the TTV species diversity and variability in renal transplant recipients and to associate species diversity with the corresponding TTV viral load. From 27 recipients, 30 plasma samples were selected. Viral load was determined using two real-time PCR assays, followed by RCA-NGS and ORF1 phylogenetic analysis. The TTV diversity was determined in all samples. Variability was determined in three patients with two sequential samples (pre- and post-transplantation). Most of the samples presented multiple TTV species, up to 15 different species were detected. In the pre-transplant samples (n = 12), the most prevalent species were TTV3 (75%) and TTV13 (75%), and the median number of species per sample was 5 (IQR: 4-7.5). TTV3 was also the most prevalent (56%) in the post-transplant samples (n = 18), and the median number of species was 2 (IQR: 1.8-5.5). No significant correlation between the number of species and viral load was found. The number and type of TTV species showed total variability over time. We report high TTV species diversity in Argentinian recipients, especially in pre-transplant period, with total intra-host variability. However, we found no significant correlation between this high diversity and TTV viral load.

Genetic susceptibility for retinopathy of prematurity and its associated comorbidities.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the leading cause of child blindness. Preterm newborns of very low gestational age (GA) and very low birth weight are at the greatest risk. Our objective was to evaluate the role of genetic variants associated with ROP risk and its comorbidities in an Argentinian sample of premature infants. METHODS: A sample of 437 preterm infants <33 weeks GA, born at a maternity hospital in Tucumán, Argentina, 2005-2010, was analyzed. Environmental factors, perinatal outcomes, and fourteen single nucleotide polymorphisms associated with ROP were evaluated, comparing ROP with non-ROP newborns. A lasso logistic regression was performed to select variables; then, a conditional logistic regression was used to identify ROP maternal and perinatal risk factors adjusting by maternal and gestational ages, respectively. RESULTS: ROP maternal risk factors were alcohol intake, periodontal infections, and severe stress. Respiratory distress, sepsis, and intracranial hemorrhage were the ROP perinatal risk factors. Markers rs186085 of EPAS1 and rs427832 of AGTR1 were significantly associated with ROP newborns. CONCLUSION: We identified three maternal and three perinatal risk factors associated with ROP. Genes EPAS1 and AGTR1, involved in angiogenesis and vascularization, were identified to be of risk for ROP. IMPACT: Genetic and environmental risk factors associated with ROP and its comorbidities are evaluated in a Latin American population. Genes EPAS1 and AGTR1, involved in angiogenesis and vascularization, were identified to be of risk for ROP. Three maternal and three perinatal risk factors associated with ROP were also identified. A matrix of significant relationships among genetic markers and comorbidities is presented. Reported data may help develop more effective preventive measures for ROP in the Latin American region.

Gene-environment interactions and preterm birth predictors: A Bayesian network approach.

Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify gene-environment interactions associated with spontaneous PTB or its predictors. We carried out a retrospective case-control study including parental sociodemographic and obstetric data as well as newborn genetic variants of 69 preterm and 61 at term newborns born at a maternity hospital from Tucumán, Argentina, between 2005 and 2010. A data-driven Bayesian network including the main PTB predictors was created where we identified gene-environment interactions. We used logistic regressions to calculate the odds ratios and confidence intervals of the interactions. From the main PTB predictors (nine exposures and six genetic variants) we identified an interaction between low neighbourhood socioeconomic status and rs2074351 (PON1, genotype GG) variant that was associated with an increased risk of toxoplasmosis (odds ratio 12.51, confidence interval 95%: 1.71 - 91.36). The results of this exploratory study suggest that structural social disparities could influence the PTB risk by increasing the frequency of exposures that potentiate the risk associated with individual characteristics such as genetic traits. Future studies with larger sample sizes are necessary to confirm these findings.

Paternal age and risk for selected birth defects in a large South American sample.

BACKGROUND: The relationship between maternal age (MA) and birth defects (BD) has been extensively studied while much less research, mostly with discordant results, has focused on the risk of paternal age (PA) for BD. Furthermore, no consensus has been reached on the best way to control the association of PA with MA. OBJECTIVES: The aim of the study was to evaluate the risk of PA increase, at 1-year intervals, for selected BD, especially controlling for the confounding effect of MA. METHODS: The sample comprised of 27,944 liveborns presenting 1 of 18 selected isolated BD. Conditional logistic regressions were applied to evaluate the risk of advanced PA and its yearly increase, adjusting by MA and other variables. RESULTS: Of the 18 analyzed BD, only the risk for preaxial polydactyly (PreP) showed a significant association with increasing PA, while advanced MA was of low risk. For esophageal and anal atresia, associations with both PA and MA increases were observed. CONCLUSIONS: Results support the hypothesis of advanced PA as a risk factor for PreP and helps clarify the so far unexplained nonrandom association between this defect and Down syndrome.

Development of a Clinical Score to Stratify the Risk for Carbapenem-Resistant Enterobacterales Bacteremia in Patients with Cancer and Hematopoietic Stem Cell Transplantation.

Identifying the risk factors for carbapenem-resistant Enterobacterales (CRE) bacteremia in cancer and hematopoietic stem cell transplantation (HSCT) patients would allow earlier initiation of an appropriate empirical antibiotic treatment. This is a prospective multicenter observational study in patients from 12 centers in Argentina, who presented with cancer or hematopoietic stem-cell transplant and developed Enterobacterales bacteremia. A multiple logistic regression model identified risk factors for CRE bacteremia, and a score was developed according to the regression coefficient. This was validated by the bootstrap resampling technique. Four hundred and forty-three patients with Enterobacterales bacteremia were included: 59 with CRE and 384 with carbapenem-susceptible Enterobacterales (CSE). The risk factors that were identified and the points assigned to each of them were: ≥10 days of hospitalization until bacteremia: OR 4.03, 95% CI 1.88-8.66 (2 points); previous antibiotics > 7 days: OR 4.65, 95% CI 2.29-9.46 (2 points); current colonization with KPC-carbapenemase-producing Enterobacterales: 33.08, 95% CI 11.74-93.25 (5 points). With a cut-off of 7 points, a sensitivity of 35.59%, specificity of 98.43%, PPV of 77.7%, and NPV of 90.9% were obtained. The overall performance of the score was satisfactory (AUROC of 0.85, 95% CI 0.80-0.91). Finally, the post-test probability of CRE occurrence in patients with none of the risk factors was 1.9%, which would virtually rule out the presence of CRE bacteremia.

A large, ten-generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: Historical, clinical, genealogical, and molecular studies.

We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far.

Lethality of Birth Defects in Live Born Infants Categorized by Gestational Age and Birth Weight.

OBJECTIVE: This study aimed to describe lethality of birth defects (BDs) in newborns categorized by gestational age and birth weight and to identify BDs associated with prematurity. STUDY DESIGN: Live born infants (n = 16,452) with isolated BDs classified by severity, and 42,511 healthy controls were assigned to categories: adequate growth, preterm, or small for gestational age (SGA). Proportion of cases and BDs' lethality rates were obtained by category and compared with controls. RESULTS: Overall fewer malformed than nonmalformed infants were of adequate growth, while the opposite occurred in the preterm and SGA categories where gastroschisis and esophageal atresia were among the most outstanding defects. For most severe BDs, the early neonatal death rate was higher than control values in all categories; for mild defects, except cleft lip in the preterm category, they did not differ. Diaphragmatic hernia showed the highest lethality values, while those of spina bifida were among the lowest. Talipes, hypospadias, and septal heart defects were mild defects significantly associated with prematurity. CONCLUSION: Although reasons, such as induced preterm delivery of fetuses with certain anomalies, could partially account for their high prematurity rates, susceptibility to preterm birth might exist through underlying mechanisms related with the defects. The identification of BDs associated with prematurity should serve to improve measures that prevent preterm birth especially of fetuses at risk. KEY POINTS: · Some BDs predispose to prematurity.. · Prematurity is an additional risk factor for mortality in infants with mild defects.. · Lethality values should be adjusted by gestational age and birth weight..

Diseases during pregnancy in a large unselected South American sample.

OBJECTIVE: Our aim was to describe the prevalence of diseases during pregnancy and the association between fetal exposure to the most frequent maternal diseases and the risk of preterm (PTB) and/or small for gestational age (SGA) newborns in an unselected sample of women who gave birth in South American countries. METHODS: We conducted a descriptive, cross-sectional study including 56,232 mothers of non-malformed infants born between 2002 and 2016, using data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC). Diseases with higher- than-expected PTB/SGA frequencies were identified. Odds ratios of confounding variables for diseases and birth outcomes were calculated with a multivariable logistic regression. RESULTS: Of the 14 most reported diseases, hypertension, genitourinary infection, epilepsy, hypothyroidism, diabetes, and HIV/AIDS showed higher PTB and/or SGA frequencies. Advanced and low maternal age, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with PTB, while advanced maternal age, primigravidity, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with SGA. After adjusting for the associated variables, the identified illnesses maintained their association with PTB and all, except epilepsy, with SGA. CONCLUSION: The description of an unselected population of mothers allowed identifying the most frequent diseases occurring during gestation and their impact on pregnancy outcomes. Six diseases were associated with PTB and two with SGA newborns. To the best of our knowledge, there are no similar reports about women not intentionally selected by specific diseases during pregnancy in South American populations.

Genes, exposures, and interactions on preterm birth risk: an exploratory study in an Argentine population.

Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify associations of spontaneous PTB with genetic variants, exposures, and interactions between and within them. We carried out a retrospective case-control study including parental sociodemographic and obstetric data, and fetal genetic variants. We sequenced the coding and flanking regions of five candidate genes from the placental blood cord of 69 preterm newborns and 61 at term newborns. We identify the characteristics with the greatest predictive power of PTB using penalized regressions, in which we include exposures (E), genetic variants (G), and two-way interactions. Few prenatal visits (< 5) was the main predictor of PTB from 26 G, 35 E, 299 G × G, 564 E × E, and 875 G × E evaluated terms. Within the fetal genetic characteristics, we observed associations of rs4845397 (KCNN3, allele T) variant; G × G interaction between rs12621551 (COL4A3, allele T) and rs73993878 (COL4A3, allele A), which showed sensitivity to anemia; and G × G interaction between rs11680670 (COL4A3, allele T) and rs2074351 (PON1, allele A), which showed sensitivity to vaginal discharge. The results of this exploratory study suggest that social disparities and metabolic pathways linked to uterine relaxation, inflammation/infections, and collagen metabolism would be involved in PTB etiology. Future studies with a larger sample size are necessary to confirm these findings and to analyze a greater number of exposures.

Dental anomaly detection using intraoral photos via deep learning.

Children with orofacial clefting (OFC) present with a wide range of dental anomalies. Identifying these anomalies is vital to understand their etiology and to discern the complex phenotypic spectrum of OFC. Such anomalies are currently identified using intra-oral exams by dentists, a costly and time-consuming process. We claim that automating the process of anomaly detection using deep neural networks (DNNs) could increase efficiency and provide reliable anomaly detection while potentially increasing the speed of research discovery. This study characterizes the use of` DNNs to identify dental anomalies by training a DNN model using intraoral photographs from the largest international cohort to date of children with nonsyndromic OFC and controls (OFC1). In this project, the intraoral images were submitted to a Convolutional Neural Network model to perform multi-label multi-class classification of 10 dental anomalies. The network predicts whether an individual exhibits any of the 10 anomalies and can do so significantly faster than a human rater can. For all but three anomalies, F1 scores suggest that our model performs competitively at anomaly detection when compared to a dentist with 8 years of clinical experience. In addition, we use saliency maps to provide a post-hoc interpretation for our model's predictions. This enables dentists to examine and verify our model's predictions.

Tooth Agenesis Patterns in Orofacial Clefting Using Tooth Agenesis Code: A Meta-Analysis.

Individuals with orofacial clefting (OFC) have a higher prevalence of tooth agenesis (TA) overall. Neither the precise etiology of TA, nor whether TA occurs in patterns that differ by gender or cleft type is yet known. This meta-analysis aims to identify the spectrum of tooth agenesis patterns in subjects with non-syndromic OFC and controls using the Tooth Agenesis Code (TAC) program. An indexed search of databases (PubMed, EMBASE, and CINAHL) along with cross-referencing and hand searches were completed from May to June 2019 and re-run in February 2022. Additionally, unpublished TAC data from 914 individuals with OFC and 932 controls were included. TAC pattern frequencies per study were analyzed using a random effects meta-analysis model. A thorough review of 45 records retrieved resulted in 4 articles meeting eligibility criteria, comprising 2182 subjects with OFC and 3171 controls. No TA (0.0.0.0) was seen in 51% of OFC cases and 97% of controls. TAC patterns 0.2.0.0, 2.0.0.0, and 2.2.0.0 indicating uni- or bi-lateral missing upper laterals, and 16.0.0.0 indicating missing upper right second premolar, were more common in subjects with OFC. Subjects with OFC have unique TA patterns and defining these patterns will help increase our understanding of the complex etiology underlying TA.

Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Preterm birth etiological pathways: a Bayesian networks and mediation analysis approach.

BACKGROUND: The aim of this study was to determine the mediating effect of spontaneous preterm birth (PTB) main predictors that would allow to suggest etiological pathways. METHODS: We carried out a case-control study, including sociodemographic characteristics, habits, health care, and obstetric data of multiparous women who gave birth at a maternity hospital from Tucumán, Argentina, between 2005 and 2010: 998 women without previous PTB who delivered at term and 562 who delivered preterm. We selected factors with the greatest predictive power using a penalized logistic regression model. A data-driven Bayesian network including the selected factors was created where we identified pathways and performed mediation analyses. RESULTS: We identified three PTB pathways whose natural indirect effect was greater than zero with a 95% confidence interval: maternal age less than 20 years mediated by few prenatal visits, vaginal bleeding in the first trimester mediated by vaginal bleeding in the second trimester, and urinary tract infection mediated by vaginal bleeding in the second trimester. The effect mediated in these pathways showed greater sensitivity to confounders affecting the variables mediator-outcome and exposure-mediator in the same direction. CONCLUSION: The identified pathways suggest PTB etiological lines related to social disparities and exposure to genitourinary tract infections. IMPACT: Few prenatal visits (<5) and vaginal bleeding are two of the main predictors for spontaneous preterm birth in the studied population. Few prenatal visits mediates part of the risk associated with maternal age less than 20 years and vaginal bleeding in the second trimester mediates part of the risk associated with vaginal bleeding in the first trimester and with urinary tract infection. Social disparities and exposure to genitourinary tract infections would be etiological lines of spontaneous preterm birth.

Diseases during pregnancy in a large unselected South American sample / Prevalência de doenças durante a gravidez em uma grande amostra sul-americana não selecionada

ABSTRACT Objective: Our aim was to describe the prevalence of diseases during pregnancy and the association between fetal exposure to the most frequent maternal diseases and the risk of preterm (PTB) and/or small for gestational age (SGA) newborns in an unselected sample of women who gave birth in South American countries. Methods: We conducted a descriptive, cross-sectional study including 56,232 mothers of non-malformed infants born between 2002 and 2016, using data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC). Diseases with higher- than-expected PTB/SGA frequencies were identified. Odds ratios of confounding variables for diseases and birth outcomes were calculated with a multivariable logistic regression. Results: Of the 14 most reported diseases, hypertension, genitourinary infection, epilepsy, hypothyroidism, diabetes, and HIV/AIDS showed higher PTB and/or SGA frequencies. Advanced and low maternal age, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with PTB, while advanced maternal age, primigravidity, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with SGA. After adjusting for the associated variables, the identified illnesses maintained their association with PTB and all, except epilepsy, with SGA. Conclusion: The description of an unselected population of mothers allowed identifying the most frequent diseases occurring during gestation and their impact on pregnancy outcomes. Six diseases were associated with PTB and two with SGA newborns. To the best of our knowledge, there are no similar reports about women not intentionally selected by specific diseases during pregnancy in South American populations.

RESUMO Objetivo: Descrever a prevalência de doenças durante a gravidez e a associação entre a exposição fetal às doenças maternas mais prevalentes e o risco de recém-nascidos prematuros (PP) e/ou pequenos para a idade gestacional (PIG) em uma amostra não selecionada de mulheres que deram à luz em países da América do Sul. Métodos: Estudo descritivo transversal que incluiu 56.232 mães de crianças não malformadas nascidas entre 2002 e 2016, utilizando dados do Estudo Colaborativo Latino-americano de Malformações Congênitas (ECLAMC). Foram identificadas as doenças com maior número de casos observado/esperado de PP/PIG. O esperado foi obtido dos controles sem doenças. Odds ratios para variáveis de confusão de doença e eventos ao nascimento foram calculadas usando regressão logística multivariada. Resultados: Das 14 doenças mais referidas, hipertensão, infecção geniturinária, epilepsia, hipotireoidismo, diabetes e HIV/AIDS apresentaram maiores frequências de PP e/ou PIG. Idade materna nos dois extremos, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PP, enquanto idade materna avançada, primigravidez, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PIG. Após ajuste para as variáveis associadas, as doenças identificadas mantiveram associação com PP e todas, exceto epilepsia, com PIG. Conclusão: A descrição de uma população não selecionada de gestantes possibilitou identificar as doenças mais frequentes e seu impacto nos resultados adversos na gravidez. Seis doenças foram associadas a PP e duas a recém-nascidos PIG. Até onde sabemos, não há relatos semelhantes sobre mulheres não selecionadas intencionalmente por doenças específicas durante a gravidez em populações sul-americanas.

Genome-Wide Association Study (GWAS) of dental caries in diverse populations.

BACKGROUND: Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent. METHODS: The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18-60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification. RESULTS: We identified several suggestive loci (5 × 10-8 < P < 5 × 10-6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis. CONCLUSION: The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.

Genome-Wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle (~1/800 and 1/900, respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (~12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p-values < 1e-06, including 10 with genome-wide significance (<5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p = 6.27e-07), 10q22.2 (rs150952246, p = 3.14e-07), and 10q24.32 (rs118107597, p = 8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, NTN1, WNT3-WNT9B, TANC2, and RHPN2. The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were (a) purely due to sample sizes, (b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups.

[Social inequities in teenage mothers and the relationship to adverse perinatal outcomes in South American populations]. / Inequidades sociales en madres adolescentes y la relación con resultados perinatales adversos en poblaciones sudamericanas.

The aim was to explain differences in the rates of adverse perinatal events in teenage mothers with low and high schooling. The sample was collected from the Latin American Colaborative Study of Congenital Malformations (ECLAMC) database. From a total of 2,443,747 births in 93 hospitals, 66,755 live newborns without congenital malformations were recruited from 2000 to 2017. Teenage mothers were classified according to low, medium, and high schooling. A multivariate model was used that included reproductive history, access to health services, demographic and socioeconomic variables, and ethnic group. The Fairlie decomposition model was applied to quantify the contribution of explanatory variables to the adverse perinatal event rates. Of the 66,755 newborns analyzed, 21.1% (n = 14,078) were born to teenage mothers. Distribution of maternal schooling was 24.2%, 59.8%, and 16% for low, medium, and high schooling, respectively. The highest rates of adverse perinatal events were seen in teenage mothers with low schooling. The variable "access to health services" explained 35%, 37%, and 23% of the disparities in low birthweight, prematurity, and intrauterine growth restriction, respectively, among teenage mother with low and high schooling. Low number of prenatal visits was the only risk factor for the two levels of schooling and the variable that best explained the differences between the rates of adverse perinatal events. From the public health perspective, prenatal care represents a low-cost intervention with the possibility of increased implementation through adequate information for the population and systematic measures in primary care.

El objetivo fue explicar las diferencias en la frecuencia de eventos perinatales adversos entre madres adolescentes con baja y alta escolaridad. La muestra poblacional se recogió en la base de datos del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Entre 2.443.747 nacimientos ocurridos en 93 hospitales, se reclutaron 66.755 recién nacidos vivos, sin defectos congénitos, durante el período 2000-2017. Las madres adolescentes se clasificaron según su escolaridad en: baja, media y alta. Se utilizó un modelo multivariado, que incluyó efectos reproductivos, acceso a servicios de salud, variables demográficas-socioeconómicas, así como de grupo étnico. El modelo de descomposición de Fairlie se aplicó para cuantificar la contribución de variables explicativas en las frecuencias de eventos perinatales adversos. De los 66.755 recién nacidos investigados, el 21,1% (n = 14.078) fue primigrávida de madres adolescentes. La distribución por escolaridad materna fue de 24,2%, 59,8% y 16% para baja, media y alta escolaridad, respectivamente. Las mayores frecuencias de eventos perinatales adversos se observaron en madres adolescentes con baja escolaridad. La variable "acceso a servicios de salud" explicó un 35%, 37% y 23% de las disparidades en el bajo peso al nacimiento, prematuridad y retardo de crecimiento intrauterino, respectivamente, entre madres adolescentes con baja y alta escolaridad. El bajo número de consultas prenatales fue el único factor de riesgo para los dos niveles de escolaridad y la variable que mejor explica las diferencias entre las frecuencias de eventos perinatales adversos. Desde el punto de vista de la salud pública, ellos representan una intervención de bajo coste, con posibilidad de que se incrementen mediante información adecuada para la población y medidas sistemáticas en los niveles de atención primaria.

O objetivo foi explicar as diferenças na frequência de eventos perinatais adversos entre mães adolescentes com baixa e alta escolaridade. A amostra populacional foi coletada na base de dados do Estudo Colaborativo Latino-Americano de Malformações Congênitas (ECLAMC). Entre 2.443.747 nascimentos ocorridos em 93 hospitais, 66.755 recém-nascidos vivos sem defeitos congênitos foram recrutados no período 2000-2017. As mães adolescentes foram classificadas segundo sua escolaridade em: baixa, média e alta. Foi utilizado um modelo multivariado que incluiu efeitos reprodutivos, acesso a serviços de saúde, variáveis demográficas-socioeconômicas e de grupo étnico. O modelo de decomposição de Fairlie foi aplicado para quantificar a contribuição de variáveis explicativas nas frequências de eventos perinatais adversos. Dos 66.755 recém-nascidos pesquisados, o 21,1% (n = 14.078) foi a mãe adolescente. A distribuição por escolaridade materna foi de 24,2%, 59,8% e 16% para baixa escolaridade, média escolaridade e alta escolaridade, respectivamente. As maiores frequências de eventos perinatais adversos foram observadas em mães adolescentes com baixa escolaridade. A variável "acesso a serviços de saúde"; explicou 35%, 37% e 23% das disparidades no baixo peso ao nascer, prematuridade e retardo de crescimento intrauterino, respectivamente, entre mães adolescentes com baixa e alta escolaridades. O baixo número de consultas pré-natais foi o único fator de risco para os dois níveis de escolaridade e a variável que melhor explica as diferenças entre as frequências de eventos perinatais adversos. Do ponto de vista da saúde pública, eles representam uma intervenção de baixo custo, com possibilidade de ser incrementadas por meio de informações adequadas à população e medidas sistemáticas nos níveis de atenção primária.

Preterm birth and genitourinary tract infections: assessing gene-environment interaction.

BACKGROUND: Preterm birth (PTB) is the leading cause of perinatal morbimortality worldwide. Genetic and environmental factors could raise PTB risk. The aim of this study was to analyze the contribution of the statistical interaction between genes and vaginal-urinary tract infections (VI-UTI) to the risk of PTB by clinical subtype. METHODS: Twenty-four SNPs were genotyped in 18 candidate genes from 352 fetal triads and 106 maternal triads. Statistical interactions were evaluated with conditional logistic regression models based on genotypic transmission/disequilibrium test. RESULTS: In PTB-idiopathic subtype mothers exposed to UTI, fetal SNPs rs11686474 (FSHR), rs4458044 (CRHR1, allele G), rs883319 (KCNN3), and maternal SNP rs1882435 (COL4A3) showed a nominal significant increment in prematurity risk. In preterm premature rupture of membranes (PPROM), fetal SNP rs2277698 (TIMP2) showed a nominal significant risk increment. In mothers exposed to VI, fetal SNP rs5742612 (IGF1) in PTB-PPROM and maternal SNP rs4458044 (CRHR1, allele C) in spontaneous PTB showed nominal significant increment in prematurity risk. CONCLUSIONS: Certain maternal and fetal genes linked to infectious/inflammatory and hormonal regulation processes increase prematurity risk according to clinical subtype when mothers are exposed to UTI or VI. These findings may help in the understanding of PTB etiology and PTB prevention. IMPACT: Preterm birth is a major cause of perinatal morbimortality worldwide and its etiology remains unknown. This work provides evidence on the statistical interaction of six genes with gestational vaginal or urinary infections leading to the occurrence of preterm births. Statistical interactions vary according to infection type, genotype (maternal and fetal), and clinical subtype of prematurity. Certain maternal and fetal genetic variants of genes linked to infectious/inflammatory and hormonal regulation processes would increase the risk of prematurity according to clinical subtype and infection type. Our findings may help in the study of etiology of preterm birth and its prevention.