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1.
Nat Commun ; 10(1): 4448, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575865

RESUMO

Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6-12 months (rs2767486, P6m = 2.0 × 10-21, ß6m = 0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P1.5y = 1.3 × 10-8, ß1.5y = 0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.

2.
Nat Commun ; 10(1): 3927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

3.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
4.
BMJ Open ; 8(10): e022929, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30385442

RESUMO

OBJECTIVES: To determine whether uterine distention is associated with human pregnancy duration in a non-invasive observational setting. DESIGN: Retrospective cohort study modelling uterine distention by interaction between maternal height and uterine load. SETTING: The study is based on the 1990-2013 population data from all delivery units in Sweden. PARTICIPANTS: Uncomplicated first pregnancies of healthy Nordic-born mothers with spontaneous onset of labour. Pregnancies were classified as twin (n=2846) or singleton (n=527 868). Singleton pregnancies were further classified as carrying a large for gestational age fetus (LGA, n=24 286) or small for gestational age fetus (SGA, n=33 780). OUTCOME MEASURES: Statistical interaction between maternal height and uterine load categories (twin vs singleton pregnancies, and LGA vs SGA singleton pregnancies), where the outcome is pregnancy duration. RESULTS: In all models, statistically significant interaction was found. Mothers carrying twins had 2.9 times larger positive linear effect of maternal height on gestational age than mothers carrying singletons (interaction p=5e-14). Similarly, the effect of maternal height was strongly modulated by the fetal growth rate in singleton pregnancies: the effect size of maternal height on gestational age in LGA pregnancies was 2.1 times larger than that in SGA pregnancies (interaction p<1e-11). Preterm birth OR was 1.4 when the mother was short, and 2.8 when the fetus was extremely large for its gestational age; however, when both risk factors were present together, the OR for preterm birth was larger than expected, 10.2 (interaction p<0.0005). CONCLUSIONS: Across all classes, maternal height was significantly associated with child's gestational age at birth. Interestingly, in short-statured women with large uterine load (twins, LGA), spontaneous delivery occurred much earlier than expected. The interaction between maternal height, uterine load size and gestational age at birth strongly suggests the effect of uterine distention imposed by fetal growth on birth timing.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30169899

RESUMO

INTRODUCTION: Preterm delivery is a major global public health challenge. The objective of this study was to determine how preterm delivery rates differ in a country with a very high human development index and to explore rural versus urban environmental and socioeconomic factors that may be responsible for this variation. MATERIAL AND METHODS: A population-based study was performed using data from the Swedish Medical Birth Register from 1998 to 2013. Sweden was chosen as a model because of its validated, routinely collected data and availability of individual social data. The total population comprised 1 335 802 singleton births. A multiple linear regression was used to adjust gestational age for known risk factors (maternal smoking, ethnicity, maternal education, maternal age, height, fetal sex, maternal diabetes, maternal hypertension, and parity). A second and a third model were subsequently fitted allowing separate intercepts for each municipality (as fixed or random effects). Adjusted gestational ages were converted to preterm delivery rates and mapped onto maternal residential municipalities. Additionally, the effects of six rural versus urban environmental and socioeconomic factors on gestational age were tested using a simple weighted linear regression. RESULTS: The study population preterm delivery rate was 4.12%. Marked differences from the overall preterm delivery rate were observed (rate estimates ranged from 1.73% to 6.31%). The statistical significance of this heterogeneity across municipalities was confirmed by a chi-squared test (P < 0.001). Around 20% of the gestational age variance explained by the full model (after adjustment for known variables described above) could be attributed to municipality-level effects. In addition, gestational age was found to be longer in areas with a higher fraction of built-upon land and other urban features. CONCLUSIONS: After adjusting for known risk factors, large geographical differences in rates of preterm delivery remain. Additional analyses to look at the effect of environmental and socioeconomic factors on gestational age found an increased gestational age in urban areas. Future research strategies could focus on investigating the urbanity effect to try to explain preterm delivery variation across countries with a very high human development index.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30007778

RESUMO

The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways. Similar to other complex human traits, gestational duration is likely to be influenced by numerous genetic variants of small effect size. The detection of these small-effect genetic variants requires very large sample sizes. In addition, several practical and analytical challenges, in particular the involvement of both maternal and fetal genomes, further complicate the genetic studies of gestational duration and other pregnancy phenotypes. Despite these challenges, large-scale GWA studies have already identified several genomic loci associated with gestational duration or the risk of preterm birth. These genomic discoveries have revealed novel insights about the biology of human birth timing. Expanding genomic discoveries in larger datasets by more refined analytical approaches, together with the functional analysis of the identified genomic loci, will collectively elucidate the biological processes underlying the control of human birth timing.

7.
BMJ Open ; 8(3): e018895, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29685923

RESUMO

OBJECTIVES: To study the association between maternal caffeine intake during pregnancy and the child's weight gain and overweight risk up to 8 years. DESIGN: Prospective nationwide pregnancy cohort. SETTING: The Norwegian Mother and Child Cohort Study. PARTICIPANTS: A total of 50 943 mothers recruited from 2002 to 2008 and their children, after singleton pregnancies, with information about average caffeine intake assessed at mid-pregnancy. OUTCOME MEASURE: Child's body size information at 11 age points from 6 weeks to 8 years. We defined excess growth in infancy as a WHO weight gain z-score of >0.67 from birth to age 1 year, and overweight according to the International Obesity Task Force. We used a growth model to assess individual growth trajectories. RESULTS: Compared with pregnant women with low caffeine intake (<50 mg/day, 46%), women with average (50-199 mg/day, 44%), high (≥200-299 mg/day, 7%) and very high (≥300 mg/day, 3%) caffeine intakes had an increased risk of their child experiencing excess growth in infancy, after adjustment for confounders (OR=1.15, 95% CI 1.09 to 1.22, OR=1.30, 95% CI 1.16 to 1.45, OR=1.66, 95% CI 1.42 to 1.93, respectively). In utero exposure to any caffeine was associated with higher risk of overweight at age 3 years and 5 years, while the association persisted at 8 years, only for very high exposures. Any caffeine intake was associated with increased body mass index from infancy to childhood. Children prenatally exposed to caffeine intake >200 mg/day had consistently higher weight. Very high caffeine exposures were associated with higher weight gain velocity from infancy to age 8 years. CONCLUSION: Any caffeine consumption during pregnancy is associated with a higher risk of excess infant growth and of childhood overweight, mainly at preschool ages. Maternal caffeine intake may modify the overall weight growth trajectory of the child from birth to 8 years. This study adds supporting evidence for the current advice to reduce caffeine intake during pregnancy.

8.
PLoS One ; 12(12): e0185244, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29253858

RESUMO

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. Previous studies have given valuable information about genetic variants associated with this disease but much is still unexplained. Our goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study. METHODS: 427 patients (293 males and 134 females) with CRSwNP and 393 controls (175 males and 218 females) were recruited from several Swedish hospitals. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX). Analyses of pathway enrichment, gene expression levels and expression quantitative trait loci were then performed in turn. RESULTS: None of the analysed SNPs reached genome wide significant association of 5.0 x 10-8. Pathway analyses using our top 1000 markers with the most significant association p-values resulted in 138 target genes. A comparison between our target genes and gene expression data from the NCBI Gene Expression Omnibus database showed significant overlap for 36 of these genes. Comparisons with data from expression quantitative trait loci showed the most skewed allelic distributions in cases with chronic rhinosinusitis with nasal polyps compared with controls for the genes HLCS, HLA-DRA, BICD2, VSIR and SLC5A1. CONCLUSION: Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. HLA-DRA has been associated with chronic rhinosinusitis with nasal polyps in previous studies and HLCS, BICD2, VSIR and SLC5A1 may be new targets for future research.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Doença Crônica , Família , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Rinite/complicações , Sinusite/complicações
9.
N Engl J Med ; 377(12): 1156-1167, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28877031

RESUMO

BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).


Assuntos
Predisposição Genética para Doença , Variação Genética , Idade Gestacional , Fatores de Alongamento de Peptídeos/genética , Nascimento Prematuro/genética , Receptor Tipo 2 de Angiotensina/genética , Transativadores/genética , Adenilil Ciclases/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Análise de Regressão , Proteína Wnt4/genética , Proteínas ras/genética
10.
G3 (Bethesda) ; 7(4): 1349-1356, 2017 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-28250013

RESUMO

Preterm delivery (PTD) is the leading cause of neonatal mortality worldwide, yet its etiology remains largely unexplained. We propose that the genetic factors controlling this trait could act in a nonuniform manner during pregnancy, with each factor having a unique "window of sensitivity." We test this hypothesis by modeling the distribution of gestational ages (GAs) observed in maternal cousins from the Swedish Medical Birth Register (MBR) (n = 35,541 pairs). The models were built using a time-to-event framework, with simulated genetic factors that increase the hazard of birth either uniformly across the pregnancy (constant effect) or only in particular windows (varying effect). By including various combinations of these factors, we obtained four models that were then optimized and compared. Best fit to the clinical data was observed when most of the factors had time-variant effects, independently of the number of loci simulated. Finally, power simulations were performed to assess the ability to discover varying-effect loci by usual methods for genome-wide association testing. We believe that the tools and concepts presented here should prove useful for the design of future studies of PTD and provide new insights into the genetic architecture determining human GA.


Assuntos
Família , Variação Genética , Nascimento Prematuro/genética , Simulação por Computador , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Idade Gestacional , Humanos , Modelos Genéticos , Parto , Nascimento Prematuro/epidemiologia , Probabilidade , Sistema de Registros , Suécia/epidemiologia , Fatores de Tempo
11.
J Am Acad Child Adolesc Psychiatry ; 55(10): 896-905.e6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27663945

RESUMO

OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Humanos , Masculino
12.
Hum Mol Genet ; 25(18): 4127-4142, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27559109

RESUMO

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.


Assuntos
Diarreia/genética , Fucosiltransferases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Pré-Escolar , Diarreia/patologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único
13.
PLoS One ; 11(8): e0160335, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27490719

RESUMO

BACKGROUND: Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet. METHODS: We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound-dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords. RESULTS: The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 × 10-7. The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A. CONCLUSION: Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Idade Gestacional , Modelos Genéticos , Nascimento Prematuro/genética , Adulto , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Noruega , Nascimento Prematuro/imunologia
14.
Nature ; 533(7604): 539-42, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27225129

RESUMO

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.


Assuntos
Encéfalo/metabolismo , Escolaridade , Feto/metabolismo , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Doença de Alzheimer/genética , Transtorno Bipolar/genética , Cognição , Biologia Computacional , Interação Gene-Ambiente , Humanos , Anotação de Sequência Molecular , Esquizofrenia/genética , Reino Unido
15.
Nat Genet ; 47(12): 1449-1456, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26482879

RESUMO

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.


Assuntos
Dermatite Atópica/etnologia , Dermatite Atópica/genética , Grupos Étnicos/genética , Loci Gênicos , Marcadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Dermatite Atópica/patologia , Humanos , Imunidade Inata/genética , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
PLoS Med ; 12(8): e1001865, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26284790

RESUMO

BACKGROUND: Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach. METHODS AND FINDINGS: We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP) data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway). We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10-9), birth weight (p = 2.19 × 10-15), and gestational age (p = 1.51 × 10-7). Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424) and demonstrated a significant (p = 0.0234) causal effect of every 1 cm increase in maternal height resulting in ~0.4 more gestational d. Limitations of this study include potential influences in causal inference by biological pleiotropy, assortative mating, and the nonrandom sampling of study subjects. CONCLUSIONS: Our results demonstrate that the observed association between maternal height and fetal growth measures (i.e., birth length and birth weight) is mainly defined by fetal genetics. In contrast, the association between maternal height and gestational age is more likely to be causal. In addition, our approach that utilizes the genetic score derived from the nontransmitted maternal haplotype as a genetic instrument is a novel extension to the Mendelian randomization methodology in casual inference between parental phenotype (or exposure) and outcomes in offspring.


Assuntos
Estatura , Peso Corporal , Causalidade , Análise da Randomização Mendeliana , Mães , Dinamarca , Feminino , Finlândia , Idade Gestacional , Haplótipos , Humanos , Recém-Nascido , Noruega , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez
17.
BMC Pregnancy Childbirth ; 14: 375, 2014 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-25361626

RESUMO

BACKGROUND: Health authorities in numerous countries recommend periconceptional folic acid supplementation to prevent neural tube defects. The objective of this study was to examine the association of dietary folate intake and folic acid supplementation during different periods of pregnancy with the risk of spontaneous preterm delivery (PTD). METHODS: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 66,014 women with singleton pregnancies resulting in live births in 2002-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until pregnancy week 24. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,755). RESULTS: The median total folate intake was 313 µg/d (interquartile range IQR 167-558) in the overall population and 530 µg/d (IQR 355-636) in the supplement users. Eighty-five percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while only 44% initiated folic acid supplementation before pregnancy. Cox regression analysis showed that the amount of dietary folate intake (hazard ratio HR 1.00; confidence interval 95% CI 0.61-1.65) and supplemental folate intake (HR 1.00; CI 1.00-1.00) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for spontaneous PTD (HR 1.18; CI 1.05-1.32) compared to no folic acid supplementation preconception. There was no significant association with PTD when supplementation was initiated within 8 weeks preconception (HR 0.99; CI 0.87-1.13). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. CONCLUSIONS: Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Preconceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of spontaneous PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.


Assuntos
Dieta , Ácido Fólico/administração & dosagem , Nascimento Prematuro/prevenção & controle , Complexo Vitamínico B/administração & dosagem , Adulto , Suplementos Nutricionais , Feminino , Ácido Fólico/efeitos adversos , Idade Gestacional , Humanos , Noruega/epidemiologia , Cuidado Pré-Concepcional , Gravidez , Nascimento Prematuro/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Inquéritos e Questionários , Fatores de Tempo , Complexo Vitamínico B/efeitos adversos , Adulto Jovem
18.
BMC Pregnancy Childbirth ; 13: 160, 2013 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-23937678

RESUMO

BACKGROUND: Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD). METHODS: The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,628). RESULTS: The median total folate intake was 266 µg/d (interquartile range IQR 154-543) in the overall population and 540 µg/d (IQR 369-651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05-1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. CONCLUSIONS: Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.


Assuntos
Dieta , Ácido Fólico/administração & dosagem , Nascimento Prematuro/prevenção & controle , Complexo Vitamínico B/administração & dosagem , Adulto , Suplementos Nutricionais , Feminino , Idade Gestacional , Humanos , Noruega , Política Nutricional , Gravidez , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
19.
PLoS One ; 8(8): e70174, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23936387

RESUMO

Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS) have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1) polarity and epithelial cell functionality; 2) intestinal smooth muscle; 3) growth and energy homeostasis, including proline and glutamine metabolism; and finally 4) innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly also other chronic disorders with an inflammatory component.


Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Doença Celíaca/genética , Fosfatases de Especificidade Dupla/genética , Genoma Humano , Sistema Imunitário/imunologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Polimorfismo de Nucleotídeo Único/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Autoimunidade/imunologia , Estudos de Casos e Controles , Doença Celíaca/imunologia , Doença Celíaca/patologia , Criança , Fosfatases de Especificidade Dupla/imunologia , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Sistema Imunitário/patologia , Intestinos/imunologia , Intestinos/patologia , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/imunologia , Núcleo Familiar
20.
BMC Med ; 11: 42, 2013 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-23421532

RESUMO

BACKGROUND: Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA). METHODS: This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves. RESULTS: The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal-28 g, Skjaerven-25 g, Gardosi-21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day. CONCLUSIONS: Coffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.


Assuntos
Peso ao Nascer , Cafeína/metabolismo , Dieta/métodos , Nascimento Prematuro , Adulto , Estudos de Coortes , Feminino , Humanos , Noruega , Gravidez , Adulto Jovem
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