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1.
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
2.
Ann Epidemiol ; 28(11): 753-758, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30241792

RESUMO

PURPOSE: To study the association between coffee and alcoholic beverage consumption and alcoholic liver disease mortality. METHODS: In total, 219,279 men and women aged 30-67 years attended cardiovascular screening in Norway from 1994 to 2003. Linkage to the Cause of Death Registry identified 93 deaths from alcoholic liver disease. Coffee consumption was categorized into four levels: 0, 1-4, 5-8, and greater than or equal to 9 cups/d and alcohol consumption as 0, greater than 0 to less than 1.0, 1.0 to less than 2.0, and greater than or equal to 2.0 units/d, for beer, wine, liquor, and total alcohol consumption. RESULTS: The hazard ratios per one category of consumption were 2.06 (95% confidence interval 1.62-2.61), 0.68 (0.46-1.00), and 2.54 (1.92-3.36) for beer, wine, and liquor, respectively. Stratification at 5 cups/d (the mean) revealed a stronger association between alcohol consumption and alcoholic liver disease at less than 5 versus 5 or more cups/d. With less than 5 cups/d, 0 alcohol units/d as reference, the hazard ratio reached to 25.5 (9.2-70.5) for greater than or equal to 2 units/d, whereas with greater than or equal to 5 cups/d, it reached 5.8 (1.9-17.9) for greater than or equal to 2 units/d. A test for interaction was significant (P = .01). CONCLUSIONS: Coffee and wine consumption were inversely associated with alcoholic liver disease death. Total alcohol consumption was adversely associated with alcoholic liver disease mortality and the strength of the association varied with the level of coffee consumption.

3.
BMJ Open ; 8(1): e018021, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362253

RESUMO

OBJECTIVES: To investigate whether the timing of probiotic milk intake before, during early or late pregnancy influences associations with preeclampsia and preterm delivery. DESIGN: Population based prospective cohort study. SETTING: Norway, between 1999 and 2008. PARTICIPANTS: 70 149 singleton pregnancies resulting in live-born babies from the Norwegian Mother and Child Cohort Study (no chronic disease, answered questionnaires, no placenta previa/cerclage/serious malformation of fetus, first enrolment pregnancy). Only nulliparous women (n=37 050) were included in the preeclampsia analysis. Both iatrogenic and spontaneous preterm delivery (between gestational weeks 22+0 and 36+6) with spontaneous term controls (between gestational weeks 39+0 and 40+6) were included in the preterm delivery analysis resulting in 34 458 cases. MAIN OUTCOME MEASURES: Adjusted OR for preeclampsia and preterm delivery according to consumption of probiotic milk at three different time periods (before pregnancy, during early and late pregnancy). RESULTS: Probiotic milk intake in late pregnancy (but not before or in early pregnancy) was significantly associated with lower preeclampsia risk (adjusted OR: 0.80 (95% CI 0.68 to 0.94) p-value: 0.007). Probiotic intake during early (but not before or during late pregnancy) was significantly associated with lower risk of preterm delivery (adjusted OR: 0.79 (0.64 to 0.97) p-value: 0.03). CONCLUSIONS: In this observational study, we found an association between timing of probiotic milk consumption during pregnancy and the incidence of the adverse pregnancy outcomes preeclampsia and preterm delivery. If future randomised controlled trials could establish a causal association between probiotics consumption and reduced risk of preeclampsia and preterm delivery, recommending probiotics would be a promising public health measure to reduce these adverse pregnancy outcomes.


Assuntos
Leite , Pré-Eclâmpsia/epidemiologia , Nascimento Prematuro/epidemiologia , Probióticos/administração & dosagem , Fatores de Tempo , Adolescente , Adulto , Animais , Bovinos , Suplementos Nutricionais , Feminino , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Modelos Logísticos , Masculino , Exposição Materna/efeitos adversos , Noruega/epidemiologia , Gravidez , Probióticos/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
4.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

5.
PLoS One ; 12(3): e0172896, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28249018

RESUMO

BACKGROUND: Dietary habits are linked to high maternal glucose levels, associated with preterm delivery. The aim of this study was to examine the associations between meal frequency and glycemic properties of maternal diet in relation to preterm delivery. METHODS: This prospective cohort study included 66,000 women from the Norwegian Mother and Child Cohort Study (MoBa). Meal frequency and food intake data were obtained from a validated food frequency questionnaire during mid-pregnancy. Principal component factor analysis was used with a data-driven approach, and three meal frequency patterns were identified: "snack meal", "main meal", and "evening meal". Pattern scores were ranked in quartiles. Glycemic index and glycemic load were estimated from table values. Intakes of carbohydrates, added sugar, and fiber were reported in grams per day and divided into quartiles. Gestational age was obtained from the Medical Birth Registry of Norway. Preterm delivery was defined as birth at <37 gestational weeks. A Cox regression model was used to assess associations with preterm delivery. RESULTS: After adjustments, the "main meal" pattern was associated with a reduced risk of preterm delivery, with hazard ratios (HRs) of 0.89 (95% confidence interval (CI): 0.80, 0.98) and 0.90 (95% CI: 0.81, 0.99) for the third and fourth quartiles, respectively, and p for trend of 0.028. This was mainly attributed to the group of women with BMI ≥25 kg/m2, with HRs of 0.87 (95% CI: 0.79, 0.96) and 0.89 (95% CI: 0.80, 0.98) for the third and fourth quartiles, respectively, and p for trend of 0.010. There was no association between glycemic index, glycemic load, carbohydrates, added sugar, fiber, or the remaining meal frequency patterns and preterm delivery. CONCLUSION: Regular consumption of main meals (breakfast, lunch, dinner) was associated with a lower risk of preterm delivery. Diet should be further studied as potential contributing factors for preterm delivery.


Assuntos
Índice Glicêmico , Fenômenos Fisiológicos da Nutrição Materna , Refeições , Nascimento Prematuro/epidemiologia , Adulto , Estudos de Coortes , Dieta , Comportamento Alimentar , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Estudos Prospectivos
7.
BMC Pregnancy Childbirth ; 17(1): 41, 2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-28103845

RESUMO

BACKGROUND: Preterm delivery increases the risk of neonatal morbidity and mortality. Studies suggest that maternal diet may affect the prevalence of preterm delivery. The aim of this study was to assess whether maternal intakes of seafood and marine long chain n-3 polyunsaturated fatty acids (LCn-3PUFA) from supplements were associated with preterm delivery. METHODS: The study population included 67,007 women from the Norwegian Mother and Child Cohort Study. Maternal food and supplement intakes were assessed by a validated self-reported food frequency questionnaire in mid-pregnancy. Information about gestational duration was obtained from the Medical Birth Registry of Norway. We used Cox regression to estimate hazard ratios (HR) with 95% confidence intervals (CI) for associations between total seafood, lean fish, fatty fish, and LCn-3PUFA intakes and preterm delivery. Preterm was defined as any onset of delivery before gestational week 37, and as spontaneous or iatrogenic deliveries and as preterm delivery at early, moderate, and late preterm gestations. RESULTS: Lean fish constituted 56%, fatty fish 34% and shellfish 10% of seafood intake. Any intake of seafood above no/rare intake (>5 g/d) was associated with lower prevalence of preterm delivery. Adjusted HRs were 0.76 (CI: 0.66, 0.88) for 1-2 servings/week (20-40 g/d), 0.72 (CI: 0.62, 0.83) for 2-3 servings/week (40-60 g/d), and 0.72 (CI: 0.61, 0.85) for ≥3 servings/week (>60 g/d), p-trend <0.001. The association was seen for lean fish (p-trend: 0.005) but not for fatty fish (p-trend: 0.411). The intake of supplementary LCn-3PUFA was associated only with lower prevalence of early preterm delivery (before 32 gestational weeks), while increasing intake of LCn-3PUFA from food was associated with lower prevalence of overall preterm delivery (p-trend: 0.002). Any seafood intake above no/rare was associated with lower prevalence of both spontaneous and iatrogenic preterm delivery, and with lower prevalence of late preterm delivery. CONCLUSIONS: Any intake of seafood above no/rare consumption was associated with lower prevalence of preterm delivery. The association was stronger for lean than for fatty fish. Intake of supplementary LCn-3PUFA was associated only with early preterm delivery. The findings corroborate the current advice to include fish and seafood as part of a balanced diet during pregnancy.


Assuntos
Suplementos Nutricionais/estatística & dados numéricos , Ácidos Graxos Ômega-3/uso terapêutico , Nascimento Prematuro/epidemiologia , Alimentos Marinhos/estatística & dados numéricos , Adulto , Estudos de Coortes , Inquéritos sobre Dietas/métodos , Ingestão de Alimentos , Feminino , Idade Gestacional , Humanos , Noruega/epidemiologia , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Prevalência , Modelos de Riscos Proporcionais , Sistema de Registros , Adulto Jovem
8.
Mol Cell Endocrinol ; 439: 308-316, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27663074

RESUMO

Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.


Assuntos
Cálcio/metabolismo , Predisposição Genética para Doença , Hiperêmese Gravídica/genética , Espaço Intracelular/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Austrália , Estudos de Coortes , Exoma/genética , Família , Feminino , Deleção de Genes , Dosagem de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Noruega , Nutrição Parenteral , Linhagem , Gravidez , Análise de Sequência de DNA , Estados Unidos
9.
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
10.
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
11.
JAMA ; 315(11): 1129-40, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26978208

RESUMO

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.


Assuntos
Peso ao Nascer/genética , Glicemia/genética , Índice de Massa Corporal , Jejum/sangue , Obesidade/genética , Adulto , Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Humanos , Recém-Nascido , Análise da Randomização Mendeliana , Obesidade/sangue , Obesidade/etnologia , Polimorfismo de Nucleotídeo Único , Gravidez , Triglicerídeos/genética
12.
Hum Mol Genet ; 25(2): 389-403, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26604143

RESUMO

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.


Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Humanos , Masculino , Risco , Adulto Jovem
13.
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
14.
Hum Mol Genet ; 24(4): 1155-68, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25281659

RESUMO

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Estatura/genética , Estudos de Associação Genética , Variação Genética , Proteínas de Membrana/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Fatores Etários , Alelos , Biologia Computacional , Bases de Dados Genéticas , Genótipo , Humanos , Recém-Nascido , Proteínas de Membrana/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
15.
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
16.
Mol Biol Rep ; 41(5): 2733-43, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24728607

RESUMO

Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.


Assuntos
Cromossomos Humanos Par 1 , Cromossomos Humanos Par 9 , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Variação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Polimorfismo de Nucleotídeo Único
17.
BMJ ; 348: g1446, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24609054

RESUMO

OBJECTIVE: To examine whether an association exists between maternal dietary patterns and risk of preterm delivery. DESIGN: Prospective cohort study. SETTING: Norway, between 2002 and 2008. PARTICIPANTS: 66 000 pregnant women (singletons, answered food frequency questionnaire, no missing information about parity or previously preterm delivery, pregnancy duration between 22+0 and 41+6 gestational weeks, no diabetes, first enrolment pregnancy). MAIN OUTCOME MEASURE: Hazard ratio for preterm delivery according to level of adherence to three distinct dietary patterns interpreted as "prudent" (for example, vegetables, fruits, oils, water as beverage, whole grain cereals, fibre rich bread), "Western" (salty and sweet snacks, white bread, desserts, processed meat products), and "traditional" (potatoes, fish). RESULTS: After adjustment for covariates, high scores on the "prudent" pattern were associated with significantly reduced risk of preterm delivery hazard ratio for the highest versus the lowest third (0.88, 95% confidence interval 0.80 to 0.97). The prudent pattern was also associated with a significantly lower risk of late and spontaneous preterm delivery. No independent association with preterm delivery was found for the "Western" pattern. The "traditional" pattern was associated with reduced risk of preterm delivery for the highest versus the lowest third (hazard ratio 0.91, 0.83 to 0.99). CONCLUSION: This study showed that women adhering to a "prudent" or a "traditional" dietary pattern during pregnancy were at lower risk of preterm delivery compared with other women. Although these findings cannot establish causality, they support dietary advice to pregnant women to eat a balanced diet including vegetables, fruit, whole grains, and fish and to drink water. Our results indicate that increasing the intake of foods associated with a prudent dietary pattern is more important than totally excluding processed food, fast food, junk food, and snacks.


Assuntos
Comportamento Alimentar , Nascimento Prematuro/epidemiologia , Adulto , Dieta , Feminino , Humanos , Noruega/epidemiologia , Gravidez , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
18.
J Allergy Clin Immunol ; 133(1): 165-71.e1-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24034345

RESUMO

BACKGROUND: Whether probiotics, which can influence the microbiome, prevent infant eczema or allergic disease remains an open question. Most studies have focused on high-risk infants. OBJECTIVES: We sought to assess whether consumption of probiotic milk products protects against atopic eczema, rhinoconjunctivitis, and asthma in early childhood in a large population-based pregnancy cohort (the Norwegian Mother and Child Cohort study). METHODS: We examined associations between consumption of probiotic milk products in pregnancy and infancy with questionnaire-reported atopic eczema, rhinoconjunctivitis, and asthma in 40,614 children. Relative risks (RRs) were calculated by using general linear models adjusted for potential confounders. RESULTS: Consumption of probiotic milk in pregnancy was associated with a slightly reduced relative risk (RR) of atopic eczema at 6 months (adjusted RR, 0.94; 95% CI, 0.89-0.99) and of rhinoconjunctivitis between 18 and 36 months (adjusted RR, 0.87; 95% CI, 0.78-0.98) compared with no consumption during pregnancy. Maternal history of allergic disease did not notably influence the associations. When both the mother (during pregnancy) and infant (after 6 months of age) had consumed probiotic milk, the adjusted RR of rhinoconjunctivitis was 0.80 (95% CI, 0.68-0.93) relative to no consumption by either. Probiotic milk consumption was not associated with asthma at 36 months. CONCLUSIONS: In this population-based cohort consumption of probiotic milk products was related to a reduced incidence of atopic eczema and rhinoconjunctivitis, but no association was seen for incidence of asthma by 36 months of age.


Assuntos
Asma/epidemiologia , Conjuntivite/epidemiologia , Dermatite Atópica/epidemiologia , Probióticos/administração & dosagem , Rinite/epidemiologia , Adulto , Animais , Asma/prevenção & controle , Bovinos , Pré-Escolar , Estudos de Coortes , Conjuntivite/prevenção & controle , Dermatite Atópica/prevenção & controle , Suplementos Nutricionais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Exposição Materna/efeitos adversos , Leite , Gravidez , Probióticos/efeitos adversos , Rinite/prevenção & controle , Adulto Jovem
19.
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
20.
J Nutr ; 143(7): 1100-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23700347

RESUMO

Several studies have found associations between microbial infections during pregnancy and preterm delivery (PTD). We investigated the influence of food with antimicrobial and prebiotic components on the risk of spontaneous PTD. A literature search identified microbes associated with spontaneous PTD. Subsequently, 2 main food types (alliums and dried fruits) were identified to contain antimicrobial components that affect the microbes associated with spontaneous PTD; they also contained dietary fibers recognized as prebiotics. We investigated intake in 18,888 women in the Norwegian Mother and Child Cohort (MoBa), of whom 950 (5%) underwent spontaneous PTD (<37 gestational weeks). Alliums (garlic, onion, leek, and spring onion) [OR: 0.82 (95% CI: 0.72, 0.94), P = 0.005] and dried fruits (raisins, apricots, prunes, figs, and dates) [OR: 0.82 (95% CI: 0.72, 0.94); P = 0.005] were associated with a decreased risk of spontaneous PTD. Intake of alliums was related to a more pronounced risk reduction in early spontaneous PTD (gestational weeks 28-31) [OR: 0.39 (95% CI: 0.19, 0.80)]. The strongest association in this group was with garlic [OR: 0.47 (95% CI: 0.25-0.89)], followed by cooked onions. Intake of dried fruits showed an association with preterm prelabor rupture of membranes (PPROM) [OR: 0.74 (95% CI: 0.65, 0.95)]; the strongest association in this group was with raisins [OR: 0.71 (95% CI: 0.56, 0.92)]. The strongest association with PPROM in the allium group was with garlic [OR: 0.74 (95% CI: 0.56, 0.97)]. In conclusion, intake of food with antimicrobial and prebiotic compounds may be of importance to reduce the risk of spontaneous PTD. In particular, garlic was associated with overall lower risk of spontaneous PTD. Dried fruits, especially raisins, were associated with reduced risk of PPROM.


Assuntos
Allium , Dieta , Frutas , Fenômenos Fisiológicos da Nutrição Materna , Nascimento Prematuro/prevenção & controle , Adulto , Criança , Feminino , Ruptura Prematura de Membranas Fetais/prevenção & controle , Manipulação de Alimentos , Humanos , Modelos Logísticos , Masculino , Noruega , Gravidez , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
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