Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

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.

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

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.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

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.

Maternal intake of seafood and supplementary long chain n-3 poly-unsaturated fatty acids and preterm delivery.

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.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

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.

Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis.

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.

Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases.

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.

Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study.

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.

Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study.

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.

Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study.

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.

Intakes of garlic and dried fruits are associated with lower risk of spontaneous preterm delivery.

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.

Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study.

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.

Controlling for high-density lipoprotein cholesterol does not affect the magnitude of the relationship between alcohol and coronary heart disease.

BACKGROUND: This study tested the hypothesis that moderate alcohol intake exerts its cardioprotective effect mainly through an increase in the serum level of high-density lipoprotein cholesterol. METHODS AND RESULTS: In the Cohort of Norway (CONOR) study, 149 729 adult participants, recruited from 1994 to 2003, were followed by linkage to the Cause of Death Registry until 2006. At recruitment, questionnaire data on alcohol intake were collected, and the concentration of high-density lipoprotein cholesterol in serum was measured. Using Cox regression, we found that the adjusted hazard ratio for men for dying from coronary heart disease was 0.52 (95% confidence interval, 0.39-0.69) when consuming alcohol more than once a week compared with never or rarely. The ratio changed only slightly, to 0.55 (0.41-0.73), after the regression model included the serum level of high-density cholesterol. For women, the corresponding hazard ratios were 0.62 (0.32-1.23) and 0.68 (0.34-1.34), respectively. CONCLUSIONS: Alcohol intake is related to a reduced risk of death from coronary heart disease in the follow-up of a large, population-based Norwegian cohort study with extensive control for confounding factors. Our findings suggest that the serum level of high-density cholesterol is not an important intermediate variable in the possible causal pathway between moderate alcohol intake and coronary heart disease.

Prepregnancy maternal body mass index and preterm delivery.

OBJECTIVE: The purpose of this study was to determine the influence of maternal prepregnancy body mass index on preterm delivery (PTD), controlling for health and lifestyle variables. STUDY DESIGN: Prospective data were from 83,544 pregnancies in the Norwegian Mother and Child Cohort Study. PTD was divided into early PTD (22 + 0 to 31 + 6 weeks' gestation) and late PTD (32 + 0 to 36 + 6 weeks' gestation). RESULTS: The overall prevalence of PTD was 5.1%. Increased body mass index was associated with an increased risk of PTD; adjusted odds ratio (aOR) ranged from 1.11 (95% confidence interval [CI], 1.03-1.20) for preobesity to 2.00 (95% CI, 1.48-2.71) for grade-III obesity in the group that included all PTD subgroups. Grade-III obese women had an increased risk of both early and late PTD: aOR, 3.24 (95% CI, 1.71-6.14) and 1.81 (95% CI, 1.29-2.54), respectively. CONCLUSION: Prepregnancy maternal overweight increases the risk of both early and late PTD.

No observed association for mitochondrial SNPs with preterm delivery and related outcomes.

BACKGROUND: Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited, creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes and PTD and related outcomes. METHODS: This study combined, through meta-analysis, two case-control, genome-wide association studies: one from the Danish National Birth Cohort Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 wk), very PTD (≤32 wk), and preterm prelabor rupture of membranes (PPROM) were examined. A total of 135 individual single-nucleotide polymorphism (SNP) associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis. RESULTS: After meta-analysis, there were four SNPs for the outcome of PTD below P ≤ 0.10 and two below P ≤ 0.05. For the additional outcomes of very PTD and PPROM, there were three and four SNPs, respectively, below P ≤ 0.10. CONCLUSION: Given the number of tests, no single SNP reached study-wide significance (P = 0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.

Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study.

Probiotics have been suggested to modify placental trophoblast inflammation, systemic inflammation, and blood pressure, all potentially interesting aspects of preeclampsia. The authors examined the association between consumption of milk-based probiotic products in pregnancy and development of preeclampsia and its subtypes. The study was performed in the Norwegian Mother and Child Cohort Study by using a prospective design in 33,399 primiparous women in the years 2002-2008. The intake of milk-based products containing probiotic lactobacilli was estimated from a self-reported food frequency questionnaire. Preeclampsia diagnoses were obtained from the Norwegian Medical Birth Registry. Intake of probiotic milk products was associated with reduced risk of preeclampsia. The association was most prominent in severe preeclampsia (adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.66, 0.96). With probiotic intakes divided into categories representing no, monthly, weekly, or daily intake, a lower risk for preeclampsia (all subtypes) was observed for daily probiotic intake (OR = 0.80, 95% CI: 0.66, 0.96). Lower risks for severe preeclampsia were observed for weekly (OR = 0.75, 95% CI: 0.57, 0.98) and daily (OR = 0.61, 95% CI: 0.43, 0.89) intakes. These results suggest that regular consumption of milk-based probiotics could be associated with lower risk of preeclampsia in primiparous women.

Candidate gene analysis of spontaneous preterm delivery: new insights from re-analysis of a case-control study using case-parent triads and control-mother dyads.

BACKGROUND: Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs. METHODS: The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery. RESULTS: The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways. CONCLUSION: This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.