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1.
J Intern Med ; 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587396

RESUMO

BACKGROUND: There is limited evidence linking type 2 diabetes (T2D) to influenza-related complications. OBJECTIVES: To test a set of research questions relating to pandemic influenza vaccination, hospitalization and mortality in people with and without T2D. METHODS: In this population-based cohort study, we linked individual-level data from several national registers for all Norwegian residents aged 30 years or older as of January 2009. People with or without T2D at baseline (n=2,992,228) were followed until December 2013. We used Cox regression to estimate adjusted hazard ratios (aHRs). RESULTS: Pandemic influenza hospitalization was more common in individuals with T2D (aHR=2.46, 95%CI 2.04-2.98). The mortality hazard ratio associated with hospitalization for pandemic influenza was lower in people with T2D (aHR=1.82, 95%CI 1.21-2.74) than in those without T2D (aHR=3.89, 95%CI 3.27-4.62). The same pattern was observed when restricting to 90 days mortality (aHR=3.89, 95%CI 1.25-12.06 among those with T2D and aHR=10.79, 95%CI 7.23-16.10 among those without T2D). The rate of hospitalization for pandemic influenza was 78% lower in those vaccinated compared to non-vaccinated among people with T2D (aHR=0.22, 95% CI 0.11-0.39), while the corresponding estimate for those without T2D was 59% lower (aHR=0.41, 95%CI 0.33-0.52). Mortality was 25% lower in those vaccinated compared to non-vaccinated among people with T2D (aHR=0.75, 95% CI 0.73-0.77), while the corresponding estimate for those without T2D was 9% (aHR=0.91, 95%CI 0.90-0.92). CONCLUSIONS: There may have been a lower threshold for pandemic influenza hospitalization for people with T2D, rather than more severe influenza infection. Our combined results support the importance of influenza vaccination among people with T2D, especially during pandemics.

2.
Am J Gastroenterol ; 114(8): 1299-1306, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31343439

RESUMO

OBJECTIVES: Celiac disease (CD) may occur in genetically predisposed individuals exposed to gluten, but it is unclear whether the amount of gluten influences the risk of disease. We aimed at determining whether the amount of gluten intake at age 18 months predicted later risk of CD. METHODS: In an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), we included 67,608 children born during 2000-2009 and followed up for a mean of 11.5 years (range 7.5-15.5) after exclusions for missing data. Information regarding CD diagnosis was obtained from the Norwegian Patient Register 2008-2016 and from parental questionnaires at child age 7 and 8 years. We estimated gluten intake at age 18 months from a prospectively collected parental questionnaire. RESULTS: CD was diagnosed in 738 children (1.1%, 62% girls). The mean estimated amount of gluten in the diet at 18 months was 8.8 g/d (SD 3.6). The adjusted relative risk of CD was 1.10 (95% confidence interval 1.03-1.18) per SD increase in daily gluten amount at age 18 months. Children in the upper quartile of gluten intake compared with the lower quartile had an increased risk of CD (adjusted relative risk 1.29, 95% confidence interval 1.06-1.58). The association with gluten amount was independent of the age at introduction of gluten. Gluten introduction ≥6 months was also an independent risk factor for CD. DISCUSSION: In this nationwide study, increased gluten intake at 18 months was associated with a modestly increased risk of CD later in childhood.

3.
Nat Microbiol ; 4(10): 1727-1736, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31285584

RESUMO

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.

4.
Pediatr Diabetes ; 20(6): 728-735, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173445

RESUMO

BACKGROUND: Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis. METHODS: Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non-inherited, non-shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort. RESULTS: We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68-2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann-Whitney P = .46). There was a possible association in the NIMA HLA-DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05-14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis. CONCLUSIONS: Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort.

5.
Am J Gastroenterol ; 114(8): 1307-1314, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082869

RESUMO

OBJECTIVES: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce. METHODS: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04). DISCUSSION: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.

6.
Eur J Epidemiol ; 34(7): 637-649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31037572

RESUMO

Ecological observations suggest an inverse relationship between smoking in pregnancy and celiac disease (CD) in offspring. While individual-level analyses have been inconsistent, they have mostly lacked statistical power or refined assessments of exposure. To examine the association between pregnancy-related smoking and CD in the offspring, as well as its consistency across data sets, we analyzed: (1) The Norwegian Mother and Child Cohort (MoBa) of 94,019 children, followed from birth (2000-2009) through 2016, with 1035 developing CD; (2) a subsample from MoBa (381 with CD and 529 controls) with biomarkers; and (3) a register-based cohort of 536,861 Norwegian children, followed from birth (2004-2012) through 2014, with 1919 developing CD. Smoking behaviors were obtained from pregnancy questionnaires and antenatal visits, or, in the MoBa-subsample, defined by measurement of cord blood cotinine. CD and potential confounders were identified through nationwide registers and comprehensive parental questionnaires. Sustained smoking during pregnancy, both self-reported and cotinine-determined, was inversely associated with CD in MoBa (multivariable-adjusted [a] OR = 0.61 [95%CI, 0.46-0.82] and aOR = 0.55 [95%CI, 0.31-0.98], respectively); an inverse association was also found with the intensity of smoking. These findings differed from those of our register-based cohort, which revealed no association with sustained smoking during pregnancy (aOR = 0.97 [95%CI, 0.80-1.18]). In MoBa, neither maternal smoking before or after pregnancy, nor maternal or paternal smoking in only early pregnancy predicted CD. In a carefully followed pregnancy cohort, a more-detailed smoking assessment than oft-used register-based data, revealed that sustained smoking during pregnancy, rather than any smoking exposure, predicts decreased likelihood of childhood-diagnosed CD.


Assuntos
Doença Celíaca/epidemiologia , Cotinina/sangue , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Celíaca/induzido quimicamente , Feminino , Sangue Fetal , Antígenos HLA , Humanos , Masculino , Pessoa de Meia-Idade , Mães , Noruega/epidemiologia , Gravidez , Sistema de Registros , Fatores de Risco , Autorrelato , Fumar/sangue , Abandono do Hábito de Fumar
7.
Diabetes Care ; 42(5): 789-796, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796108

RESUMO

OBJECTIVE: To study the association of gluten intake with development of islet autoimmunity and progression to type 1 diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows children with an increased risk of type 1 diabetes. Blood samples were collected at 9, 15, and 24 months of age, and annually thereafter. Islet autoimmunity was defined by the appearance of at least one autoantibody against insulin, IA2, GAD, or ZnT8 (zinc transporter 8) in at least two consecutive blood samples. Using food frequency questionnaires, we estimated the gluten intake (in grams per day) annually from 1 year of age. Cox regression modeling early gluten intake, and joint modeling of the cumulative gluten intake during follow-up, were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: By August 2017, 1,916 subjects were included (median age at end of follow-up 13.5 years), islet autoimmunity had developed in 178 participants, and 56 of these progressed to type 1 diabetes. We found no association between islet autoimmunity and gluten intake at 1-2 years of age or during follow-up (aHR per 4 g/day increase in gluten intake 1.00, 95% CI 0.85-1.17 and 1.01, 0.99-1.02, respectively). We found similar null results for progression from islet autoimmunity to type 1 diabetes. Introduction of gluten at <4 months of age was associated with an increased risk of progressing from islet autoimmunity to type 1 diabetes compared with introduction at 4-5.9 months (aHR 8.69, 95% CI 1.69-44.8). CONCLUSIONS: Our findings indicate no strong rationale to reduce the amount of gluten in high-risk children to prevent development of type 1 diabetes.

8.
BMJ ; 364: l231, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760441

RESUMO

OBJECTIVE: To determine whether infection with human enterovirus or adenovirus, both common intestinal viruses, predicts development of coeliac disease. DESIGN: Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016. SETTING: Norwegian population. PARTICIPANTS: Children carrying the HLA genotype DR4-DQ8/DR3-DQ2 conferring increased risk of coeliac disease. EXPOSURES: Enterovirus and adenovirus detected using real time polymerase chain reaction in monthly stool samples from age 3 to 36 months. MAIN OUTCOME MEASURE: Coeliac disease diagnosed according to standard criteria. Coeliac disease antibodies were tested in blood samples taken at age 3, 6, 9, and 12 months and then annually. Adjusted odds ratios from mixed effects logistic regression model were used to assess the relation between viral infections before development of coeliac disease antibodies and coeliac disease. RESULTS: Among 220 children, and after a mean of 9.9 (SD 1.6) years, 25 children were diagnosed as having coeliac disease after screening and were matched to two controls each. Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls (adjusted odds ratio 1.49, 95% confidence interval 1.07 to 2.06; P=0.02). The association was restricted to infections after introduction of gluten. High quantity samples (>100 000 copies/µL) (adjusted odds ratio 2.11, 1.24 to 3.60; P=0.01) and long lasting infections (>2 months) (2.16, 1.16 to 4.04; P=0.02) gave higher risk estimates. Both the commonly detected enterovirus species Enterovirus A and Enterovirus B were significantly associated with coeliac disease. The association was not found for infections during or after development of coeliac disease antibodies. Adenovirus was not associated with coeliac disease. CONCLUSIONS: In this longitudinal study, a higher frequency of enterovirus, but not adenovirus, during early childhood was associated with later coeliac disease. The finding adds new information on the role of viral infections in the aetiology of coeliac disease.


Assuntos
Doença Celíaca/virologia , Infecções por Enterovirus/complicações , Autoanticorpos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Enterovirus/isolamento & purificação , Infecções por Enterovirus/epidemiologia , Fezes/virologia , Feminino , Genótipo , Humanos , Lactente , Estudos Longitudinais , Masculino , Noruega/epidemiologia , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
9.
Diabetes Care ; 42(4): 553-559, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30692241

RESUMO

OBJECTIVE: Circumstantial evidence links 25-hydroxy vitamin D [25(OH)D], vitamin D-binding protein (DBP), vitamin D-associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D. RESEARCH DESIGN AND METHODS: From a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography-tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, and VDR). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders. RESULTS: Higher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 [95% CI 0.74-0.98] per µmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 [95% CI 0.77-0.98] per 10 nmol/L increase) in children carrying the VDR rs11568820 G/G genotype (P interaction = 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions. CONCLUSIONS: Higher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on VDR genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include VDR genotype and DBP levels.

10.
J Med Virol ; 91(4): 606-614, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30537228

RESUMO

OBJECTIVES: Direct genotyping of adenovirus or enterovirus from clinical material using polymerase chain reaction (PCR) followed by Sanger sequencing is often difficult due to the presence of multiple virus types in a sample, or due to varying efficacy of PCR amplifying the capsid gene on the background of foreign nucleic acids. Here we present a simple protocol for virus genotyping using massive parallel amplicon sequencing. METHODS: The protocol utilized a set of 16 tailed degenerate primers flanking the seventh hypervariable region of the adenovirus hexon gene and 9 tailed degenerate primers targeted to the proximal portion of the enterovirus VP1 gene. Subsequent addition of dual indices enabled simultaneous sequencing of 384 different samples on an Illumina MiSeq instrument. Downstream bioinformatic analysis was based on remapping to a set of references representative of the presently known repertoire of virus types. RESULTS: After validation with known virus types, the sequencing method was applied on 301 adenovirus-positive samples and 350 enterovirus-positive samples from a longitudinally collected series of stools from 83 children aged 3 to 36 months. We detected 7 different adenovirus types and 27 different enterovirus types. There were 37 (6.2%) samples containing more than one genotype of the same viral genus. At least one dual infection was experienced by 23 of 83 (28%) of the children observed over the 3 years' observation period. CONCLUSIONS: Amplicon sequencing with a multiplex set of degenerate primers seems to be a rapid and reliable technical solution for genotyping of large collections of samples where simultaneous infections with multiple strains can be expected.

11.
Epidemiology ; 29(6): 848-856, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30074542

RESUMO

BACKGROUND: A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear. METHODS: We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general. RESULTS: In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes. CONCLUSION: Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.

12.
BMJ ; 361: k2167, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925546

RESUMO

OBJECTIVE: To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia. DESIGN: One and two sample mendelian randomisation analyses. SETTING: Two European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study). PARTICIPANTS: 7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis. EXPOSURES: Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables. MAIN OUTCOME MEASURES: Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy. RESULTS: In the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L. CONCLUSIONS: No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

13.
Int J Epidemiol ; 47(5): 1538-1548, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868838

RESUMO

Background: Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D. Methods: Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D. Results: Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D. Conclusions: Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases.

14.
Sci Rep ; 8(1): 9067, 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899542

RESUMO

Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR = 1.05 [95%CI: 0.99-1.13] per 50 mg/L increase; soluble transferrin receptor: OR = 0.91 [95%CI: 0.81-1.01] per 0.5 mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.

15.
Diabetologia ; 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934759

RESUMO

AIMS/HYPOTHESIS: Case reports have linked influenza infections to the development of type 1 diabetes. We investigated whether pandemic and seasonal influenza infections were associated with subsequent increased risk of type 1 diabetes. METHODS: In this population-based registry study, we linked individual-level data from national health registries for the entire Norwegian population under the age of 30 years for the years 2006-2014 (2.5 million individuals). Data were obtained from the National Registry (population data), the Norwegian Patient Registry (data on inpatient and outpatient specialist care), the Primary Care Database, the Norwegian Prescription Database and the Norwegian Surveillance System for Communicable Diseases. Pandemic influenza was defined as either a clinical influenza diagnosis during the main pandemic period or a laboratory-confirmed test. Seasonal influenza was defined by a clinical diagnosis of influenza between 2006 and 2014. We used Cox regression to estimate HRs for new-onset type 1 diabetes after an influenza infection, adjusted for year of birth, sex, place of birth and education. RESULTS: The adjusted HR for type 1 diabetes after pandemic influenza infection was 1.19 (95% CI 0.97, 1.46). In the subgroup with laboratory-confirmed influenza A (H1N1), influenza was associated with a twofold higher risk of subsequent type 1 diabetes before age 30 years (adjusted HR: 2.26, 95% CI 1.51, 3.38). CONCLUSIONS/INTERPRETATION: Overall, we could not demonstrate a clear association between clinically reported pandemic influenza infection and incident type 1 diabetes. However, we found a twofold excess of incident diabetes in the subgroup with laboratory-confirmed pandemic influenza A (H1N1).

17.
Am J Epidemiol ; 187(6): 1174-1181, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186303

RESUMO

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

18.
Am J Reprod Immunol ; 79(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29266506

RESUMO

PROBLEM: Previous studies have suggested that immune perturbations during pregnancy can affect offspring type 1 diabetes (T1D) risk. We aimed to identify immunological markers that could predict offspring T1D or that were linked to T1D risk factors. METHOD OF STUDY: We quantified selected circulating immunological markers in mid-pregnancy (interleukin [IL]-1ß, IL-1ra, IL-2Rα, IL-2, -4, -5, -6, -10, -12p70, 13, -17A, GM-CSF, IFN-γ, CXCL10, CCL 2, CCL3, CCL4, TNF) and cord blood plasma (neopterin and kynurenine/tryptophan ratio) in a case-control study with 175 mother/child T1D cases (median age 5.8, range 0.7-13.0 years) and 552 controls. RESULTS: Pre-pregnancy obesity was positively associated with CCL4, CXCL10, kynurenine/tryptophan ratio and neopterin (P < .01). The established T1D SNPs rs1159465 (near IL2RA) and rs75352297 (near CCR2 and CCR3) were positively associated with IL-2Rα and CCL4, respectively (P < .01). There was a borderline association of CCL4 and offspring T1D risk, independent of maternal obesity and genotype. When grouping the immunological markers, there was a borderline association (P = .05) with M1 phenotype and no association between M2-, Th1-, Th2- or Th17 phenotypes and offspring T1D risk. CONCLUSION: Increased mid-pregnancy CCL4 levels showed borderline associations with increased offspring T1D risk, which may indicate a link between environmental factors in pregnancy and offspring T1D risk.


Assuntos
Biomarcadores/metabolismo , Filho de Pais Incapacitados/estatística & dados numéricos , Diabetes Mellitus Tipo 1/epidemiologia , Sangue Fetal/metabolismo , Macrófagos/imunologia , Adolescente , Estudos de Casos e Controles , Quimiotaxia , Criança , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Masculino , Noruega/epidemiologia , Obesidade , Gravidez , Risco
19.
Scand J Gastroenterol ; 53(1): 15-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29076383

RESUMO

OBJECTIVES: Influenza has been linked to autoimmune conditions, but its relationship to subsequent celiac disease (CD) is unknown. Our primary aim was to determine the risk of CD after influenza. A secondary analysis examined the risk of CD following pandemic influenza vaccination. METHODS: This nationwide register-based cohort study included 2,637,746 Norwegians (born between 1967-2013) followed during 2006-2014 with information on influenza diagnosed in primary or non-primary care, pandemic vaccination (Pandemrix), and subsequent CD. Cox regression yielded hazard ratios adjusted (HR) for socio-demographic characteristics and earlier healthcare use. RESULTS: During 13,011,323 person-years of follow-up 7321 individuals were diagnosed with CD (56/100,000 person-years). There were 351,666 individuals diagnosed with influenza, including 82,980 during the 2009-2010 pandemic, and 969,968 individuals were vaccinated. Compared with participants without influenza, who had a CD incidence of 55/100,000 person-years, those diagnosed with seasonal and pandemic influenza had a rate of 68 and 78, per 100,000 person-years, respectively. The HR for CD was 1.29 (95%CI, 1.21-1.38) after seasonal influenza and 1.29 (95%CI, 1.15-1.44) after pandemic influenza; HRs remained significantly increased one year after exposure, when restricted to laboratory-confirmed influenza, and after multivariate adjustments. The reverse association, i.e., risk of influenza after CD, was not significant (HR 1.05; 95%CI, 0.98-1.12). The HR for CD after pandemic vaccination was 1.08 (95%CI, 1.03-1.14). CONCLUSION: A positive association with influenza diagnosis is consistent with the hypothesis that infections may play a role in CD development. We could neither confirm a causal association with pandemic vaccination, nor refute entirely a small excess risk.


Assuntos
Doença Celíaca/epidemiologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Distribuição por Sexo , Adulto Jovem
20.
J Clin Endocrinol Metab ; 102(11): 4072-4079, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938476

RESUMO

Objective: Several genetic polymorphisms determine vitamin D status. We aimed to estimate the strength of association of established 25-hydroyxvitamin D (25OHD)-associated variants in the mother and in the fetus, with 25OHD concentration in newborn umbilical cord plasma. Methods: We randomly selected 578 mother and child dyads from the prospective Norwegian Mother and Child Cohort study. 25OHD was assayed in maternal samples taken shortly after delivery and in cord samples. We genotyped the mother and child for single nucleotide polymorphisms in or near GC, DHCR7, CYP2R1, and CYP24A1, previously confirmed to be associated with 25OHD, and computed genetic risk score (GRS). The genetic associations were replicated in an independent sample of 594 subjects. Results: Although both fetal and maternal GRS were associated with cord 25OHD, only fetal GRS remained significantly associated with cord 25OHD in a regression model with maternal and fetal GRS simultaneously (1.6 nmol/L per fetal 25OHD-increasing allele; 95% confidence interval, 0.6 to 2.5, P = 0.0001). Two fetal single nucleotide polymorphisms in the GC gene (rs2282679 and rs222040) were the strongest genetic predictors of cord 25OHD [4.0 (2.1 to 5.9) and 3.0 (1.3 to 4.8) nmol/L per fetal allele, P < 0.001], followed by rs12785878 in DHCR7 [2.0 (0.1 to 3.8) nmol/L, P = 0.037]. The independent replication sample gave similar results. With fetal genotype included in a regression model with environmental factors, R2 for cord 25OHD was 0.28. Conclusions: We show that fetal 25OHD-modifying genotype was a stronger predictor of cord 25OHD than corresponding maternal genotype. This raises interesting questions about fetal acquisition and placental transfer of 25OHD.


Assuntos
Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/congênito , Deficiência de Vitamina D/genética , Vitamina D/sangue , Adulto , Estudos de Coortes , Suplementos Nutricionais , Feminino , Feto/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Troca Materno-Fetal/genética , Mães , Gravidez , Cuidado Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Adulto Jovem
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