Publications by authors named "Mads Melbye"

372 Publications

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

J Transl Genet Genom 2021 17;5:200-217. Epub 2021 Jun 17.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.

Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.

Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, = 1.6 × 10) and FL (β = 11.4, SE = 5.82, = 0.02) but not DLBCL ( = 1.0) or MZL ( = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, = 2.4 × 10). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.

Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
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http://dx.doi.org/10.20517/jtgg.2021.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494431PMC
June 2021

Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

Sci Rep 2021 08 31;11(1):17463. Epub 2021 Aug 31.

Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark.

Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10) and adults (P = 2.748 × 10) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.
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http://dx.doi.org/10.1038/s41598-021-97069-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408253PMC
August 2021

Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study.

Diabetologia 2021 Oct 13;64(10):2204-2214. Epub 2021 Jul 13.

Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Aims/hypothesis: Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries.

Methods: We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency.

Results: The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years).

Conclusions/interpretation: In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.
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http://dx.doi.org/10.1007/s00125-021-05508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423638PMC
October 2021

Co-occurring hydrocephalus in autism spectrum disorder: a Danish population-based cohort study.

J Neurodev Disord 2021 04 28;13(1):19. Epub 2021 Apr 28.

Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.

Background: The association between autism spectrum disorder and hydrocephalus is not well understood, despite demonstrated links between autism spectrum disorder and cerebrospinal fluid abnormalities. Based on the hypothesis that autism spectrum disorder and hydrocephalus may, at least in some cases, be two manifestations of a shared congenital brain pathology, we investigated the potential association between autism spectrum disorder and hydrocephalus in a large Danish population-based cohort.

Methods: Patients and controls were obtained from the Lundbeck Foundation Initiative for Integrative Psychiatric Research iPSYCH2012 case-cohort, which includes all patients with selected psychiatric disorders born in Denmark 1981-2005 along with randomly selected population controls (end of follow-up, December 31, 2016). The associations between individual psychiatric disorders and hydrocephalus were estimated using binary logistic regression with adjustment for age and sex.

Results: The cohort consisted of 86,571 individuals, of which 14,654 were diagnosed with autism spectrum disorder, 28,606 were population controls, and the remaining were diagnosed with other psychiatric disorders. We identified 201 hydrocephalus cases; 68 among autism spectrum disorder patients and 40 among controls (OR 3.77, 95% CI 2.48-5.78), which corresponds to an absolute risk of 0.46 % (i.e. approximately one in 217 children with autism spectrum disorder had co-occurring hydrocephalus). The autism spectrum disorder-hydrocephalus association was significant over the entire subgroup spectrum of autism spectrum disorder.

Conclusions: Given the considerable risk of hydrocephalus among patients with autism spectrum disorder, we suggest that patients with autism spectrum disorder should be evaluated for co-occurring hydrocephalus on a routine basis as timely neurosurgical intervention is important. Likewise, attention must be paid to traits of autism spectrum disorder in children with hydrocephalus. The results of this study call for future investigations on a potential shared aetiology between hydrocephalus and autism spectrum disorder, including the role abnormal CSF dynamics in the pathogenesis of autism spectrum disorder.
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http://dx.doi.org/10.1186/s11689-021-09367-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082886PMC
April 2021

Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection.

Clin Infect Dis 2021 06;72(12):e1084-e1089

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed.

Methods: A nationwide cohort study among adults in Denmark, 2010-2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for.

Results: 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0-6 months after treatment cessation, 123 occurred 6-12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74-2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31-1.80) for 0-6 months, 1.24 (1.00-1.53) for 6-12 months after current use.

Conclusions: Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.
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http://dx.doi.org/10.1093/cid/ciaa1857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204777PMC
June 2021

Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis.

Metabolomics 2021 01 8;17(1). Epub 2021 Jan 8.

Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark.

Introduction: Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle.

Objectives: Since previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns.

Methods: We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case-control design.

Results: The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 × 10) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case-control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 × 10). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS.

Conclusions: We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.
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http://dx.doi.org/10.1007/s11306-020-01763-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794101PMC
January 2021

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Nat Commun 2020 11 25;11(1):5976. Epub 2020 Nov 25.

Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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http://dx.doi.org/10.1038/s41467-020-19733-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688949PMC
November 2020

Data Mining for Adverse Events of Tumor Necrosis Factor-Alpha Inhibitors in Pediatric Patients: Tree-Based Scan Statistic Analyses of Danish Nationwide Health Data.

Clin Drug Investig 2020 Dec 26;40(12):1147-1154. Epub 2020 Oct 26.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Background And Objectives: Tumor necrosis factor-alpha (TNF-α) inhibitors are efficacious and considered generally safe in adults. However, pediatric-specific safety evidence is scarce. The aim of this study was to screen for signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients.

Methods: We conducted a data-mining study based on routinely collected, nationwide Danish healthcare data for 2004-2016. Using tree-based scan statistics to identify events with unexpectedly high incidence during TNF-α inhibitor use among patients with inflammatory bowel disease or juvenile idiopathic arthritis, two analyses were performed: comparison with episodes of no use and with other time periods from the same patient. Based on incident physician-assigned diagnosis codes from outpatient and inpatient visits in specialist care, we screened thousands of potential adverse events while adjusting for multiple testing.

Results: We identified 1310 episodes of new TNF-α inhibitor use that met the eligibility criteria. Two signals of adverse events of TNF-α inhibitors, as compared with no use, were detected. First, there were excess events of dermatologic complications (ICD-10: L00-L99, 87 vs. 44 events, risk difference [RD] 3.3%), which have been described previously in adults and children. Second, there were excess events of psychiatric diagnosis adjustment disorders (ICD-10: F432, 33 vs. 7 events, RD 2.0%), which was likely associated with the underlying disease and its severity, rather than with the treatment. The self-controlled analysis generated no signal.

Conclusions: No signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients were detected. The study showed that real-world data and newly developed methods for adverse events data mining can play a particularly important role in pediatrics where pre-approval drug safety data are scarce.
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http://dx.doi.org/10.1007/s40261-020-00977-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701063PMC
December 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.

PLoS Med 2020 08 25;17(8):e1003305. Epub 2020 Aug 25.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Background: Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved.

Methods And Findings: Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10-4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10-17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10-4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10-3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10-2 and p = 4.5 × 10-3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10-6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10-3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10-3) and a stronger fetal effect (p = 1.3 × 10-5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10-4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10-2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits.

Conclusions: We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.
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http://dx.doi.org/10.1371/journal.pmed.1003305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447062PMC
August 2020

Danish premature birth rates during the COVID-19 lockdown.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 11;106(1):93-95. Epub 2020 Aug 11.

Department of Neonatology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

To explore the impact of COVID-19 lockdown on premature birth rates in Denmark, a nationwide register-based prevalence proportion study was conducted on all 31 180 live singleton infants born in Denmark between 12 March and 14 April during 2015-2020.The distribution of gestational ages (GAs) was significantly different (p=0.004) during the lockdown period compared with the previous 5 years and was driven by a significantly lower rate of extremely premature children during the lockdown compared with the corresponding mean rate for the same dates in the previous years (OR 0.09, 95% CI 0.01 to 0.40, p<0.001). No significant difference between the lockdown and previous years was found for other GA categories.The reasons for this decrease are unclear. However, the lockdown has provided a unique opportunity to examine possible factors related to prematurity. Identification of possible causal mechanisms might stimulate changes in clinical practice.
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http://dx.doi.org/10.1136/archdischild-2020-319990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421710PMC
January 2021

Use of Pregabalin and Worsening Heart Failure: A Nationwide Cohort Study.

Drug Saf 2020 10;43(10):1035-1044

Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen S, Denmark.

Introduction: Concerns regarding the increased risk of worsening heart failure with pregabalin have been raised. We assessed the association between use of pregabalin and risk of worsening heart failure in routine clinical practice.

Methods: We conducted a population-based cohort study in Denmark using data from nationwide registers, from 1 January 2008 to 31 December 2017. The study population consisted of patients 50 years of age or older with a diagnosis of heart failure who were new users of pregabalin or gabapentin (active comparator). We matched a total of 1395 new users of pregabalin to 1395 new users of gabapentin on a propensity score based on 55 covariates. Using proportional hazards regression, we estimated hazard ratios (HRs) for worsening heart failure (hospitalization with, or death from, heart failure) within 90 days of the start of treatment.

Results: We observed 33 patients with worsening heart failure among users of pregabalin [incidence rate (IR) 105.7 per 1000 person-years] versus 43 patients among users of gabapentin (IR 133.8 per 1000 person-years), corresponding to an HR of 0.79 [95% confidence interval (CI) 0.50-1.23]. The corresponding absolute risk difference was - 28.6 (95% CI - 66.8 to 31.3) per 1000 person-years. In sensitivity analysis using duloxetine as an alternative active comparator, including 847 new users of pregabalin and 847 new users of duloxetine, the results were similar (HR 1.08, 95% CI 0.60-1.94).

Conclusions: The present study found no evidence to support an association between the use of pregabalin and increased risk of worsening heart failure, compared with gabapentin and duloxetine.
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http://dx.doi.org/10.1007/s40264-020-00969-6DOI Listing
October 2020

Male hormone-interfering drugs and meningioma development.

Neurooncol Adv 2019 May-Dec;1(1):vdz046. Epub 2019 Nov 14.

Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark.

Background: Extremely strong associations between male hormone-interfering drugs and meningiomas have been reported in two previous studies, but these findings are limited by small size of the study populations and possibly by surveillance- and selection bias. Thus, such possible and indeed very interesting association must be investigated in a large, unselected cohort. Accordingly, the aim of this study was to determine whether patients exposed to male hormone-interfering drugs had a higher risk of meningioma development in a nationwide cohort study.

Methods: A retrospective Danish nationwide cohort study with follow-up from January 1, 1996 to December 31, 2016. Exposure was use of male hormone-interfering drugs (5-α-reductase-inhibitors, luteinizing hormone-releasing hormone agonist, steroidal antiandrogen, and nonsteroidal antiandrogen). Hazard ratio of first-time diagnosis of meningioma according to drug use was estimated using Cox proportional hazards model with adjustment for age and birth year.

Results: The cohort included 244,696 men of which 64,047 had used male hormone-interfering drugs. Overall 444 meningiomas occurred during follow-up. No significant association was observed between use of male hormone-interfering drugs and the occurrence of meningioma (hazard ratio 1.02, 95% confidence interval 0.82-1.27). Similar results were observed 0-1, 2-4, and 5+ years after first use. In explorative analyses, no elevated risk association was observed for specific drugs (5-α-reductase-inhibitors, luteinizing hormone-releasing hormone agonist, steroidal antiandrogen, and nonsteroidal antiandrogen).

Conclusion: As opposed to previous studies, we found no evidence of an increased risk of meningioma in men treated with male hormone-interfering drugs.
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http://dx.doi.org/10.1093/noajnl/vdz046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212874PMC
November 2019

Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.

Cell 2020 06;181(7):1680-1692.e15

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2300, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.
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http://dx.doi.org/10.1016/j.cell.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327522PMC
June 2020

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

Breast Cancer Res Treat 2020 Jul 21;182(1):229-238. Epub 2020 May 21.

Department of Pathology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Purpose: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC.

Methods: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models.

Results: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics.

Conclusion: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.
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http://dx.doi.org/10.1007/s10549-020-05689-0DOI Listing
July 2020

Use of sodium-glucose co-transporter 2 inhibitors and risk of serious renal events: Scandinavian cohort study.

BMJ 2020 04 29;369:m1186. Epub 2020 Apr 29.

Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

Objective: To assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice.

Design: Cohort study using an active comparator, new user design and nationwide register data.

Setting: Sweden, Denmark, and Norway, 2013-18.

Participants: Cohort of 29 887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29 887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years.

Exposures: SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat.

Main Outcome Measures: The main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome.

Results: The mean age of the study population was 61.3 (SD 10.5) years; 11 108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference -3.6 (-4.4 to -2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark.

Conclusions: In this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.
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http://dx.doi.org/10.1136/bmj.m1186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188014PMC
April 2020

Use of Glucagon-Like Peptide 1 Receptor Agonists and Risk of Serious Renal Events: Scandinavian Cohort Study.

Diabetes Care 2020 06 15;43(6):1326-1335. Epub 2020 Apr 15.

Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

Objective: To assess the association between use of glucagon-like peptide 1 (GLP-1) receptor agonists and risk of serious renal events in routine clinical practice.

Research Design And Methods: This was a cohort study using an active-comparator, new-user design and nationwide register data from Sweden, Denmark, and Norway during 2010-2016. The cohort included 38,731 new users of GLP-1 receptor agonists (liraglutide 92.5%, exenatide 6.2%, lixisenatide 0.7%, and dulaglutide 0.6%), matched 1:1 on age, sex, and propensity score to a new user of the active comparator, dipeptidyl peptidase 4 (DPP-4) inhibitors. The main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospitalization for renal events. Secondary outcomes were the individual components of the main outcome. Hazard ratios (HRs) were estimated using Cox models and an intention-to-treat exposure definition. Mean (SD) follow-up time was 3.0 (1.7) years.

Results: Mean (SD) age of the study population was 59 (10) years, and 18% had cardiovascular disease. A serious renal event occurred in 570 users of GLP-1 receptor agonists (incidence rate 4.8 events per 1,000 person-years) and in 722 users of DPP-4 inhibitors (6.3 events per 1,000 person-years, HR 0.76 [95% CI 0.68-0.85], absolute difference -1.5 events per 1,000 person-years [-2.1 to -0.9]). Use of GLP-1 receptor agonists was associated with a significantly lower risk of renal replacement therapy (HR 0.73 [0.62-0.87]) and hospitalization for renal events (HR 0.73 [0.65-0.83]) but not death from renal causes (HR 0.72 [0.48-1.10]). When we used an as-treated exposure definition in which patients were censored at treatment cessation or switch to the other study drug, the HR for the primary outcome was 0.60 (0.49-0.74).

Conclusions: In this large cohort of patients seen in routine clinical practice in three countries, use of GLP-1 receptor agonists, as compared with DPP-4 inhibitors, was associated with a reduced risk of serious renal events.
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http://dx.doi.org/10.2337/dc19-2088DOI Listing
June 2020

Prognosis regarding shunt revision and mortality among hydrocephalus patients below the age of 2 years and the association to patient-related risk factors.

Acta Neurochir (Wien) 2020 10 26;162(10):2475-2485. Epub 2020 Mar 26.

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Little is known about the prognosis regarding shunt revision and mortality among hydrocephalus patients below 2 years of age. The aims of this study were to investigate (1) the cumulative risks of shunt revision (SR) and mortality and (2) the potential associations between prematurity, low weight for gestational age (LWGA), underlying aetiology, sex, age of the child at shunt placement, and the risk of SR.

Method: This was a purely register-based cohort study including all shunted hydrocephalic infants in Denmark 1996-2015. The cumulative risks of SR and mortality were estimated using the Aalen-Johansen and Kaplan-Meier estimators, respectively. A multivariable Cox-regression model was used to estimate hazard ratios (HRs) for SR according to the listed patient-related risk factors.

Results: Among 374 shunted infantile hydrocephalus patients accounting for 1047 SRs, the 3-month and 1-year cumulative risks of SR were 36% and 50%, respectively. The overall 10-year cumulative mortality was 12%, and for non-tumour subgroups 7-16% (isolated hydrocephalus 7%). The 10-year cumulative mortality for children born with LWGA was 21%. Except for aetiology, we observed no strong overall associations between the investigated risk factors and the risk of SR but interaction analyses for aetiology showed that patients with Dandy-Walker malformation born with LWGA had a higher risk of SR compared to patients of similar aetiology with normal WGA (HR 2.47, 95% CI: 1.39-4.40).

Conclusions: We found very high cumulative risks of SR and mortality among this youngest group of hydrocephalus patients, disregarding aetiology, but none of them were strongly related to the investigated risk factors.
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http://dx.doi.org/10.1007/s00701-020-04299-5DOI Listing
October 2020

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Front Oncol 2019 28;9:1539. Epub 2020 Jan 28.

Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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http://dx.doi.org/10.3389/fonc.2019.01539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999122PMC
January 2020

Nationwide prediction of type 2 diabetes comorbidities.

Sci Rep 2020 02 4;10(1):1776. Epub 2020 Feb 4.

The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Identification of individuals at risk of developing disease comorbidities represents an important task in tackling the growing personal and societal burdens associated with chronic diseases. We employed machine learning techniques to investigate to what extent data from longitudinal, nationwide Danish health registers can be used to predict individuals at high risk of developing type 2 diabetes (T2D) comorbidities. Leveraging logistic regression-, random forest- and gradient boosting models and register data spanning hospitalizations, drug prescriptions and contacts with primary care contractors from >200,000 individuals newly diagnosed with T2D, we predicted five-year risk of heart failure (HF), myocardial infarction (MI), stroke (ST), cardiovascular disease (CVD) and chronic kidney disease (CKD). For HF, MI, CVD, and CKD, register-based models outperformed a reference model leveraging canonical individual characteristics by achieving area under the receiver operating characteristic curve improvements of 0.06, 0.03, 0.04, and 0.07, respectively. The top 1,000 patients predicted to be at highest risk exhibited observed incidence ratios exceeding 4.99, 3.52, 1.97 and 4.71 respectively. In summary, prediction of T2D comorbidities utilizing Danish registers led to consistent albeit modest performance improvements over reference models, suggesting that register data could be leveraged to systematically identify individuals at risk of developing disease comorbidities.
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http://dx.doi.org/10.1038/s41598-020-58601-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000818PMC
February 2020

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

PLoS Genet 2020 01 24;16(1):e1008544. Epub 2020 Jan 24.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.
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http://dx.doi.org/10.1371/journal.pgen.1008544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001991PMC
January 2020

Dietary glycemic index and glycemic load during pregnancy and offspring risk of congenital heart defects: a prospective cohort study.

Am J Clin Nutr 2020 03;111(3):526-535

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Prepregnancy diabetes, especially when severely dysregulated, is associated with an increased risk of congenital heart defects in offspring. This suggests that glucose plays a role in embryonic heart development.

Objective: The aim was to investigate the association between midpregnancy dietary glycemic index (GI), glycemic load (GL), and sugar-sweetened beverages and the risk of congenital heart defects in the offspring.

Methods: Offspring of mothers from the Danish National Birth Cohort who filled out a food-frequency questionnaire (FFQ) covering midpregnancy dietary intake were included. Individual-level information on GI and GL, offspring congenital heart defects, and health and lifestyle covariates was linked. The association between GI and GL and offspring congenital heart defects was estimated by logistic regression. Further, we evaluated whether maternal intake of sugar-sweetened drinks increased the risk of offspring congenital heart defects.

Results: In total, 66,387 offspring of women who responded to the FFQ were included; among offspring, 543 had a congenital heart defect. The adjusted OR (aOR) of congenital heart defects among offspring of mothers belonging to the highest versus the lowest GI quintile was 1.02 (95% CI: 0.78, 1.34; P-trend = 0.86). Results were similar for GL (aOR: 0.95; 95% CI: 0.72, 1.24). A high intake of sugar-sweetened carbonated beverages was associated with a statistically significant increased risk of offspring congenital heart defects (highest vs lowest intake-aOR: 2.41; 95% CI: 1.26, 4.64; P-trend = 0.03). No association was found with other types of beverages.

Conclusions: The study does not support an association between a high GI and GL in midpregnancy and increased offspring risk of congenital heart defects. Nevertheless, a statistically significant association between sugar-sweetened carbonated beverages and a moderately increased risk of offspring congenital heart defects was observed.
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http://dx.doi.org/10.1093/ajcn/nqz342DOI Listing
March 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Oral corticosteroids during pregnancy and offspring risk of congenital heart defects: a nationwide cohort study.

Int J Epidemiol 2020 04;49(2):638-647

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Pre-pregnancy diabetes is a strong risk factor for congenital heart defects (CHDs), suggesting a role for glucose in the causal pathway. Oral corticosteroids may cause hyperglycemia and maternal use could affect embryonic heart development. The objective of this study was to determine the association between maternal intake of oral corticosteroids 0-8 weeks after conception and CHDs in offspring.

Methods: A register-based nationwide prevalence study including all live singleton births in Denmark, 1996-2016, was conducted. In total, 1 194 687 individuals and their mothers were identified and linked with information on offspring CHDs and the mothers' use of oral corticosteroids in early pregnancy. Corticosteroid use was defined as a filled prescription for maternal use of oral corticosteroid 0-8 weeks after conception. CHDs were identified through International Classification of Diseases codes. The association was estimated by prevalence (odds) ratios using logistic regression and propensity score-matched analyses.

Results: Among 1 194 687 live births, 2032 had a mother who had used oral corticosteroids 0-8 weeks from conception. Of these offspring, 32 had a heart defect. Among the offspring of never-users of oral corticosteroids, 10 534 had a heart defect. The adjusted prevalence ratio was 1.29 (95% confidence interval, 0.90-1.84) comparing offspring prevalence of heart defects in oral corticosteroid users with that in oral corticosteroid never-users. Propensity score-matched analysis yielded similar results (prevalence ratio 1.38; 95% confidence interval, 0.95-2.02).

Conclusions: This study supports that there is no association between maternal use of oral corticosteroids in the first 8 weeks after conception and CHDs.
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http://dx.doi.org/10.1093/ije/dyz213DOI Listing
April 2020

Evaluation of the antibody response to the EBV proteome in EBV-associated classical Hodgkin lymphoma.

Int J Cancer 2020 08 14;147(3):608-618. Epub 2019 Nov 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratios observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases.
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http://dx.doi.org/10.1002/ijc.32741DOI Listing
August 2020

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

Hum Mol Genet 2020 01;29(1):70-79

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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http://dx.doi.org/10.1093/hmg/ddz228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001601PMC
January 2020

Use of tumour necrosis factor-α inhibitors and the risk of serious infection in paediatric inflammatory bowel disease in Denmark: a nationwide cohort study.

Lancet Gastroenterol Hepatol 2019 11 4;4(11):845-853. Epub 2019 Sep 4.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Studies have shown an association between use of tumour necrosis factor-α (TNFα) inhibitors and increased risk of serious infection in adult inflammatory bowel disease (IBD). However, data on this topic for paediatric patients are scarce and inconclusive. The aim of this study was to investigate whether there is an association between the use of TNFα inhibitors and the risk of serious infection in children with IBD.

Methods: In this nationwide Danish cohort study, we searched health registers (from Jan 1, 2007, to Dec 31, 2016) to identify episodes of children and adolescents (<18 years) with at least two recorded IBD diagnoses in specialist care. We categorised follow-up time in mutually exclusive episodes of incident TNFα inhibitor use or no TNFα inhibitor use from specialist care records. We used Cox proportional hazards models to estimate hazard ratios (HRs), adjusting using propensity score weighting for demographic characteristics, comorbidities, treatment history, health-care use, and indicators of disease severity. The primary outcome, incident serious infection, was defined as infection requiring a stay in hospital and was identified through hospital records.

Findings: Among 2817 paediatric patients with IBD, we identified 618 episodes of incident TNFα inhibitor use and 2925 episodes of no TNFα inhibitor use. In the cohort of exposed and not exposed episodes that was propensity-score weighted, 53·9% were of male sex, the mean age was 15·1 (SD 1·7) years, 69·9% had Crohn's disease, and 30·1% had ulcerative colitis or IBD-unclassified; median follow-up was 1·4 years (IQR 0·4-3·0). The weighted incidence of serious infection was 54·6 events per 1000 patient-years for the TNFα inhibitor episodes and 61·9 events per 1000 patient-years for the no-use episodes. The weighted HR of serious infection associated with TNFα inhibitor use was 0·81 (95% CI 0·54-1·21).

Interpretation: There was no significant association between use of TNFα inhibitors and the risk of serious infection in children with IBD, and, based on the upper bound of the confidence interval, a relatively small risk increase seems unlikely, contrary to previous findings in adults. Observational data such as these can support paediatric clinical practice.

Funding: Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.
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http://dx.doi.org/10.1016/S2468-1253(19)30266-3DOI Listing
November 2019
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