Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.

BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.

A genome-wide association study of susceptibility to upper urinary tract infections.

BACKGROUND: Our goal was to identify genetic and modifiable risk factors for upper urinary tract infections (UTIs). METHODS: We used data from UK Biobank, The Trøndelag Health Study (HUNT), and Michigan Genomics Initiative (MGI) to conduct genome-wide association studies (GWASs) and sex-stratified analyses on upper UTI. Mendelian randomization (MR) analyses were conducted to examine potential causal relationships between cardiometabolic risk factors and upper UTIs. RESULTS: One genome-wide significant (P ≤ 5E-08) locus was associated with the susceptibility to upper UTI, located near TSN in the female-only analysis. Additionally, we identified suggestive (P ≤ 5E-06) loci near DNAI3 for the females, SCAMP1-AS1 for the males, and near TSN, LINC00603, and HLA-DQA2 for both sexes. In MR analyses, higher genetically predicted lifetime smoking scores were associated with an increased risk of developing upper UTI for females and both sexes (OR of 4.84, P = 4.50E-06 and OR of 2.79, P = 3.02E-05, respectively). CONCLUSIONS: We found that genetic variants near TSN was associated with the risk of upper UTIs among females. In addition, we found several genetic loci with suggestive associations with the risk of upper UTIs. Finally, MR analyses found smoking to be a potential causal risk factor for upper UTIs.

Chronic kidney disease and risk of bloodstream infections and sepsis: a 17-year follow-up of the population-based Trøndelag Health Study in Norway.

PURPOSE: Bloodstream infections (BSI) and sepsis are important causes of hospitalization, loss of health, and death globally. Targetable risk factors need to be identified to improve prevention and treatment. In this study, we aimed to evaluate the association of chronic kidney disease (CKD) and risk of and mortality from BSI and sepsis in the general population during a 22-year period. METHODS: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT Study, where 68,438 participated. The median follow-up time was 17.4 years. The exposures were estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in urine. The outcomes were hazard ratios (HR) of hospital admission or death due to BSI or sepsis. The associations were adjusted for age, sex, diabetes, obesity, systolic blood pressure, smoking status, and cardiovascular disease. RESULTS: Participants with eGFR < 30 ml/min/1.732 had HR 3.35 for BSI (95% confidence intervals (CI) 2.12-5.3) and HR 2.94 for sepsis (95% CI 1.82-4.8) compared to normal eGFR (≥ 90 ml/min/1.732). HRs of death from BSI and sepsis were 4.2 (95% CI 1.71-10.4) and 4.1 (95% CI 1.88-8.9), respectively. Participants with severely increased albuminuria (ACR > 30 mg/mmol) had HR 3.60 for BSI (95% CI 2.30-5.6) and 3.14 for sepsis (95% CI 1.94-5.1) compared to normal albumin excretion (ACR < 3 mg/mmol). HRs of death were 2.67 (95% CI 0.82-8.7) and 2.16 (95% CI 0.78-6.0), respectively. CONCLUSION: In this large population-based cohort study, CKD was clearly associated with an increased risk of BSI and sepsis and related death.

Circulating levels of micronutrients and risk of infections: a Mendelian randomization study.

BACKGROUND: Micronutrients play an essential role at every stage of the immune response, and deficiencies can therefore lead to increased susceptibility to infections. Previous observational studies and randomized controlled trials of micronutrients and infections are limited. We performed Mendelian randomization (MR) analyses to evaluate the effect of blood levels of eight micronutrients (copper, iron, selenium, zinc, beta-carotene, vitamin B12, vitamin C, and vitamin D) on the risk of three infections (gastrointestinal infections, pneumonia, and urinary tract infections). METHODS: Two-sample MR was conducted using publicly available summary statistics from independent cohorts of European ancestry. For the three infections, we used data from UK Biobank and FinnGen. Inverse variance-weighted MR analyses were performed, together with a range of sensitivity analyses. The threshold for statistical significance was set at P < 2.08E-03. RESULTS: We found a significant association between circulating levels of copper and risk of gastrointestinal infections, where a one standard deviation increase in blood levels of copper was associated with an odds ratio of gastrointestinal infections of 0.91 (95% confidence interval 0.87 to 0.97, P = 1.38E-03). This finding was robust in extensive sensitivity analyses. There was no clear association between the other micronutrients and the risk of infection. CONCLUSIONS: Our results strongly support a role of copper in the susceptibility to gastrointestinal infections.

Insomnia symptoms and risk of bloodstream infections: prospective data from the prospective population-based Nord-Trøndelag Health Study (HUNT), Norway.

Previous research suggests decreased immune function and increased risk of infections in individuals with insomnia. We examined the effect of insomnia symptoms on risk of bloodstream infections (BSIs) and BSI-related mortality in a population-based prospective study. A total of 53,536 participants in the second Norwegian Nord-Trøndelag Health Study (HUNT2) (1995-97) were linked to prospective data on clinically relevant BSIs until 2011. In Cox regression, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for a first-time BSI and for BSI-related mortality (BSI registered ≤30 days prior to death) associated with insomnia symptoms. Compared with participants who reported "no symptoms", participants reporting having "difficulty initiating sleep" (DIS) often/almost every night had a HR for a first-time BSI of 1.14 (95% CI 0.96-1.34). Participants reporting "difficulties maintaining sleep" (DMS) often/almost every night had a HR of 1.19 (95% CI 1.01-1.40), whereas those having a feeling of "non-restorative sleep" once a week or more had a HR of 1.23 (95% CI 1.04-1.46). Participants frequently experiencing all three of the above symptoms had a HR of 1.39 (1.04-1.87), whilst those who had both DIS and DMS had a HR of 1.15 (0.93-1.41) and being troubled by insomnia symptoms to a degree that affected work performance was associated with a HR of 1.41 (95% CI 1.08-1.84). The HRs for BSI-related mortality suggest an increased risk with increasing insomnia symptoms, but the CIs are wide and inconclusive. We found that frequent insomnia symptoms and insomnia symptoms that affected work performance were associated with a weak positive increased risk of BSI.

The Role of FER rs4957796 in the Risk of Developing and Dying from a Bloodstream Infection: A 23-Year Follow-up of the Population-based Nord-Trøndelag Health Study.

BACKGROUND: Bloodstream infection and sepsis are major causes of health loss worldwide, and it is important to identify patients at risk of developing and dying from these conditions. The single-nucleotide polymorphism most strongly associated with sepsis mortality is FER rs4957796. However, it is not known how this variant is associated with bloodstream infection incidence and mortality. METHODS: We used prospective data from 1995-2017 from the population-based HUNT Study. Genotypes were ascertained from blood samples, and additional genotypes were imputed. Information on bloodstream infection and diagnosis codes at hospitalization were collected through record linkage with all hospitals in the area. RESULTS: A total of 69 294 patients were included. Patients with the rs4957796 CC genotype had an increased risk of developing a bloodstream infection compared with the TT genotype (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.00-1.43). However, there was a protective additive effect of the C allele in terms of mortality in the total study population (HR, 0.77; 95% CI, .64-.92 per copy of the C allele) and among bloodstream infection patients (odds ratio, 0.70; 95% CI, .58-.85 per copy of the C allele). The results did not appear to be affected by selection bias. CONCLUSIONS: The rs4957796 CC genotype was associated with an increased risk of contracting a bloodstream infection but with a reduced risk of dying from one. The latter finding is in line with studies of sepsis case fatality, while the former expands our understanding of the immunoregulatory role of this polymorphism.

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: What is the association between BMI and subfertility? SUMMARY ANSWER: We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis. WHAT IS KNOWN ALREADY: High BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Cohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). MAIN RESULTS AND THE ROLE OF CHANCE: Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 26% greater odds of subfertility (8-48%) among obese men. Low genetically predicted BMI values were also related to greater subfertility risk in men at the lower end of the BMI distribution. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: Our results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values <20 kg/m2 may have an increased risk of subfertility. These results suggest that BMI values between 20 and 25 kg/m2 are optimal for a minimal risk of subfertility. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Epidemiological and clinical characteristics of immunocompromised patients infected with Pneumocystis jirovecii in a twelve-year retrospective study from Norway.

BACKGROUND: Pneumocystis pneumonia (PCP) severely menaces modern chemotherapy and immunosuppression. Detailed description of the epidemiology of Pneumocystis jirovecii today is needed to identify candidates for PCP-prophylaxis. METHODS: We performed a 12-year retrospective study of patients with P. jirovecii detected by polymerase chain reaction in Central Norway. In total, 297 patients were included. Comprehensive biological, clinical and epidemiological data were abstracted from patients' medical records. Regional incidence rates and testing trends were also assessed. RESULTS: From 2007 to 2017 we found a 3.3-fold increase in testing for P. jirovecii accompanied by a 1.8-fold increase in positive results. Simultaneously, regional incidence rates doubled from 5.0 cases per 100,000 person years to 10.8. A majority of the study population had predisposing conditions other than human immunodeficiency virus (HIV). Hematological (36.0%) and solid cancers (25.3%) dominated. Preceding corticosteroids were a common denominator for 72.1%. Most patients (74.4%) presented with at least two cardinal symptoms; cough, dyspnea or fever. Main clinical findings were hypoxia, cytopenias and radiological features consistent with PCP. A total of 88 (29.6%) patients required intensive care and 121 (40.7%) suffered at least one complication. In-hospital mortality was 21.5%. Three patients (1.0%) had received prophylaxis. CONCLUSIONS: P. jirovecii is re-emerging; likely due to increasing immunosuppressants use. This opportunistic pathogen threatens the life of heterogenous non-HIV immunosuppressed populations currently at growth. Corticosteroids seem to be a major risk factor. A strategy to increase prophylaxis is called for.

The promise and pitfalls of composite endpoints in sepsis and COVID-19 clinical trials.

Composite endpoints reveal the tendency for statistical convention to arise locally within subfields. Composites are familiar in cardiovascular trials, yet almost unknown in sepsis. However, the VITAMINS trial in patients with septic shock adopted a composite of mortality and vasopressor-free days, and an ordinal scale describing patient status rapidly became standard in COVID studies. Aware that recent use could incite interest in such endpoints, we are motivated to flag their potential value and pitfalls for sepsis research and COVID studies.

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study.

BACKGROUND: In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. METHODS AND FINDINGS: We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. CONCLUSIONS: Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the "obesity paradox," where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis.

Genome-Wide Linkage Analysis of the Risk of Contracting a Bloodstream Infection in 47 Pedigrees Followed for 23 Years Assembled From a Population-Based Cohort (the HUNT Study).

OBJECTIVES: Bloodstream infection is an important cause of death worldwide. The main objective of this study was to identify genetic loci linked to risk of contracting a bloodstream infection. DESIGN: Genome-wide linkage analysis. SETTING: Population-based, Norwegian cohort, followed between 1995 and 2017. SUBJECTS: Among 69,423 genotyped subjects, there were 47 families with two or more second-degree relatives with bloodstream infection in the follow-up period. There were 365 subjects in these families, of which 110 were affected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was genotyped using Illumina HumanCoreExome (Illumina, San Diego, CA) arrays. Before linkage analysis, single-nucleotide polymorphisms were pruned and clumped. In nonparametric linkage analysis using an exponential model, we found three loci with a suggestive linkage to bloodstream infection, all on chromosome 4, at 46.6 centimorgan (logarithm of odds, 2.3), 57.7 centimorgan (logarithm of odds, 3.2), and 70.0 centimorgan (logarithm of odds, 2.1). At the peak of the lead region are three genes: TLR10, TLR1, and TLR6. CONCLUSIONS: Variations in the TLR10/1/6 locus appear to be linked with the risk of contracting a bloodstream infection.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Association between low blood glucose increase during glucose tolerance tests in pregnancy and impaired fetal growth.

OBJECTIVE: To evaluate how different levels of increase in maternal blood glucose from a fasting state to 2 h after an oral glucose challenge in late pregnancy are associated with fetal growth, with special emphasis on those with a low increase. DESIGN: Prospective cohort study. SUBJECTS: We followed 855 women, of whom 70% had an increased risk for carrying lighter babies. STUDY DESIGN AND METHODS: Ultrasound was used to estimate fetal growth in gestational weeks 25, 33 and 37. In week 37 the women had a 75-g oral glucose tolerance test, and fasting and 2-h capillary glucose values were recorded with the difference between these two called delta (∆) glucose. Three groups were constructed from the ∆ glucose distribution: Low below the 10th centile; Medium between the 10th and 90th centiles; and High above the 90th centile. Missing data were imputed. Linear and Poisson regression models were applied. OUTCOME MEASURES: Estimated fetal weight, percent deviation from expected fetal weight and anthropometric measures at birth. RESULTS: The Low group carried the lightest fetuses and the High group the heaviest. The fetal growth in the Low group deviated increasingly more in a negative direction from week 25 to 37 than in the other groups. CONCLUSION: In a high-risk population, a positive relation between ∆ glucose and fetal growth was found. The Low group demonstrated impaired growth. More attention should be paid to pregnant women with an insufficient increase in glucose after a glucose challenge. Future studies should challenge our findings in high-risk and low-risk populations.

Adverse pregnancy outcomes and coronary artery disease risk: A negative control Mendelian randomization study.

Background: Adverse pregnancy outcomes are predictive for future cardiovascular disease risk, but it is unclear whether they play a causal role. We conducted a Mendelian randomization study with males as a negative control population to estimate the associations between genetic liability to adverse pregnancy outcomes and risk of coronary artery disease. Methods: We extracted uncorrelated (R2<0.01) single-nucleotide polymorphisms strongly associated (p-value<5e-8) with miscarriage, gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, placental abruption, poor fetal growth and preterm birth from relevant genome-wide association studies. Genetic associations with risk of coronary artery disease were extracted separately for females and males. The main analysis was the inverse-variance weighted analysis, while MR Egger, weighted median and weighted mode regression, bidirectional analyses, and the negative control population with males were sensitivity analyses to evaluate bias due to genetic pleiotropy. Results: The number of cases for the adverse pregnancy outcomes ranged from 691 (182,824 controls) for placental abruption to 49,996 (174,109 controls) for miscarriage, and there were 22,997 (310,499 controls) and 54,083 (240,453 controls) cases of coronary artery disease for females and males, respectively. We observed an association between genetic liability to hypertensive disorders of pregnancy and preeclampsia, and to some extent gestational diabetes, poor fetal growth and preterm birth, with an increased risk of coronary artery disease among females, which was supported by the MR Egger, weighted median and weighted mode regressions. However, in the negative control population of males, we observed largely the same associations as for females. Conclusions: The associations between adverse pregnancy outcomes and coronary artery disease risk were likely driven by confounding (e.g., shared genetic liability). Thus, our study does not support the hypothesis that adverse pregnancy outcomes are causal risk factors for cardiovascular diseases.

Autoimmune diseases and risk of non-Hodgkin lymphoma: A Mendelian randomisation study.

Objective: To examine whether genetically predicted susceptibility to ten autoimmune diseases (Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes) is associated with risk of non-Hodgkin lymphoma (NHL). Design: Two sample Mendelian randomization (MR) study. Setting: Genome wide association studies (GWASs) of ten autoimmune diseases, NHL, and four NHL subtypes (i.e., follicular lymphoma, mature T/natural killer-cell lymphomas, non-follicular lymphoma, and other and unspecified types of NHL). Analysis: We used data from the largest publicly available GWASs of European ancestry for each autoimmune disease, NHL, and NHL subtypes. For each autoimmune disease, we extracted single nucleotide polymorphisms (SNPs) strongly associated (P < 5×10-8) with that disease and that were independent of one another (R2 < 1×10-3) as genetic instruments. SNPs within the human leukocyte antigen region were not considered due to potential pleiotropy. Our primary MR analysis was the inverse-variance weighted analysis. Additionally, we conducted MR-Egger, weighted mode, and weighted median regression to address potential bias due to pleiotropy, and robust adjusted profile scores to address weak instrument bias. We carried out sensitivity analysis limited to the non-immune pathway for nominally significant findings. To account for multiple testing, we set the thresholds for statistical significance at P < 5×10-3. Participants: The number of cases and controls identified in the relevant GWASs were 437 and 3,325 for Behçet's disease, 4,918 and 5,684 for coeliac disease, 435 and 341,188 for dermatitis herpetiformis, 4,576 and 8,039 for lupus, 11,988 and 275,335 for psoriasis, 22,350 and 74,823 for rheumatoid arthritis, 3,597 and 337,121 for sarcoidosis, 2,735 and 332,115 for Sjögren's syndrome, 9,095 and 17,584 for systemic sclerosis, 18,942 and 501,638 for type 1 diabetes, 2,400 and 410,350 for NHL; and 296 to 2,340 cases and 271,463 controls for NHL subtypes. Exposures: Genetic variants predicting ten autoimmune diseases: Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes. Main outcome measures: Estimated associations between genetically predicted susceptibility to ten autoimmune diseases and the risk of NHL. Results: The variance of each autoimmune disease explained by the SNPs ranged from 0.3% to 3.1%. Negative associations between type 1 diabetes and sarcoidosis and the risk of NHL were observed (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.92 to 0.98, P = 5×10-3, and OR 0.92, 95% CI: 0.85 to 0.99, P = 2.8×10-2, respectively). These findings were supported by the sensitivity analyses accounting for potential pleiotropy and weak instrument bias. No significant associations were found between the other eight autoimmune diseases and NHL risk. Of the NHL subtypes, type 1 diabetes was most strongly associated with follicular lymphoma (OR 0.91, 95% CI: 0.86 to 0.96, P = 1×10-3), while sarcoidosis was most strongly associated with other and unspecified NHL (OR 0.86, 95% CI: 0.75 to 0.97, P = 1.8×10-2). Conclusions: These findings suggest that genetically predicted susceptibility to type 1 diabetes, and to some extent sarcoidosis, might reduce the risk of NHL. However, future studies with different datasets, approaches, and populations are warranted to further examine the potential associations between these autoimmune diseases and the risk of NHL.

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes: A Mendelian Randomization Study.

Importance: Lower educational attainment is associated with increased risk of adverse pregnancy outcomes, but it is unclear which pathways mediate this association. Objective: To investigate the association between educational attainment and pregnancy outcomes and the proportion of this association that is mediated through modifiable cardiometabolic risk factors. Design, Setting, and Participants: In this 2-sample mendelian randomization (MR) cohort study, uncorrelated (R2 < 0.01) single-nucleotide variants (formerly single-nucleotide polymorphisms) associated with the exposure (P < 5 × 10-8) and mediators and genetic associations with the pregnancy outcomes from genome-wide association studies were extracted. All participants were of European ancestry and were largely from Finland, Iceland, the United Kingdom, or the US. The inverse variance-weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. In mediation analyses, the direct effect of educational attainment estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Data were extracted between December 1, 2022, and April 30, 2023. Exposure: Genetically estimated educational attainment. The mediators considered were genetically estimated type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure. Main Outcomes and Measures: Ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring birth weight. Results: The analyses included 3 037 499 individuals with data on educational attainment, and those included in studies on pregnancy outcomes ranged from 141 014 for ectopic pregnancy to 270 002 with data on offspring birth weight. Each SD increase in genetically estimated educational attainment (ie, 3.4 years) was associated with an increased birth weight of 42 (95% CI, 28-56) g and an odds ratio ranging from 0.53 (95% CI, 0.46-0.60) for ectopic pregnancy to 0.81 (95% CI, 0.71-0.93) for preeclampsia. The combined proportion of the association that was mediated by the 5 cardiometabolic risk factors ranged from -17% (95% CI, -46% to 26%) for hyperemesis gravidarum to 78% (95% CI, 10%-208%) for preeclampsia. Sensitivity analyses accounting for pleiotropy were consistent with the main analyses. Conclusions and Relevance: In this MR cohort study, intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure may lead to reductions in several adverse pregnancy outcomes associated with lower levels of education. Such public health interventions would serve to reduce health disparities attributable to social inequalities.

High ambient temperature in pregnancy and risk of childhood acute lymphoblastic leukaemia: an observational study.

BACKGROUND: High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukaemia is the most common malignancy in children, the incidence is increasing, and in the USA disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood acute lymphoblastic leukaemia. METHODS: We used data from California birth records (children born from Jan 1, 1982, to Dec 31, 2015) and California Cancer Registry (those diagnosed with childhood cancer in California from Jan 1, 1988, to Dec 31, 2015) to identify acute lymphoblastic leukaemia cases diagnosed in infants and children aged 14 years and younger and controls matched by sex, race, ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. The association between ambient temperature and acute lymphoblastic leukaemia was evaluated per gestational week, restricted to May-September, adjusting for confounders. Bayesian meta-regression was applied to identify critical exposure windows. For sensitivity analyses, we evaluated a 90-day pre-pregnancy period (assuming no direct effect before pregnancy), adjusted for relative humidity and particulate matter less than 2·5 microns in aerodynamic diameter, and constructed an alternatively matched dataset for exposure contrast by seasonality. FINDINGS: 6849 cases of childhood acute lymphoblastic leukaemia were identified and, of these, 6258 had sufficient data for study inclusion. We also included 307 579 matched controls. Most of the study population were male (174 693 [55·7%] of the 313 837 included in the study) and of Latino ethnicity (174 906 [55·7%]). The peak association between ambient temperature and risk of acute lymphoblastic leukaemia was observed in gestational week 8, where a 5°C increase was associated with an odds ratio of 1·07 (95% CI 1·04-1·11). A slightly larger effect was seen among Latino children (OR 1·09 [95% CI 1·04-1·14]) than non-Latino White children (OR 1·05 [1·00-1·11]). The sensitivity analyses supported the results of the main analysis. INTERPRETATION: Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood acute lymphoblastic leukaemia. Further replication and investigation of mechanistic pathways might inform mitigation strategies. FUNDING: Yale Center on Climate Change and Health, The National Center for Advancing Translational Science, National Institutes of Health.

Dyslipidemia and Risk of Preeclampsia: A Multiancestry Mendelian Randomization Study.

BACKGROUND: Preeclampsia is a leading cause of maternal morbidity, and dyslipidemia has been associated with preeclampsia in observational studies. We use Mendelian randomization analyses to estimate the association between lipid levels, their pharmacological targets, and the risk of preeclampsia in 4 ancestry groups. METHODS: We extracted uncorrelated (R2<0.001) single-nucleotide polymorphisms strongly associated (P<5×10-8) with LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and triglycerides from genome-wide association studies of European, admixed African, Latino, and East Asian ancestry participants. Genetic associations with risk of preeclampsia were extracted from studies of the same ancestry groups. Inverse-variance weighted analyses were performed separately for each ancestry group before they were meta-analyzed. Sensitivity analyses were conducted to evaluate bias due to genetic pleiotropy, demography, and indirect genetic effects. RESULTS: The meta-analysis across 4 ancestry groups included 1.5 million subjects with lipid measurements, 7425 subjects with preeclampsia, and 239 290 without preeclampsia. Increasing HDL-C was associated with reduced risk of preeclampsia (odds ratio, 0.84 [95% CI, 0.74-0.94]; P=0.004; per SD increase in HDL-C), which was consistent across sensitivity analyses. We also observed cholesteryl ester transfer protein inhibition-a drug target that increases HDL-C-may have a protective effect. We observed no consistent effect of LDL-C or triglycerides on the risk of preeclampsia. CONCLUSIONS: We observed a protective effect of elevated HDL-C on risk of preeclampsia. Our findings align with the lack of effect in trials of LDL-C modifying drugs but suggest that HDL-C may be a new target for screening and intervention.