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.

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.

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.

Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis.

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies-lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67-1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32-1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Association of Genetically Predicted Insomnia With Risk of Sepsis: A Mendelian Randomization Study.

Importance: Insomnia has been associated with altered inflammatory response as well as increased risk of infections and sepsis in observational studies. However, these studies are prone to bias, such as residual confounding. To further understand the potential causal association between insomnia and sepsis risk, a 2-sample Mendelian randomization (MR) approach should be explored. Objective: To evaluate whether genetically predicted insomnia is associated with risk of sepsis. Design, Setting, and Participants: Two-sample MR was performed to estimate the association between genetically predicted insomnia and sepsis risk. Data were obtained from a genome-wide association study identifying 555 independent genetic variants (R2 < 0.01) strongly associated with insomnia (P < 5 × 10-8). Sensitivity analyses were conducted to address bias due to pleiotropy and sample overlap, along with mediation analyses and sex-stratified analyses. The insomnia data set included 2.4 million individuals of European ancestry from the UK Biobank and 23andMe. For sepsis, 462 918 individuals of European ancestry from the UK Biobank were included. Data were extracted between February and December 2022 and analyzed between March 2022 and March 2023. Exposure: Genetically predicted insomnia. Main Outcome and Measure: Sepsis. Results: There were 593 724 individuals with insomnia and 10 154 cases of sepsis. A doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.37 (95% CI, 1.19-1.57; P = 7.6 × 10-6) for sepsis. Sensitivity analyses supported this observation. One-third of the association between genetically predicted insomnia and risk of sepsis was mediated through a combination of cardiometabolic risk factors for sepsis (body mass index, type 2 diabetes, smoking, or cardiovascular disease; overall proportion, 35.2%; 95% CI, 5.1-76.9). The association between insomnia and sepsis was more pronounced among women compared with men (women: odds ratio, 1.44; 95% CI, 1.24-1.68; men: OR, 1.10; 95% CI, 0.86-1.40). Conclusions and Relevance: The concordance between these findings and previous observational studies supports that insomnia is potentially causally associated with the risk of sepsis. Thus, insomnia is a potential preventable risk factor of sepsis that should be further investigated, also in non-European populations.

Gestational age at birth and hospitalisations for infections among individuals aged 0-50 years in Norway: a longitudinal, register-based, cohort study.

Background: Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages. Methods: In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway (January 01, 1967-December 31, 2016) to nationwide hospital data (January 01, 2008-December 31, 2017). Gestational age was categorised as 23-27, 28-31, 32-33, 34-36, 37-38, 39-41, and 42-44 completed weeks. The analyses were stratified by age at follow-up: 0-11 months and 1-5, 6-14, 15-29, and 30-50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk. Findings: Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28-31) and late preterm (34-36) to full-term (39-41 weeks), RRs (95% confidence interval) for hospitalisation for any infectious disease at ages 1-5 were 3.3 (3.0-3.7) and 1.7 (1.6-1.8), respectively. At 30-50 years, the corresponding estimates were 1.4 (1.2-1.7) and 1.2 (1.1-1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs. Interpretation: Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vaccinations and other prevention strategies should be investigated. Funding: St. Olav's University Hospital and Norwegian University of Science and Technology, Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, Sigrid Jusélius Foundation, Foundation for Pediatric Research, and Signe and Ane Gyllenberg Foundation.

High Ambient Temperature in Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia.

Background: High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, the incidence is increasing, and in the United States it disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood ALL. Methods: We used data from California birth records (1982-2015) and California Cancer Registry (1988-2015) to identify ALL cases diagnosed <14 years and 50 times as many controls matched by sex, race/ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. Association between ambient temperature and ALL 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) and constructed an alternatively matched dataset for exposure contrast by seasonality. Findings: Our study included 6,258 ALL cases and 307,579 controls. The peak association between ambient temperature and risk of ALL was observed in gestational week 8, where a 5 °C increase was associated with an odds ratio of 1.09 (95% confidence interval 1.04-1.14) and 1.05 (95% confidence interval 1.00-1.11) among Latino and non-Latino White children, respectively. The sensitivity analyses supported this. Interpretation: Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood ALL. Further replication and investigation of mechanistic pathways may inform mitigation strategies.

Role of fungal burden in risk stratification of HIV-negative patients with Pneumocystis pneumonia: A 12-year, retrospective, observational, multicenter cohort.

OBJECTIVES: This study aimed to explore the role of fungal burden in risk stratification of patients without HIV-negative patients with Pneumocystis pneumonia (PCP). METHODS: This was a retrospective analysis of the characteristics associated with 30-day mortality in patients who were positive for P. jirovecii using polymerase chain reaction in bronchoalveolar lavage fluid between 2006 and 2017 in a multicenter cohort from Central Norway. The fungal burden was indicated by the cycle threshold (CT) values from semiquantitative real-time polymerase chain reaction targeting the ß-tubulin gene. RESULTS: We included 170 patients with proven or probable PCP. The all-cause 30-day mortality was 18.2%. After adjusting for host characteristics and premorbid corticosteroid use, a higher fungal burden was associated with a higher risk of dying: adjusted odds ratio 1.42 (95% confidence interval 0.48-4.25) for a CT value 31-36, increasing to odds ratio 5.43 (95% confidence interval 1.48-19.9) for a CT value ≤30 compared with patients with a CT value ≥37. The Charlson comorbidity index (CCI) improved the risk stratification: patients with a CT value ≥37 and CCI ≤2 had a 9% mortality risk compared with 70% among those with a CT value ≤30 and CCI ≥6. Comorbid cardiovascular disease, solid tumors, immunological disorders, premorbid corticosteroids, hypoxemia, abnormal leukocyte counts, low serum albumin, and C-reactive protein ≥100 were also independently associated with 30-day mortality. The sensitivity analyses did not suggest selection bias. CONCLUSION: Fungal burden may improve the risk stratification of patients without HIV-negative patients with PCP.

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.

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.

Sex-Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.

Background Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. Methods and Results Uncorrelated (r2<0.001), genome-wide significant (P<5×10-8) single-nucleotide polymorphisms were extracted from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse-variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28-1.74], P=3.72×10-7) heart failure (OR, 1.27 [95% CI, 1.06-1.53], P=0.009), and stroke (OR, 1.25 [95% CI, 1.00-1.56], P=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16-7.29], P=0.023), heart failure (OR, 1.90 [95% CI, 1.28-2.82], P=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03-3.37], P=0.039), and stroke (OR, 2.07 [95% CI, 1.22-3.52], P=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06-1.14], P=1.68×10-6) and heart failure (OR, 1.12 [95% CI, 1.07-1.17], P=5.06×10-7); both associations were at least partly mediated by body mass index. Conclusions These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.

Outdoor artificial light at night, air pollution, and risk of childhood acute lymphoblastic leukemia in the California Linkage Study of Early-Onset Cancers.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0-14 years); however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case-control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000-2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM2.5). After adjusting for known and suspected risk factors, the highest tertile of ALAN was associated with an increased risk of ALL in Hispanic children (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.01-1.32). There also appeared to be a borderline association between PM2.5 level and risk of ALL among non-Hispanic White children (OR per 10 µg/m3 = 1.24, 95% CI 0.98-1.56). We observed elevated risk of ALL in Hispanic children residing in areas of greater ALAN. Further work is needed to understand the role of ALAN and air pollution in the etiology of childhood ALL in different racial/ethnic groups.

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.

Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study.

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01-1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97-1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94-2.86, P = 0.09) for women and OR 1.21 (CI 0.92-1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.

Incidence, recurring admissions and mortality of severe bacterial infections and sepsis over a 22-year period in the population-based HUNT study.

PURPOSE: Severe bacterial infections are important causes of hospitalization and loss of health worldwide. In this study we aim to characterize the total burden, recurrence and severity of bacterial infections in the general population during a 22-year period. METHODS: We investigated hospitalizations due to bacterial infection from eight different foci in the prospective population-based Trøndelag Health Study (the HUNT Study), where all inhabitants aged ≥ 20 in a Norwegian county were invited to participate. Enrollment was between 1995 and 1997, and between 2006 and 2008, and follow-up ended in February 2017. All hospitalizations, positive blood cultures, emigrations and deaths in the follow-up period were captured through registry linkage. RESULTS: A total of 79,393 (69.5% and 54.1% of the invited population) people were included, of which 42,237 (53%) were women and mean age was 48.5 years. There were 37,298 hospitalizations due to infection, affecting 15,496 (22% of all included) individuals. The median time of follow-up was 20 years (25th percentile 9.5-75th percentile 20.8). Pneumonia and urinary tract infections were the two dominating foci with incidence rates of 639 and 550 per 100,000 per year, respectively, and with increasing incidence with age. The proportion of recurring admissions ranged from 10.0% (central nervous system) to 30.0% (pneumonia), whilst the proportion with a positive blood culture ranged from 4.7% (skin- and soft tissue infection) to 40.9% (central nervous system). The 30-day mortality varied between 3.2% (skin- and soft tissue infection) and 20.8% (endocarditis). CONCLUSIONS: In this population-based cohort, we observed a great variation in the incidence, positive blood culture rate, recurrence and mortality between common infectious diseases. These results may help guide policy to reduce the infectious disease burden in the population.

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

OBJECTIVE: To investigate the association between smoking and infertility. DESIGN: Prospective study. SETTING: Nationwide cohort. PATIENTS: 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. INTERVENTION: Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. MAIN OUTCOME MEASURE: Infertility (time-to-pregnancy ≥12 months). RESULTS: Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11-1.28; ORadjusted 1.12; 95% CI, 1.03-1.21), also after adjusting for the partner's tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88-0.99; ORadjusted 0.89; 95% CI, 0.84-0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75-0.91; ORadjusted, 0.83; 95% CI, 0.75-0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. CONCLUSIONS: We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.