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.

Prevalence and associations of impaired awareness of hypoglycemia in a pediatric type 1 diabetes population - The Norwegian Childhood Diabetes Registry.

AIMS: To determine the prevalence and associations of impaired awareness of hypoglycemia (IAH) in pediatric type 1 diabetes. METHODS: Nationwide, population-based cross-sectional study with 51 % participation. Participants (n = 1329; 53 % males) aged 2-19 years (median 13.3) with type 1 diabetes ≥ 6 months (median 4.6 years) self-assessed hypoglycemia awareness with a validated questionnaire ('Clarke'). Parents responded for children aged < 9 years (n = 235). We estimated associations between IAH and clinical data in the Norwegian Childhood Diabetes Registry. RESULTS: The overall prevalence of IAH was 22 %, but gradually decreased from 53 % in preschoolers to 12 % in adolescents aged ≥ 16 years. IAH was associated (adjusted OR; 95 %CI) with episodes of severe hypoglycemia (6.0; 3.04, 11.8) and diabetic ketoacidosis (3.45; 1.37, 8.68) the preceding year, increased fear of hypoglycemia (highest quartile vs. lowest: 2.27; 1.51, 3.40), female sex (1.41; 1.05, 1.90), and HbA1c ≥ 8.5 % (69 mmol/mol) vs. 7.5-8.4 % (58-68 mmol/mol) (1.48; 1.01, 2.18), but not with disease duration, use of insulin pump or continuous glucose monitoring, or HbA1c < 7.5 % (58 mmol/mol). CONCLUSIONS: IAH is prevalent in pediatric diabetes and more likely reported in young children. IAH is associated with severe hypoglycemia and fear of hypoglycemia, but good metabolic control seems achievable without increased risk of IAH.

Height, Autoimmune Thyroid Disease, and Thyroid Cancer: A Mendelian Randomization Study.

Background: Increased height has been associated with increased risk of hypothyroidism or thyroid cancer in epidemiological studies. However, the potential causal association between height and hypothyroidism or thyroid cancer has not been thoroughly explored. Autoimmune thyroid disease (AITD) mainly presents as hypothyroidism, thus we aim to evaluate the causal relationship between height as exposure and its association with AITD or thyroid cancer. Methods: Mendelian randomization (MR) analyses were performed by using genetic instruments associated with height, which were selected from the largest genome-wide association meta-analysis for height in up to 5.4 million individuals. Summary-level data for AITD and thyroid cancer (including 30,234 and 3001 cases, respectively) were collected from the large number of available genome-wide association studies. Bidirectional MR was performed to test for reverse causal association between AITD and adult height. Results: MR analyses showed that increased genetically predicted height was associated with a 4% increased risk of AITD ([CI 1.02 to 1.07], p-value = 1.99E-03) per 1-standard deviation (SD) increase in genetically predicted height. The bidirectional MR did not show any causal association between AITD and adult height. Additionally, increased genetically predicted height was associated with 15% increased risk of thyroid cancer ([CI 1.07 to 1.23], p-value = 2.32E-04) per 1-SD increase in height. Sensitivity analysis confirmed the main results. Conclusions: This MR study showed that 1-SD increase in genetically predicted height was associated with increased risk of AITD and thyroid cancer. In contrast, there was no evidence of a causal association of genetically predicted AITD with height. These results could further aid in investigation of height-related pathways as a means of gaining new mechanistic insights into AITD and thyroid cancer.

Incidence of LADA and Type 2 Diabetes in Relation to Tobacco Use and Genetic Susceptibility to Type 2 Diabetes and Related Traits: Findings From a Swedish Case-Control Study and the Norwegian HUNT Study.

OBJECTIVE: Smoking and Swedish smokeless tobacco (snus) are associated with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Our aim was to investigate whether genetic susceptibility to T2D, insulin resistance (IR), and insulin secretion (IS) aggravate these associations. RESEARCH DESIGN AND METHODS: We used data from two population-based Scandinavian studies with case subjects with LADA (n = 839) and T2D (n = 5,771), matched control subjects (n = 3,068), and 1,696,503 person-years at risk. Pooled, multivariate relative risks (RR) with 95% CI were estimated for smoking/genetic risk scores (T2D-GRS, IS-GRS, and IR-GRS), and ORs for snus or tobacco/GRS (case-control data). We estimated additive (proportion attributable to interaction [AP]) and multiplicative interaction between tobacco use and GRS. RESULTS: The RR of LADA was elevated in high IR-GRS heavy smokers (≥15 pack-years; RR 2.01 [CI 1.30, 3.10]) and tobacco users (≥15 box/pack-years; RR 2.59 [CI 1.54, 4.35]) compared with low IR-GRS individuals without heavy use, with evidence of additive (AP 0.67 [CI 0.46, 0.89]; AP 0.52 [CI 0.21, 0.83]) and multiplicative (P = 0.003; P = 0.034) interaction. In heavy users, there was additive interaction between T2D-GRS and smoking, snus, and total tobacco use. The excess risk conferred by tobacco use did not differ across GRS categories in T2D. CONCLUSIONS: Tobacco use may confer a higher risk of LADA in individuals with genetic susceptibility to T2D and insulin resistance, whereas genetic susceptibility does not seem to influence the increased T2D incidence associated with tobacco use.

A fast linkage method for population GWAS cohorts with related individuals.

Linkage analysis, a class of methods for detecting co-segregation of genomic segments and traits in families, was used to map disease-causing genes for decades before genotyping arrays and dense SNP genotyping enabled genome-wide association studies in population samples. Population samples often contain related individuals, but the segregation of alleles within families is rarely used because traditional linkage methods are computationally inefficient for larger datasets. Here, we describe Population Linkage, a novel application of Haseman-Elston regression as a method of moments estimator of variance components and their standard errors. We achieve additional computational efficiency by using modern methods for detection of IBD segments and variance component estimation, efficient preprocessing of input data, and minimizing redundant numerical calculations. We also refined variance component models to account for the biases in population-scale methods for IBD segment detection. We ran Population Linkage on four blood lipid traits in over 70,000 individuals from the HUNT and SardiNIA studies, successfully detecting 25 known genetic signals. One notable linkage signal that appeared in both was for low-density lipoprotein (LDL) cholesterol levels in the region near the gene APOE (LOD = 29.3, variance explained = 4.1%). This is the region where the missense variants rs7412 and rs429358, which together make up the ε2, ε3, and ε4 alleles each account for 2.4% and 0.8% of variation in circulating LDL cholesterol. Our results show the potential for linkage analysis and other large-scale applications of method of moments variance components estimation.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

All-cause and cardiovascular mortality after hysterectomy and oophorectomy in a large cohort (HUNT2).

INTRODUCTION: Hysterectomy and bilateral oophorectomy are common major surgical procedures that have been associated with increased mortality risk. We aimed to assess the association of hysterectomy and/or bilateral oophorectomy with all-cause and cardiovascular mortality in a Norwegian population. MATERIAL AND METHODS: Cohort study with data from The Trøndelag Health Study (HUNT2) linked to the Norwegian Cause of Death Registry, with follow-up from 1996 until 2014 or death. The unexposed group (n = 18 673) included women with both their ovaries and uterus intact, while the two exposed groups included women with hysterectomy alone (n = 1199), or bilateral oophorectomy with or without hysterectomy (n = 907). We compared mortality in exposed vs unexposed groups and adjusted for relevant covariates by Cox regression. Further, we performed analyses stratified by age at surgery (≤39, 40-52, ≥53 years) and subgroup analyses among women ≤52 years of age at inclusion. RESULTS: Among the 47 312 women in HUNT2 (1995-1997), 20 779 provided complete information regarding gynecological surgery and previous health. The hysterectomy group had increased all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.06-1.58) and cardiovascular mortality (HR 1.47, 95% CI 1.09-1.97). We found no significant association between bilateral oophorectomy and all-cause or cardiovascular mortality in the total population. However, among women ≤52 years at inclusion, cardiovascular mortality was increased in the hysterectomy group (HR 2.71, 95% CI 1.19-6.17) with a similar, but less precise estimate in the bilateral oophorectomy group (HR 2.42, 95% CI 0.84-6.93). CONCLUSIONS: Hysterectomy was associated with increased all-cause and cardiovascular mortality, whereas bilateral salpingo-oophorectomy was not. Among women ≤52 years at inclusion, both hysterectomy and bilateral oophorectomy were associated with a twofold increased risk of cardiovascular mortality, but the results were imprecise. Women after hysterectomy and/or bilateral salpingo-oophorectomy constitute a group with increased cardiovascular mortality that may need closer attention to cardiovascular disease risk from the healthcare system to ensure timely and effective preventive interventions.

Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults.

AIMS/HYPOTHESES: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. METHODS: Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. RESULTS: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. CONCLUSIONS/INTERPRETATION: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. DATA AVAILABILITY: Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ).

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants.

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

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.

Risk of cardiovascular disease in women and men with subfertility: the Trøndelag Health Study.

OBJECTIVE: To investigate the association between subfertility and risk of cardiovascular disease (CVD) outcomes. DESIGN: Prospective study. SETTING: Population-based cohort. PATIENT(S): We studied 31,629 women and 17,630 men participating in the Trøndelag Health Study. INTERVENTION(S): Self-reported subfertility. As men were not directly asked about fertility, male partners of female participants were identified through linkage to the Medical Birth Registry of Norway and assigned the fertility information obtained from their partners. MAIN OUTCOME MEASURE(S): The primary outcomes were stroke and coronary heart disease in women and men with and without a history of subfertility. The secondary outcomes were myocardial infarction and angina (subgroups of coronary heart disease) and any CVD (stroke or coronary heart disease). Information on CVD was available by linkage to hospital records. We used Cox proportional hazards models adjusted for age at participation in the Trøndelag Health Study (linear + squared), birth year, smoking history, cohabitation, and education. Cardiometabolic factors were assessed in separate models. RESULT(S): A total of 17% of women and 15% of men reported subfertility. In women, subfertility was modestly associated with an increased risk of stroke (age-adjusted hazard ratio [aaHR], 1.19; 95% confidence interval [CI], 1.02-1.39; adjusted hazard ratio [aHR]; 1.18; 95% CI, 1.01-1.37) and coronary heart disease (aaHR, 1.19; 95% CI, 1.06-1.33; aHR, 1.16; 95% CI, 1.03-1.30) compared with fertile women. In men, we observed a weak positive association for stroke (aaHR, 1.11; 95% CI, 0.91-1.34; aHR, 1.10; 95% CI, 0.91-1.33) and a weak inverse association for coronary heart disease (aaHR, 0.92; 95% CI, 0.81-1.05; aHR, 0.93; 95% CI, 0.81-1.06). CONCLUSION(S): We observed modestly increased risks of CVD outcomes in women and some weak associations in men, although with no strong statistical evidence on sex differences. We acknowledge that we were only able to include men linked to pregnancies ending at 12 completed gestational weeks or later, potentially resulting in selection bias and misclassification of history of subfertility in analyses of male partners. Despite the large sample size, our results indicate the need for larger studies to obtain precise results in both sexes and determine whether there are true sex differences.

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood.

Importance: People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. Objective: To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. Design, Setting, and Participants: This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Exposures: Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). Main Outcomes and Measures: The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Results: Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). Conclusions and Relevance: These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls.

Objective: Diabetes is a heterogeneous disease and a precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls. Design: This cross-sectional case-control study included participants from the third survey of the HUNT study. Methods: We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n = 51), type 2 diabetes (n = 50) and latent autoimmune diabetes in adult (LADA, n = 51), as well as non-diabetic HUNT3 participants as control group (n = 51). Differential expression analysis of the sRNAs was performed in R using limma-voom. Results: We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on miRNA, we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced downregulation of a tRNA fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA. Conclusions: Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study.

Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis, using summary statistics from large genome-wide association studies (GWASs) in Europeans (N = 49 269-755 406), we examined the genetic associations between thyroid function, PA and markers of erythropoiesis. We performed inverse variance weighted random-effects MR, several sensitivity MR analyses, and bidirectional MR and MR Steiger for directionality. AITD and PA were associated bidirectionally (P ≤ 8 × 10-6). Neither euthyroid thyroid stimulating hormone (TSH) nor free thyroxine (FT4) were causally associated with PA. One standard deviation (SD) increase in euthyroid FT4 regulated by genetic variants in deiodinases 1 and 2 genes (DIO1/DIO2), corresponding to low-normal free triiodothyronine (FT3) levels, was causally associated with a pernicious/macrocytic anemia pattern, i.e. decreased erythrocyte counts (rank-based inverse normal transformed ß = -0,064 [95% confidence interval: -0,085, -0,044], P = 8 × 10-10) and hemoglobin (-0.028 [-0.051, -0.005], P = 0.02) and increased mean corpuscular hemoglobin (0.058 [0.025, 0.091], P = 5 × 10-4) and mean corpuscular volume levels (0.075 [0.052, 0.098], P = 1 × 10-8). Meanwhile, subclinical hyperthyroidism mirrored that pattern. AITD was causally associated with increased erythrocyte distribution width (P = 0.007) and decreased reticulocyte counts (P ≤ 0.02), whereas high-normal FT4 regulated by DIO1/DIO2 variants was causally associated with decreased bilirubin (-0.039 (-0.064, -0.013), P = 0.003). In conclusion, the bidirectional association between AITD and PA suggests a shared heritability for these two autoimmune diseases. AITD was causally associated with impaired erythropoiesis and not autoimmune hemolysis. Additionally, in euthyroid individuals, local regulation of thyroid hormones by deiodinases likely plays a role in erythropoiesis.

Risk of lower respiratory tract infections: a genome-wide association study with Mendelian randomization analysis in three independent European populations.

OBJECTIVE: Lower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality worldwide. Few studies have previously investigated genetic susceptibility and potential risk factors for LRTI. METHODS: We used data from the UK Biobank, Trøndelag Health Study (HUNT), and FinnGen to conduct a genome-wide association study (GWAS). Cases were subjects hospitalized with LRTI, and controls were subjects with no such hospitalization. We conducted stratification and interaction analyses to evaluate whether the genetic effect of LRTI differed by sex or smoking. Mendelian randomization (MR) analyses were conducted to identify the unconfounded relationship between cardiometabolic risk factors and LRTI. RESULTS: A total of 25 320 cases and 575 294 controls were included. The 15q25.1 locus reached genome-wide significance in the meta-analysis (rs10519203: OR 0.94, p 3.87e-11). The protective effect of effect allele of rs10519203 was present among smokers (OR 0.90, 95%CI 0.87-0.92, p 1.38e-15) but not among never-smokers (OR 1.01, 95%CI 0.97-1.06, p 5.20e-01). In MR analyses, we found that increasing body mass index (OR 1.31, 95%CI 1.24-1.40, p 3.78e-18), lifetime smoking (OR 2.83, 95%CI 2.34-3.42, p 6.56e-27), and systolic blood pressure robustly increased the risk of LRTIs (OR 1.11, 95%CI 1.02-1.22, p 1.48e-02). CONCLUSION: A region in 15q25.1 was strongly associated with LRTI susceptibility. Reduction in the prevalence of smoking, overweight, obesity, and hypertension may reduce the disease burden of LRTIs.

Thyroid function and risk of bloodstream infections: Results from the Norwegian prospective population-based HUNT Study.

OBJECTIVE: Previous studies on thyroid function and risk of infection is conflicting and often stem from intensive care cohorts were nonthyroidal illness syndrome (NTIS) may be present. The objective of this study was to identify the risk of bloodstream infections (BSI) and BSI-related mortality with thyroid-stimulating hormone (TSH) levels within the reference range in a general population. DESIGN: Prospective follow-up. PARTICIPANTS: The HUNT2 (1995-97) included 34,619 participants with information on TSH levels. MEASUREMENTS: Hazard ratios (HRs) with 95% confidence interval (CI) confirmed BSIs and BSI-related mortality until 2011. RESULTS: During a median follow-up of 14.5 years, 1179 experienced at least one episode of BSI and 208 died within 30 days after a BSI. TSH levels within the reference range of 0.5-4.5 mU/L were not associated with the risk of first-time BSI, with an HR of 0.97 (95% CI: 0.90-1.04) per mU/L. Stratified by baseline age < or ≥65 years, TSH was inversely associated with the risk of BSI (HR: 0.88; 95% CI: 0.78-1.00 per mU/L) in the youngest age group only. Persons with any baseline thyroid disease had a 30% risk and the hyperthyroid subgroup a 57%, and hypothyroidism a 20% increased risk of BSI. TSH levels were not clearly associated with BSI mortality, but the HRs were imprecise due to few BSI-related deaths. CONCLUSION: There was some evidence of a weak inverse association between TSH levels and the risk of BSI in persons below 65 years of age. The increased risk seen in persons with thyroid illness is probably explained by confounding by concurrent ill health.

Thyroid Function and the Risk of Alzheimer's Disease: A Mendelian Randomization Study.

Background: Observational studies suggest an association between thyroid function and risk of dementia, but the causality and direction of these effects are unclear. We aim to test whether genetically predicted variation within the normal range of thyroid function and hypothyroidism is causally associated with the risk of Alzheimer's disease (AD). Methods: Mendelian randomization (MR) analyses using genetic instruments are associated with normal range thyrotropin (TSH) and free thyroxine (fT4) levels. Secondary analyses included investigation of the role of hypothyroidism. Bidirectional MR was conducted to address the presence of a potential reverse causal association. Summary statistics were obtained from the ThyroidOmics Consortium involving up to 119,715 individuals and the latest AD genome-wide association study data including up to 71,880 cases. Results: MR analyses show an association between increased genetically predicted normal range TSH levels and a decreased risk of AD (p = 0.02). One standard deviation increased normal range TSH levels were associated with a decreased risk of AD in individuals younger than 50 years old (p = 0.04). There was no evidence for a causal association between fT4 (p = 0.54) and AD. We did not identify any effect of the genetically predicted full range TSH levels (p = 0.06) or hypothyroidism (p = 0.23) with AD. Bidirectional MR did not show any effect of genetic predisposition to AD on TSH or fT4 levels. Conclusions: This MR study shows that increased levels of genetically predicted TSH within the normal range and in younger individuals are associated with a decreased risk of AD. We observed a marginal association between genetically predicted full range TSH and AD risk. There was no evidence for an effect between genetically predicted fT4 or hypothyroidism on AD. Future studies should clarify the underlying pathophysiological mechanisms.

The role of cardiovascular risk factors in maternal cardiovascular disease according to offspring birth characteristics in the HUNT study.

A history of preterm or small (SGA) or large (LGA) for gestational age offspring is associated with smoking and unfavorable levels of BMI, blood pressure, glucose and lipids. Whether and to what extent the excess cardiovascular risk observed in women with these pregnancy complications is explained by conventional cardiovascular risk factors (CVRFs) is not known. We examined the association between a history of SGA, LGA or preterm birth and cardiovascular disease among 23,284 parous women and quantified the contribution of individual CVRFs to the excess cardiovascular risk using an inverse odds weighting approach. The hazard ratios (HR) between SGA and LGA offspring and CVD were 1.30 (95% confidence interval (CI) 1.15, 1.48) and 0.89 (95% CI 0.76, 1.03), respectively. Smoking explained 49% and blood pressure may have explained ≈12% of the excess cardiovascular risk in women with SGA offspring. Women with preterm birth had a 24% increased risk of CVD (HR 1.24, 95% CI 1.06, 1.45), but we found no evidence for CVRFs explaining any of this excess cardiovascular risk. While smoking explains a substantial proportion of excess cardiovascular risk in women with SGA offspring and blood pressure may explain a small proportion in these women, we found no evidence that conventional CVRFs explain any of the excess cardiovascular risk in women with preterm birth.