Search

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 β = −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.

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.

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 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.

Psoriasis has been associated with increased adiposity measures driving systemic inflammation, which may lead to metabolic dysfunction and comorbidities. In this population-based, cross-sectional study, we used data from 56 042 individuals in the fourth wave of the Trøndelag Health Study (HUNT4), to investigate the associations between psoriasis and body composition measures assessed using bioelectrical impedance analysis, cardiometabolic risk factors, and comorbidities. Further, we investigated the associations betweenHLA-C*06:02status, a potential clinical biomarker for a distinct psoriasis endotype, and these outcomes. Psoriasis was associated with increased adiposity measures, including increased body and visceral fat, and lower levels of skeletal muscle and soft lean mass, as well as higher prevalence of cardiovascular, respiratory and endocrine disorders.HLA-C*06:02-positive individuals with psoriasis had lower levels of hsCRP, increased prevalence of atrial fibrillation and decreased prevalence of migraine. Our results point to altered body composition in psoriasis with increased levels of fat, and particularly metabolically active visceral fat, and provide support for a broad clinical approach to psoriatic patients in a general population.

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). Graphical abstract

ObjectivesTo examine association of conception by assisted reproductive technology (ART) with offspring cardio-metabolic health outcomes, and whether these differ by offspring age.DesignMulti-cohort study.SettingFourteen population-based cohort studies with offspring from the UK, Ireland, France, the Netherlands, Portugal, Greece, Italy, Norway, Singapore, and Australia for meta-analysis of various ages. Four cohorts (three European and one Singaporean) with repeated measures for pooled age-change (from 3 to 26 years) trajectory analysis.ParticipantsYoung people sampled from the general population with complete data on mode of conception, confounders, and ≥1 cardio-metabolic outcome measured after birth.ExposuresConception by ART versus natural conception (NC).Main outcome measuresSystolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), glucose, insulin, and glycated haemoglobin (HbA1c).ResultsBetween 35,780 (605 ART) and 4,502 (67 ART) offspring were included in meta-analysis of various ages for each outcome. Mean age at outcome assessment ranged from 13 months to 27.4 years, with most cohorts ((11/14) having mean age mmHg; 95%CI: -1.91 to 0.14), DBP (−0.50mmHg; -1.65 to 0.66), and HR (0.02beats/min; -1.00 to 1.03). Cholesterol measures were higher in ART-conceived than NC offspring, for TC (mean % difference: 2.54%; 0.46 to 4.61), HDLc (4.17%; 1.79 to 6.56), and LDLc (4.95%; 0.99 to 8.92), whereas triglycerides were similar (−1.53%; -6.19 to 3.13). No clear differences were seen for glucose (0.25%; -1.38 to 1.88), insulin (−5.04%; -13.20 to 3.12), or HbA1c (−0.07%; -0.14 to 0.00). Trajectory models in up to 17,244 (244 ART) offspring showed that early life trajectory differences were consistent with the above pooled results and showed higher SBP emerging from mid-adolescence to adulthood with ART (e.g., predicted mean difference in SBP at age 26 years for ART versus NC was 5.06mmHg; 1.76 to 8.35).ConclusionsChildren conceived through ART had higher cholesterol and similar blood pressure and hyperglycaemic/insulin resistance measures compared with NC children. Whilst overall this is reassuring, our trajectory analysis in a sub-group of cohorts suggested that those conceived by ART may go on to develop higher blood pressure in early adulthood. Our study shows the importance of follow-up into adulthood and requires validation by independent studies with different study designs including within-sibship and mechanistic studies.

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.Prospective follow-up.The HUNT2 (1995-97) included 34,619 participants with information on TSH levels.Hazard ratios (HRs) with 95% confidence interval (CI) confirmed BSIs and BSI-related mortality until 2011.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 ageor ≥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.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.

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.

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.

To study associations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in maternal circulation with the risk of preeclampsia with and without fetal growth restriction.Nested case-control study.A cohort of 29 948 pregnant women in Norway.Cases were identified through linkage to the Medical Birth Registry of Norway. We selected 69 preterm and 36 term preeclampsia cases with delivery of a small-for-gestational-age (SGA) infant, 83 preterm and 154 term preeclampsia cases without SGA delivery, and 384 normotensive controls.We measured PlGF and sFlt-1 in maternal serum samples from each trimester.Odds ratios of preeclampsia subtypes by tertile categories of PlGF and sFlt-1.Low (lowest third) PlGF and sFlt-1 levels in the first trimester, and low (lowest third) increase in PlGF and strong (highest third) increase in sFlt-1 from first to second trimester were associated with increased risk of preterm preeclampsia, both with and without SGA offspring. For term preeclampsia with SGA offspring, the associations were similar to the findings for preterm preeclampsia. For term preeclampsia without SGA offspring, low increase in PlGF from first to second trimester and high sFlt-1 in the third trimester were associated with increased risk.Low PlGF and high sFlt-1 levels in maternal circulation are associated with subsequent development of preeclampsia, regardless of whether fetal growth is affected or not. For term preeclampsia without fetal growth restriction, the imbalance in angiogenic factors seems to appear later in pregnancy than for preterm preeclampsia.

Background Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. Methods Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. Results Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR, 1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95% CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03). Conclusion Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Objective: To investigate the association between subfertility and risk of cardiovascular disease (CVD) outcomes.Design: Prospective study.Setting: Population-based cohort.Subjects: We studied 31,629 women and 17,630 men participating in the Trøndelag Health Study (HUNT).Exposure: Self-reported subfertility. Men were not directly asked about fertility, so 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 Measures: The primary outcomes were risk of stroke and coronary heart disease in women and men with and without a history of subfertility. The secondary outcomes were risk of 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 HUNT (linear + squared), birth year, smoking history, cohabitation, and education. Cardiometabolic factors were assessed in separate models.Results: A total of 17% of women and 15% of men reported subfertility. In women, subfertility was modestly associated with 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 to 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: We observed modest increased risks of CVD outcomes in women and some weak associations in men, though 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 largesample size, our results indicate the need for larger studies to obtain precise results in both sexes and determine whether there are true sex differences.