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George J Kahaly and Luigi Bartalena

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Carolin Girschik, Sophie-Charlotte Drogge, Bernd Kowall, Nils Lehmann, Andreas Stang, Denise Zwanziger, Raimund Erbel, Dagmar Führer, and Karl-Heinz Jöckel

Objective

Studies that evaluated the genetic influences on thyroid-stimulating hormone (TSH) concentrations were primarily performed in twin cohorts. The aim of this study was to investigate the sex-specific association of serum TSH concentrations between parents and their offspring.

Methods

We used data from the population-based Heinz Nixdorf Recall Study and the associated MultiGeneration Study, including offspring and their biological parents. In 3115 participants (including 1558 offspring from 1138 families), self-reported thyroid diseases and median TSH concentrations depending on thyroid status were assessed. Familial associations of TSH concentrations were investigated in 1485 healthy subjects using linear regression modeling in each group of the parent–offspring relationship using the parent’s TSH concentration as the exposure of interest. To account for the family effect, a mixed‐effects ordinal logistic regression model with random intercept varying at the family level was fitted, using the TSH concentration of the offspring classified into sex- and age-specific quartiles as the outcome.

Results

For every 1 mIU/L increase in the mother’s or father’s TSH concentration, the daughter’s TSH concentration increases by 0.13 mIU/L (95% CI: −0.01; 0.27) and 0.19 mIU/L (0.05; 0.33), respectively, and the son’s TSH concentration increases by 0.13 mIU/L (0.02; 0.25) and 0.20 mIU/L (0.08; 0.32), respectively. Further sensitivity analyses by expanding inclusion criteria and taking family clustering into account corroborated these results.

Conclusions

Serum TSH concentrations of parents are positively associated with those of their offspring in all sex-specific relationships.

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Danae A Delivanis, Maria D Hurtado Andrade, Tiffany Cortes, Shobana Athimulam, Aakanksha Khanna, Elizabeth Atkinson, Travis McKenzie, Naoki Takahashi, Michael R Moynagh, and Irina Bancos

Objective

Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease.

Design

Cross-sectional study, 2014–2018.

Methods

Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level.

Results

Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18–89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9–6.5), 2.0 (1.3–3.2), and 1.8 (1.2–2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0–0.09), 0.31 (0.18–0.49), and 0.3 (1.2–2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm2 (P = 0.03).

Conclusion

Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

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Yu Xie, Changzhi Huang, Xingchen Zhu, Jiayu Wang, Xikang Fan, Zan Fu, Yanan Ma, and Dong Hang

Background

Insulin-like growth factor 1 (IGF1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF1 concentrations influence early death risk in the general population remains largely unknown.

Methods

We included 380 997 participants who had serum IGF1 measurement and no history of cancer, cardiovascular disease (CVD), or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006–2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality.

Results

Over a median follow-up of 8.8 years, 10 753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose–response analysis showed a U-shaped relationship between IGF1 levels and mortality. Compared to the fifth decile of IGF1, the lowest decile was associated with 39% (95% CI: 29–50%), 20% (95% CI: 8–34%), and 39% (95% CI: 14–68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7–28%) and 38% (95% CI: 11–71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses.

Conclusions

Our findings indicate that both low and high concentrations of serum IGF1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF1 in early death occurrence and possible implications for mitigating the risk.

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Zhi-Hao Li, Pei-Dong Zhang, Qing Chen, Xiang Gao, Vincent C H Chung, Dong Shen, Xi-Ru Zhang, Wen-Fang Zhong, Qing-Mei Huang, Dan Liu, Pei-Liang Chen, Wei-Qi Song, Xian-Bo Wu, Virginia Byers Kraus, and Chen Mao

Objective

To examine the association of incident type 2 diabetes (T2D) risk with sleep factors, genetic risk, and their combination effects.

Design

Large prospective population-based cohort study.

Methods

This population-based prospective cohort study included 360 403 (mean (s.d.) age: 56.6 (8.0) years) participants without T2D at baseline from the UK Biobank. Genetic risk was categorised as high (highest quintile), intermediate (quintiles: 2–4), and low (lowest quintile) based on a polygenic risk score for T2D. Sleep scores, including long or short sleep duration, insomnia, snoring, late chronotype, and excessive daytime sleepiness, were categorized as an unfavourable, intermediate, or favourable sleep and circadian pattern.

Results

During a median follow-up of 9.0 years, 13 120 incident T2D cases were recorded. Among the participants with an unfavourable sleep and circadian pattern, 6.96% (95% CI: 6.68–7.24%) developed T2D vs 2.37% (95% CI: 2.28–2.46%) of participants with a favourable sleep and circadian pattern (adjusted hazard ratio (HR): 1.53, 95% CI: 1.45–1.62). Of participants with a high genetic risk, 5.53% (95% CI: 5.36–5.69%) developed T2D vs 2.01% (95% CI: 1.91–2.11%) of participants with a low genetic risk (adjusted HR: 2.89, 95% CI: 2.72–3.07). The association with sleep and circadian patterns was independent of genetic risk strata. Participants in the lowest quintile with an unfavourable sleep and circadian pattern were 3.97-fold more likely to develop T2D than those in the lowest quintile with a favourable sleep and circadian pattern.

Conclusions

Sleep and circadian patterns and genetic risk were independently associated with incident T2D. These results indicate the benefits of adhering to a healthy sleep and circadian pattern in entire populations, independent of genetic risk.

Open access

Min Sun, Jonathan W Mueller, Lorna C Gilligan, Angela E Taylor, Fozia Shaheen, Anna Noczyńska, Guy T’Sjoen, Louise Denvir, Savitha Shenoy, Piers Fulton, Timothy D Cheetham, Helena Gleeson, Mushtaqur Rahman, Nils P Krone, Norman F Taylor, Cedric H L Shackleton, Wiebke Arlt, and Jan Idkowiak

Context

17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.

Objective

To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.

Design

Case series.

Patients and results

We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.

Conclusion

Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.

Significance statement

Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.

Open access

Alexandra Kautzky-Willer

In this SARS-COV2-pandemic, diabetes mellitus (DM) soon emerged as one of the most prominent risk factors for a severe course of corona virus disease-2019 (COVID-19) and increased mortality due to hyperglycemia/insulin resistance, obesity, inflammation, altered immune status, and cardiovascular complications. In general, men are at a higher risk of severe or fatal COVID-19 disease irrespective of age, region and despite comparable infection rates in both sexes. In COVID-19, there is also a male predominance among hospitalized patients with diabetes, however, overall, data among patients with diabetes are ambiguous so far. Of note, similar to cardiovascular complications, women with type 2 diabetes (DM2) appear to lose their biological female advantage resulting in comparable death rates to those of men. The complex interplay of biological and behavioral factors, which may put men at greater risk of a severe or fatal course of COVID-19, and gender-related psychosocial factors, which may cause disadvantage to women concerning the infection rates, might explain why sex-disaggregated data among infected patients with diabetes are conflicting. Better knowledge on biological factors leading to functionally different immune responses and of gender-sensitive sociocultural determinants of COVID-19 infection rates may help to optimize prevention and management in the high-risk groups of men and women with diabetes.

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Amanda Sampaio Mangolim, Leonardo de Andrade Rodrigues Brito, and Vania dos Santos Nunes-Nogueira

Objective: This systematic review evaluated the effect of testosterone replacement therapy (TRT) in men with obesity having low testosterone levels (LTLs).

Design and methods: Search strategies were performed in MEDLINE, Embase, LILACS, and CENTRAL databases. Two reviewers selected the studies, assessed the risk of bias, and extracted data from the included studies. A random-effects model was used to pool results across studies and the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the certainty of evidence.

Results: A total of 16 randomized controlled trials were included. With moderate certainty of the evidence, no difference was found between TRT and placebo regarding total adverse events, TRT led to a 2-kg lean body mass gain and slightly improved low-density lipoprotein (LDL), without effects on the blood pressure. Due to imprecision/heterogeneity, effects in cardiovascular events (relative risk 0.52, 95% CI 0.26 to 1.05, 7 trials, 583 participants), high-density lipoprotein, hematocrit, prostate-specific antigen, HbA1c, and quality of life were unclear. TRT was effective for waist circumference and body mass index; however, large between-study heterogeneity was found, with 95% prediction intervals crossing the null effect line. Meta-regression revealed that the average age of participants was a significant modifier for both outcomes.

Conclusion: TRT slightly improved the lean body mass and LDL in men with obesity having LTLs, but did not affect the blood pressure. The effects of TRT on cardiovascular events, HbA1c, and quality of life are unclear. The mean age of participants significantly modified the effect of TRT on weight loss.

Open access

Tansit Saengkaew, Heena R Patel, Kausik Banerjee, Gary Butler, Mehul T Dattani, Michael McGuigan, Helen L Storr, Ruben H Willemsen, Leo Dunkel, and Sasha R Howard

Context

Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective

To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients.

Design

Retrospective study.

Methods

Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results

Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion

This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

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James Nolan, Purdey J Campbell, Suzanne J Brown, Gu Zhu, Scott Gordon, Ee Mun Lim, John Joseph, Simone M Cross, Vijay Panicker, Sarah E Medland, Phillip E Melton, Lawrence J Beilin, Trevor A Mori, Benjamin H Mullin, Craig E Pennell, Carol A Wang, Frank Dudbridge, John P Walsh, Nicholas G Martin, and Scott G Wilson

Objective

Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance.

Methods

Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9–16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery.

Results

Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7–74.9%) for TSH, 67.5% (59.8–75.3%) for fT4, 59.7% (54.4–65.0%) for fT3 and 48.8% (40.6–56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4.

Conclusion

Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.