RESUMO
OBJECTIVE: Cushing's syndrome is characterized by hypercortisolaemia and is frequently accompanied by comorbidities such as type 2 diabetes, hypertension, osteoporosis, depression and schizophrenia. It is unclear whether moderate but lifelong hypercortisolaemia is causally associated with these diseases in the general population. We aimed to address this research gap using a Mendelian randomization approach. METHODS: We used three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as genetic instruments in a two-sample, inverse-variance-weighted Mendelian randomization analysis. We obtained summary-level statistics for cortisol and disease outcomes from publicly available genetic consortia, and meta-analysed them as appropriate. We conducted a multivariable Mendelian randomization analysis to assess potential mediating effects. RESULTS: A 1 standard deviation higher genetically predicted plasma cortisol was associated with greater odds of hypertension (odds ratio: 1.12; 95% confidence interval [CI]: 1.05-1.18) as well as higher systolic blood pressure (mean difference [MD]: 0.03 SD change; 95% CI: 0.01-0.05) and diastolic blood pressure (MD: 0.03 SD change; 95% CI: 0.01-0.04). There was no evidence of association with type 2 diabetes, osteoporosis, depression and schizophrenia. The association with hypertension was attenuated upon adjustment for waist circumference, suggesting potential mediation through central obesity. CONCLUSION: There is strong evidence for a causal association between plasma cortisol and greater risk for hypertension, potentially mediated by obesity.
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Síndrome de Cushing , Diabetes Mellitus Tipo 2 , Hipertensão , Osteoporose , Humanos , Diabetes Mellitus Tipo 2/genética , Hidrocortisona , Análise da Randomização Mendeliana , Hipertensão/genética , Doença Crônica , Síndrome de Cushing/genética , Obesidade , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Type 2 diabetes disparities in the USA persist in both the prevalence of disease and diabetes-related complications. We conducted a literature review related to diabetes prevention, management, and complications across racial and ethnic groups in the USA. The objective of this review is to summarise the current understanding of diabetes disparities by examining differences between and within racial and ethnic groups and among young people (aged <18 years). We also examine the pathophysiology of diabetes as it relates to race and ethnic differences. We use a conceptual framework built on the socioecological model to categorise the causes of diabetes disparities across the lifespan looking at factors in five domains of health behaviours and social norms, public awareness, structural racism, economic development, and access to high-quality care. The range of disparities in diabetes prevalence and management in the USA calls for a community-engaged and multidisciplinary approach that must involve community partners, researchers, practitioners, health system administrators, and policy makers. We offer recommendations for each of these groups to help to promote equity in diabetes prevention and care in the USA.
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Diabetes Mellitus Tipo 2 , Etnicidade , Humanos , Estados Unidos/epidemiologia , Adolescente , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Prevalência , Disparidades em Assistência à Saúde , Qualidade da Assistência à SaúdeRESUMO
INTRODUCTION: In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. RESULTS: Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780). CONCLUSIONS: This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.
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Embolia Pulmonar , Tromboembolia Venosa , Humanos , Hidrocortisona , Análise da Randomização Mendeliana , Embolia Pulmonar/complicações , Fatores de Risco , Tromboembolia Venosa/complicações , Tromboembolia Venosa/genéticaRESUMO
A small-sized chromophore, BTTA-2OH, manifesting favorable solubility, large two-photon excitation efficiency, and good fluorescence photostability was synthesized to label the membrane of living cells for visualizing the dynamic movement of membrane-related vesicles via a two-photon fluorescence imaging technique based on wavelength-tunable temporal-focusing multiphoton excitation microscopy.
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Membrana Celular/química , Corantes Fluorescentes/química , Imagem Óptica , Fótons , Humanos , Microscopia de Fluorescência por Excitação MultifotônicaRESUMO
BACKGROUND: Cortisol's immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation. METHODS: Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10-8) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis. RESULTS: A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13-1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer. CONCLUSIONS: These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.
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Hidrocortisona/sangue , Análise da Randomização Mendeliana/métodos , Neoplasias/genética , Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Humanos , Neoplasias/sangue , Polimorfismo de Nucleotídeo Único , Reino UnidoRESUMO
CONTEXT: Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally. OBJECTIVE: To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design. METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants). RESULTS: One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38). CONCLUSION: Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.
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Fibrilação Atrial/genética , Síndrome de Cushing/sangue , Síndrome de Cushing/genética , Hidrocortisona/sangue , Pressão Sanguínea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Transcortina/genética , Circunferência da Cintura/genética , População Branca/genética , alfa 1-Antitripsina/genéticaRESUMO
Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability in humans. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental mechanisms that underlie defective axonogenesis in Nab2 mutants remain undefined. Nab2 null phenotypes in the brain mushroom bodies (MBs) resemble defects caused by alleles that disrupt the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells via a non-canonical arm of the Wnt/Wg pathway. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP mutant alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR>Nab2) and, subsequently, for modification of a viability defect among Nab2 nulls. Multiple PCP alleles dominantly modify GMR>Nab2 eye roughening and a subset rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Collectively, these genetic interactions identify the PCP pathway as a potential target of the Nab2 RNA-binding protein in developing eye and wing tissues and suggest that altered PCP signaling could contribute to neurological defects that result from loss of Drosophila Nab2 or its vertebrate ortholog ZC3H14.