Journal of Clinical Endocrinology & Metabolism最新文献

{"title":"The Impact of Minimal Sunlight Exposure on Bone Health: Insights From a Cohort Study in Erythropoietic Protoporphyria.","authors":"Louisa G Kluijver, Margreet A E M Wagenmakers, J H Paul Wilson, Janneke G Langendonk","doi":"10.1210/clinem/dgae729","DOIUrl":"10.1210/clinem/dgae729","url":null,"abstract":"<p><strong>Context: </strong>Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disease, causing lifelong painful phototoxic reactions, minimal sunlight exposure, and vitamin D deficiency. Previous studies reported a high osteoporosis prevalence in EPP patients.</p><p><strong>Objective: </strong>To identify those at risk for low bone mineral density (BMD) and assess which factors, including treatment with cholecalciferol and afamelanotide, improve BMD in EPP.</p><p><strong>Methods: </strong>A longitudinal ambispective single-center cohort study. Data from patient files and two-time questionnaires from adult patients with EPP who underwent at least one dual-energy x-ray absorptiometry (DXA) scan between 2012 and 2023 were used.</p><p><strong>Results: </strong>BMD is low in EPP patients, with 82.7% of the 139 patients having a Z-score below 0 SD at baseline. Low BMD classified as osteopenia was found in 39.5%, and osteoporosis in 15.3%. There were 50 osteoporosis-related fractures in 34.2% of patients. Aging (odds ratio [OR] 1.08; CI, 1.03-1.12), persistent vitamin D deficiency (OR 1.11; 95% CI, 1.00-1.23) and a low body mass index (OR 0.91; 95% CI, 0.82-0.99) increased the odds of low BMD. Patients with a vitamin D deficiency (OR 5.51; 95% CI, 1.69-17.92) and no cholecalciferol at baseline (OR 0.22; 95% CI, 0.04-1.34) had the highest odds of improving their BMD. Afamelanotide did not improve BMD.</p><p><strong>Conclusion: </strong>25-hydroxyvitamin D (25(OH)D) status plays a crucial role in both preventing low BMD and improving BMD. EPP is a natural model for lack of sunlight exposure and vitamin D deficiency, underlining the importance of lifelong adequate vitamin D status for bone health in the general population.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1633-1646"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble Immune Checkpoints Associated With Disease Activity and Treatment Response in GD and TED.","authors":"Qinglei Yin, Tianyi Zhu, Dalong Song, Sijie Fang, Huifang Zhou, Haixia Guan","doi":"10.1210/clinem/dgae763","DOIUrl":"10.1210/clinem/dgae763","url":null,"abstract":"<p><strong>Context: </strong>Soluble immune checkpoints play an important role in peripheral tolerance that has seldom been investigated in Graves' disease (GD) and thyroid eye disease (TED).</p><p><strong>Objective: </strong>The objective of this work is to examine the alteration of soluble immune checkpoints in GD and TED.</p><p><strong>Methods: </strong>We performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum from 50 GD patients without TED, 28 GD patients with TED, and 40 healthy controls. The association with demographic, serologic, clinical features and 27 cytokines was analyzed. A follow-up was conducted in GD patients without TED. Functional outcomes of sLAG-3 and sGITR were assessed in cell cultures using rh-LAG3, rh-GITR, an antagonistic LAG-3 antibody, and an antagonistic GITR antibody.</p><p><strong>Results: </strong>GD Patients with TED had distinct sICP and cytokine profiles compared with GD patients without TED. Active patients with TED exhibited elevation in the levels of sBTLA, sLAG-3, sGITR, sCD80, sCD86, and sPD-L1. Further, GD patients without TED with high sBTLA, sCD27, and sCD40 levels at baseline showed a better improvement in thyrotropin receptor antibody titers after antithyroid drug treatment. Adding recombinant human GITR and LAG-3 to peripheral blood mononuclear cell cultures resulted in increased inflammatory cytokine secretion and decreased anti-inflammatory cytokine secretion.</p><p><strong>Conclusion: </strong>The present study uncovers disturbed soluble immune checkpoints and cytokines in GD patients with and without TED and may pave the way for novel immunological screening, allowing for identification of patients with TED at higher risk of developing active disease and patients with GD a better treatment response after antithyroid drug treatment.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1537-1549"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: \"Cabozantinib Plus Ipilimumab/Nivolumab in Patients With Previously Treated Advanced Differentiated Thyroid Cancer\".","authors":"","doi":"10.1210/clinem/dgaf185","DOIUrl":"10.1210/clinem/dgaf185","url":null,"abstract":"","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e2106"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Accrual Trajectories in Children and Adolescents With Perinatal HIV Infection.","authors":"Linda Anne DiMeglio, Wendy Yu, Heidi J Kalkwarf, Sean Brummel, Janet S Chen, Mitchell E Geffner, Elizabeth J McFarland, Ayesha Mirza, Kunjal Patel, Stephanie Shiau, Denise L Jacobson","doi":"10.1210/clinem/dgae631","DOIUrl":"10.1210/clinem/dgae631","url":null,"abstract":"<p><strong>Context: </strong>Low bone mineral density (BMD) has been reported in children and adolescents living with perinatally acquired HIV (PHIV). Little is known about their bone accrual through puberty compared to an uninfected healthy cohort.</p><p><strong>Objective: </strong>To compare bone accrual in PHIV and healthy children.</p><p><strong>Design: </strong>PHIV children aged 7 to 16 years had dual-energy X-ray absorptiometry at entry, at 2 years, and then at least 2 years later. Bone accrual was compared to healthy children from the Bone Mineral Density in Childhood Study (BMDCS).</p><p><strong>Setting: </strong>US academic clinical research centers.</p><p><strong>Patients: </strong>172 PHIV; 1321 BMDCS.</p><p><strong>Analysis: </strong>We calculated height-adjusted whole-body and spine BMD and bone mineral content (BMC) Z-scores in PHIV using BMDCS reference curves. We fit piecewise weighted linear mixed effects models with change points at 11 and 15 years, adjusted for age, sex, race, height Z-score, and Tanner stage, to compare BMD and BMC Z-scores across actual age by cohort.</p><p><strong>Main outcome measure: </strong>BMD/BMC Z-scores.</p><p><strong>Results: </strong>Height-adjusted whole-body BMD and BMC Z-scores in PHIV were lower across age compared to BMDCS children. Spine BMD Z-score across age was higher in PHIV after height adjustment. Whole-body and spine bone area tended to be lower in PHIV children. PHIV children had slower accrual in whole-body and spine bone area before 14 years. After 15 years, bone area accruals were similar, as were height-adjusted spine BMC Z-scores, across age.</p><p><strong>Conclusion: </strong>PHIV children had persistent deficits in all measures except height-adjusted spine BMD and BMC Z-scores. Data are needed on PHIV children followed to adulthood.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1783-e1792"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Comparisons of Different Treatments for Active Graves Orbitopathy: A Systematic Review and Bayesian Model-Based Network Meta-Analysis.","authors":"Yanlin Xu, Ruikang Liu, Liying Huang, You Qin, Wei Liu, Shenyu Huang, Jiaoyue Zhang","doi":"10.1210/clinem/dgae877","DOIUrl":"10.1210/clinem/dgae877","url":null,"abstract":"<p><strong>Context: </strong>Graves orbitopathy is a specialized immunoinflammatory disorder related to abnormal thyroid function. Due to the complexity of the disease and its propensity to reoccur, targeted treatment is essential to improve the symptoms.</p><p><strong>Objective: </strong>This study aims to assess the efficacy and safety of various treatments for active thyroid eye disease.</p><p><strong>Methods: </strong>We conducted a comprehensive search for randomized controlled trials (RCTs), and ongoing RCTs registered on Controlled Trials, targeting treatments for thyroid eye disease until November 20, 2024. Employing a Bayesian framework, this network meta-analysis calculated risk ratios (RRs) or mean differences (MDs) with 95% CIs to size the effects for the predetermined outcomes. The study is registered with PROSPERO (CRD42024548030).</p><p><strong>Outcome: </strong>The primary outcomes evaluated were overall response rate, clinical activity score (CAS), proptosis, diplopia, and adverse events.</p><p><strong>Results: </strong>For the overall response rate, teprotumumab (RR 5.5, 95% CI 2.3 to 16), mycophenolate combined intravenous glucocorticosteroids (IVGCs) demonstrated effectiveness over no treatment, ranked from most to least effective. Notably, teprotumumab showed the highest efficacy in reducing CAS (MD -1.57, 95% CI -3.81 to 0.68) and proptosis (MD -2.29, 95% CI -2.73 to -1.86). For diplopia improvement, teprotumumab and IVGCs were effective compared with no treatment.</p><p><strong>Conclusion: </strong>Teprotumumab emerges as potentially the most effective treatment for reducing inflammation and increasing overall response rates when compared with no treatment; oral mycophenolate combined with IVGCs appears to be the best for improving proptosis. While some treatments raise safety concerns due to reported adverse events, oral methotrexate combined with IVGCs appear to offer a favorable balance between efficacy and safety among the evaluated treatments.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1792-1801"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin Sensitivity and Skeletal Muscle Mitochondrial Respiration in Black and White Women With Obesity.","authors":"Justine M Mucinski, Giovanna Distefano, John Dubé, Frederico G S Toledo, Paul M Coen, Bret H Goodpaster, James P DeLany","doi":"10.1210/clinem/dgae600","DOIUrl":"10.1210/clinem/dgae600","url":null,"abstract":"<p><strong>Objectives: </strong>Non-Hispanic Black women (BW) have a greater risk of type 2 diabetes (T2D) and insulin resistance (IR) compared to non-Hispanic White women (WW). The mechanisms leading to these differences are not understood, and it is unclear whether synergistic effects of race and obesity impact disease risk. To understand the interaction of race and weight, hepatic and peripheral IR were compared in WW and BW with and without obesity.</p><p><strong>Methods: </strong>Hepatic and peripheral IR were measured by a labeled, hyperinsulinemic-euglycemic clamp in BW (n = 32) and WW (n = 32) with and without obesity. Measurements of body composition, cardiorespiratory fitness, and skeletal muscle (SM) respiration were completed. Data were analyzed by mixed model ANOVA.</p><p><strong>Results: </strong>Subjects with obesity had greater hepatic and peripheral IR and lower SM respiration (P < .001). Despite 14% greater insulin (P = .066), BW tended to have lower peripheral glucose disposal (Rd; P = .062), which was driven by women without obesity (P = .002). BW had significantly lower glucose production (P = .005), hepatic IR (P = .024), and maximal coupled and uncoupled respiration (P < .001) than WW. Maximal coupled and uncoupled SM mitochondrial respiration was strongly correlated with peripheral and hepatic IR (P < .01).</p><p><strong>Conclusion: </strong>While BW without obesity had lower Rd than WW, race and obesity did not synergistically impact peripheral IR. Paradoxically, WW with obesity had greater hepatic IR compared to BW. Relationships between SM respiration and IR persisted across a range of body weights. These data provide support for therapies in BW, like exercise, that improve SM mitochondrial respiration to reduce IR and T2D risk.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e2026-e2036"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of Cardiovascular Disease in Individuals With Dysbetalipoproteinemia: A Prospective Study in the UK Biobank.","authors":"Martine Paquette, Mark Trinder, Simon-Pierre Guay, Liam R Brunham, Alexis Baass","doi":"10.1210/clinem/dgae618","DOIUrl":"10.1210/clinem/dgae618","url":null,"abstract":"<p><strong>Background: </strong>Dysbetalipoproteinemia (DBL) is a disorder of remnant cholesterol metabolism associated with a severe risk of atherosclerotic cardiovascular disease (ASCVD).</p><p><strong>Objective: </strong>The objective of this study was to investigate the univariate and multivariate predictors of ASCVD in individuals with DBL.</p><p><strong>Methods: </strong>Data from 2699 individuals with ɛ2/ɛ2 genotypes from the UK Biobank were included in this study. DBL was defined as having an ɛ2ɛ2 genotype with evidence of dyslipidemia, defined as total cholesterol ≥ 200 mg/dL (5.2 mmol/L) and triglyceride ≥ 175 mg/dL (2.0 mmol/L) or lipid-lowering therapy use (n = 964).</p><p><strong>Results: </strong>Age, hypertension, waist circumference, and a polygenic risk score for coronary artery disease (PRSCAD) were independent predictors of ASCVD among individuals with DBL. Cumulative ASCVD-free survival was lower in the ɛ2/ɛ2 DBL group (84%) compared to the ɛ2/ɛ2 non-DBL group (94%) (P < .0001) and for DBL individuals with a PRSCAD ≥ median (79%) compared to those with a PRSCAD < median (89%) (P = .001).</p><p><strong>Conclusion: </strong>We show in a large prospective cohort that a PRSCAD predicts the ASCVD risk among individuals with DBL. The findings of the present study highlight the need for better risk stratification in ɛ2/ɛ2 carriers to identify high-risk individuals who would need aggressive cardiovascular management despite their low apolipoprotein B value.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1959-e1965"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Phosphate in the General Population: A Need for Sex-Specific Reference Intervals.","authors":"Ariadne Bosman, Natalia Campos-Obando, Christian Ramakers, M Carola Zillikens","doi":"10.1210/clinem/dgae633","DOIUrl":"10.1210/clinem/dgae633","url":null,"abstract":"<p><strong>Context: </strong>Phosphate is important for several metabolic functions and essential for bone mineralization. Sex differences exist in the relation between serum phosphate and certain diseases. The reference interval for phosphate is age-adjusted in infants, but most institutions use the same intervals for adult men and women despite increasing evidence for age and sex differences.</p><p><strong>Objective: </strong>We aimed to study these differences in 2 large population-based cohorts to evaluate whether current reference intervals are adequate.</p><p><strong>Methods: </strong>A total of 8837 participants from 3 cohorts of the Rotterdam Study (RS) and 422 443 participants from the UK Biobank (UKBB), aged 40 and older and without chronic kidney disease, were analyzed for sex differences in serum phosphate using standard reference values (0.8-1.45 mmol or 2.5-4.5 mg/dL). Analyses were further stratified in women by menopausal status.</p><p><strong>Results: </strong>Women had higher serum phosphate concentrations and a higher population range compared to men in all cohorts. Hypophosphatemia was more prevalent in men and hyperphosphatemia was more prevalent in women. Sex differences were present in all age categories. Perimenopausal women had higher serum phosphate concentrations than men of the same age, but lower than postmenopausal women of the same age.</p><p><strong>Conclusion: </strong>This study in 2 population-based cohorts showed that women have higher serum phosphate concentrations than men and that women show a marked increase in serum phosphate during menopause. Moreover, the population range for serum phosphate was higher in women than in men. These findings indicate a need for sex-specific reference intervals for serum phosphate in adults older than 45 years.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"e1885-e1891"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discrimination and Precision of Continuous Glucose Monitoring in Staging Children With Presymptomatic Type 1 Diabetes.","authors":"Elisabeth Huber, Tarini Singh, Melanie Bunk, Mayscha Hebel, Kerstin Kick, Andreas Weiß, Mirjam Kohls, Melanie Köger, Maja Hergl, Jose Maria Zapardiel Gonzalo, Ezio Bonifacio, Anette-G Ziegler","doi":"10.1210/clinem/dgae691","DOIUrl":"10.1210/clinem/dgae691","url":null,"abstract":"<p><strong>Context: </strong>Staging and monitoring of presymptomatic type 1 diabetes includes the assessment for dysglycemia.</p><p><strong>Objective: </strong>To assess the ability of continuous glucose monitoring (CGM) to differentiate between islet autoantibody-negative controls and early-stage type 1 diabetes and explore whether CGM classifiers predict progression to clinical diabetes.</p><p><strong>Research design and methods: </strong>Children and adolescents participating in public health screening for islet autoantibodies in Bavaria, Germany, were invited to undergo CGM with Dexcom G6. In total, 118 participated and valid data was obtained from 97 [57 female; median age 10 (range 3-17) years], including 46 with stage 1, 18 with stage 2, and 33 with no islet autoantibodies.</p><p><strong>Results: </strong>Mean glucose during CGM in islet autoantibody-negative controls was high (median, 115.3 mg/dL) and varied substantially (interquartile range, 106.8-124.4). Eleven (33%) of the controls had more than 10% of glucose values above 140 mg/dL (TA140). Using thresholds corresponding to 100% specificity in controls, differences between controls and stage 1 and stage 2 were obtained for glucose SD, TA140, TA160, and TA180. Elevations in any 2 of these parameters identified 12 (67%) with stage 2 and 9 (82%) of 11 participants who developed clinical diabetes within 1 year. However, there was marked variation within groups for all parameters and poor consistency observed in a second CGM performed in 18 participants.</p><p><strong>Conclusion: </strong>This study demonstrated the potential of integrating CGM into staging and monitoring of early-stage type 1 diabetes. However, substantial improvement in the precision of CGM is required for its application in routine monitoring practices.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1624-1632"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared Genetic Architecture and Causal Relationship Between Serum 25-Hydroxyvitamin D and Bone Mineral Density.","authors":"Linna Sha, Li Zhang, Xunying Zhao, Rong Xiang, Xueyao Wu, Jiangbo Zhu, Jiaojiao Hou, Qin Deng, Chenjiarui Qin, Changfeng Xiao, Yang Qu, Tao Han, Jinyu Zhou, Sirui Zheng, Ting Yu, Xin Song, Bin Yang, Mengyu Fan, Xia Jiang","doi":"10.1210/clinem/dgae738","DOIUrl":"10.1210/clinem/dgae738","url":null,"abstract":"<p><strong>Context: </strong>Despite the well-established regulatory role of vitamin D in maintaining bone health, little is known about the shared genetics and causality of the association between serum 25-hydroxyvitamin D (25OHD) and bone mineral density (BMD).</p><p><strong>Objective: </strong>We aimed to investigate the shared genetic architecture and causal relationship between serum 25OHD and BMD, providing insights into their underlying biological mechanisms.</p><p><strong>Methods: </strong>Leveraging individual-level data from the UK Biobank (UKB) cohort and summary-level data from the genome-wide association studies (GWASs) conducted on European individuals for serum 25OHD (N = 417 580) and estimated heel BMD (eBMD, N = 426 824), we systematically elucidated the shared genetic architecture underlying serum 25OHD and eBMD through a comprehensive genome-wide cross-trait design.</p><p><strong>Results: </strong>Despite a lack of global genetic correlation (rg=-0.001; P = .95), a statistically significant local signal was discovered at 5p11-5q11.9. Two-sample mendelian randomization (MR) indicated no causal association in the overall population (β=.003, 95% CI, -0.04 to 0.03; P = .93), while positive causal effects were observed in males (β=.005, 95% CI, 0.00 to 0.01; P = .03) and older individuals (β=.009, 95% CI, 0.00∼0.02; P = .01) according to one-sample MR. A total of 49 pleiotropic single-nucleotide variations (SNVs), with 4 novel SNVs (rs1077151, rs79873740, rs12150353, and rs4760401), were identified, and a total of 95 gene-tissue pairs exhibited overlap, predominantly enriched in the nervous, digestive, exocrine/endocrine, and cardiovascular systems. Protein-protein interaction analysis identified RPS9 and RPL7A as hub genes.</p><p><strong>Conclusion: </strong>This study illuminates the potential health benefits of enhancing serum 25OHD levels to mitigate the risk of osteoporosis among men and individuals older than 65 years. It also unveils a shared genetic basis between serum 25OHD and eBMD, offering valuable insights into the intricate biological pathways.</p>","PeriodicalId":50238,"journal":{"name":"Journal of Clinical Endocrinology & Metabolism","volume":" ","pages":"1605-1616"},"PeriodicalIF":5.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}