nach oben

Clinical Reviews in Allergy & Immunology

30.03.2024 | Review

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis

verfasst von: Yi Wu, Qiwei Qian, Qiaoyan Liu, Rui Wang, Xiting Pu, Yao Li, Huayang Zhang, Zhengrui You, Qi Miao, Xiao Xiao, Min Lian, Qixia Wang, Minoru Nakamura, M. Eric Gershwin, Zhiqiang Li, Xiong Ma, Ruqi Tang

Erschienen in: Clinical Reviews in Allergy & Immunology

Einloggen, um Zugang zu erhalten

Abstract

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016–1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023–1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025–1.067; P = 8.17 × 10⁻⁶). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.

Graphical Abstract

Nur mit Berechtigung zugänglich

EASL Clinical Practice Guidelines (2017) the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 67(1):145–172CrossRef

Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 8:303–330PubMedCrossRef

Lleo A et al (2020) Primary biliary cholangitis. Lancet 396(10266):1915–1926PubMedCrossRef

Trivedi PJ, Hirschfield GM (2021) Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 70(10):1989–2003PubMedCrossRef

Zeng N et al (2019) Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis. Hepatol Int 13(6):788–799PubMedCrossRef

Parés A, Guañabens N (2018) Primary biliary cholangitis and bone disease. Best Pract Res Clin Gastroenterol 34–35:63–70PubMedCrossRef

Chen JL et al (2023) Prevalence and risk factors of osteoporosis detected by dual-energy X-ray absorptiometry among Chinese patients with primary biliary cholangitis. World J Gastroenterol 29(29):4580–4592PubMedPubMedCentralCrossRef

Liao CY et al (2018) Increased risk of osteoporosis in patients with primary biliary cirrhosis. PLoS ONE 13(3):e0194418PubMedPubMedCentralCrossRef

Schmidt T et al (2018) Disease duration and stage influence bone microstructure in patients with primary biliary cholangitis. J Bone Miner Res 33(6):1011–1019PubMedCrossRef

10.

Guañabens N et al (2005) Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis. J Hepatol 42(4):573–577PubMedCrossRef

11.

Guañabens N et al (2010) Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis. Gastroenterology 138(7):2348–2356PubMedCrossRef

12.

Schönau J et al (2023) Risk of fractures and postfracture mortality in 3980 people with primary biliary cholangitis: a population-based cohort study. J Intern Med 294(2):164–177PubMedCrossRef

13.

Curry SJ et al (2018) Screening for osteoporosis to prevent fractures: US Preventive Services Task Force Recommendation Statement. JAMA 319(24):2521–2531PubMedCrossRef

14.

Pouresmaeili F et al (2018) A comprehensive overview on osteoporosis and its risk factors. Ther Clin Risk Manag 14:2029–2049PubMedPubMedCentralCrossRef

15.

Cosman F et al (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 25(10):2359–2381PubMedPubMedCentralCrossRef

16.

Danford CJ et al (2020) The Pharmacologic management of osteoporosis in primary biliary cholangitis: a systematic review and meta-analysis. J Clin Densitom 23(2):223–236PubMedCrossRef

17.

Boonstra K, Beuers U, Ponsioen CY (2012) Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 56(5):1181–1188PubMedCrossRef

18.

Estrada K et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44(5):491–501PubMedPubMedCentralCrossRef

19.

Roshandel D et al (2010) Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men. J Bone Miner Res 25(8):1830–1838PubMedCrossRef

20.

Juran BD et al (2012) Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet 21(23):5209–5221PubMedPubMedCentralCrossRef

21.

Tang R et al (2016) A common variant in CLDN14 is associated with primary biliary cirrhosis and bone mineral density. Sci Rep 6:19877PubMedPubMedCentralCrossRef

22.

Wu S et al (2023) The causal relationship between autoimmune diseases and osteoporosis: a study based on Mendelian randomization. Front Endocrinol (Lausanne) 14:1196269PubMedCrossRef

23.

Davey Smith G, Hemani G (2014) Hemani, Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23(R1):89–98CrossRef

24.

Skrivankova VW et al (2021) Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ 375:n2233PubMedPubMedCentralCrossRef

25.

Emdin CA, Khera AV, Kathiresan S (2017) Mendelian randomization. JAMA 318(19):1925–1926PubMedCrossRef

26.

Cordell HJ et al (2021) An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs. J Hepatol 75(3):572–581PubMedPubMedCentralCrossRef

27.

Zhou W et al (2018) Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet 50(9):1335–1341PubMedPubMedCentralCrossRef

28.

Sakaue S et al (2021) A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet 53(10):1415–1424PubMedCrossRef

29.

Lam M et al (2020) RICOPILI: Rapid Imputation for COnsortias PIpeLIne. Bioinformatics 36(3):930–933PubMedCrossRef

30.

Watanabe K et al (2017) Functional mapping and annotation of genetic associations with FUMA. Nat Commun 8(1):1826PubMedPubMedCentralCrossRef

31.

Pulit SL et al (2019) Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet 28(1):166–174PubMedCrossRef

32.

Revez JA et al (2020) Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun 11(1):1647PubMedPubMedCentralCrossRef

33.

Mbatchou J et al (2021) Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53(7):1097–1103PubMedCrossRef

34.

Graham SE et al (2021) The power of genetic diversity in genome-wide association studies of lipids. Nature 600(7890):675–679PubMedPubMedCentralCrossRef

35.

Schmitz D et al (2021) Genome-wide association study of estradiol levels and the causal effect of estradiol on bone mineral density. J Clin Endocrinol Metab 106(11):e4471–e4486PubMedPubMedCentralCrossRef

36.

Ruth KS et al (2020) Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med 26(2):252–258PubMedPubMedCentralCrossRef

37.

Burgess S, Davies NM, Thompson SG (2016) Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol 40(7):597–608PubMedPubMedCentralCrossRef

38.

Bulik-Sullivan BK et al (2015) LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 47(3):291–295PubMedPubMedCentralCrossRef

39.

Mounier N, Kutalik Z (2023) Bias correction for inverse variance weighting Mendelian randomization. Genet Epidemiol 47(4):314–331PubMedCrossRef

40.

Davies NM, Holmes MV, Davey Smith G (2018) Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. Bmj 362:k601

41.

Hemani G, Tilling K, Davey Smith G (2017) Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet 13(11):e1007081

42.

Staley JR et al (2016) PhenoScanner: a database of human genotype-phenotype associations. Bioinformatics 32(20):3207–3209PubMedPubMedCentralCrossRef

43.

Kamat MA et al (2019) PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 35(22):4851–4853PubMedPubMedCentralCrossRef

44.

Bowden J et al (2017) A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med 36(11):1783–1802PubMedPubMedCentralCrossRef

45.

Palmer TM et al (2011) Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. Am J Epidemiol 173(12):1392–1403PubMedCrossRef

46.

Sanderson E (2021) Multivariable Mendelian Randomization and mediation. Cold Spring Harb Perspect Med 11(2)

47.

Bowden J et al (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40(4):304–314PubMedPubMedCentralCrossRef

48.

Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44(2):512–25PubMedPubMedCentralCrossRef

49.

Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32(5):377–389PubMedPubMedCentralCrossRef

50.

Verbanck M et al (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50(5):693–698PubMedPubMedCentralCrossRef

51.

Morrison J et al (2020) Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet 52(7):740–747PubMedPubMedCentralCrossRef

52.

Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558PubMedCrossRef

53.

Burgess S et al (2019) Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res 4:186PubMedCrossRef

54.

Bowden J et al (2018) Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and radial regression. Int J Epidemiol 47(4):1264–1278PubMedPubMedCentralCrossRef

55.

Raszeja-Wyszomirska J, Miazgowski T (2014) Osteoporosis in primary biliary cirrhosis of the liver. Prz Gastroenterol 9(2):82–87PubMedPubMedCentral

56.

Imamudeen N et al (2022) Management of osteoporosis and spinal fractures: contemporary guidelines and evolving paradigms. Clin Med Res 20(2):95–106PubMedPubMedCentralCrossRef

57.

Trivedi HD et al (2020) Osteoporosis in primary biliary cholangitis: prevalence, impact and management challenges. Clin Exp Gastroenterol 13:17–24PubMedPubMedCentralCrossRef

58.

Ruiz-Gaspà S et al (2011) Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases. Hepatology 54(6):2104–2113PubMedCrossRef

59.

Kitaura H et al (2020) Osteocyte-Related cytokines regulate osteoclast formation and bone resorption. Int J Mol Sci 21(14)

60.

Chen X et al (2023) Vitamin D status and its associations with bone mineral density, bone turnover markers, and parathyroid hormone in Chinese postmenopausal women with osteopenia and osteoporosis. Front Nutr 10:1307896PubMedCrossRef

61.

Adejuyigbe B et al (2023) Osteoporosis: molecular pathology, diagnostics, and therapeutics. Int J Mol Sci 24(19)

62.

Stokes CS et al (2013) Vitamin D in chronic liver disease. Liver Int 33(3):338–352PubMedCrossRef

Titel: Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis
verfasst von: Yi Wu
Qiwei Qian
Qiaoyan Liu
Rui Wang
Xiting Pu
Yao Li
Huayang Zhang
Zhengrui You
Qi Miao
Xiao Xiao
Min Lian
Qixia Wang
Minoru Nakamura
M. Eric Gershwin
Zhiqiang Li
Xiong Ma
Ruqi Tang
Publikationsdatum: 30.03.2024
Verlag: Springer US
Erschienen in: Clinical Reviews in Allergy & Immunology
Print ISSN: 1080-0549
Elektronische ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-024-08986-4

Neu im Fachgebiet HNO

Betalaktam-Allergie: praxisnahes Vorgehen beim Delabeling

16.05.2024 Pädiatrische Allergologie Nachrichten

Die große Mehrheit der vermeintlichen Penicillinallergien sind keine. Da das „Etikett“ Betalaktam-Allergie oft schon in der Kindheit erworben wird, kann ein frühzeitiges Delabeling lebenslange Vorteile bringen. Ein Team von Pädiaterinnen und Pädiatern aus Kanada stellt vor, wie sie dabei vorgehen.

Eingreifen von Umstehenden rettet vor Erstickungstod

15.05.2024 Fremdkörperaspiration Nachrichten

Wer sich an einem Essensrest verschluckt und um Luft ringt, benötigt vor allem rasche Hilfe. Dass Umstehende nur in jedem zweiten Erstickungsnotfall bereit waren, diese zu leisten, ist das ernüchternde Ergebnis einer Beobachtungsstudie aus Japan. Doch es gibt auch eine gute Nachricht.

Real-World-Daten sprechen eher für Dupilumab als für Op.

14.05.2024 Rhinosinusitis Nachrichten

Zur Behandlung schwerer Formen der chronischen Rhinosinusitis mit Nasenpolypen (CRSwNP) stehen seit Kurzem verschiedene Behandlungsmethoden zur Verfügung, darunter Biologika, wie Dupilumab, und die endoskopische Sinuschirurgie (ESS). Beim Vergleich der beiden Therapieoptionen war Dupilumab leicht im Vorteil.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Update HNO

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert – ganz bequem per eMail.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis

Abstract

Graphical Abstract

Neu im Fachgebiet HNO

Betalaktam-Allergie: praxisnahes Vorgehen beim Delabeling

Eingreifen von Umstehenden rettet vor Erstickungstod

Real-World-Daten sprechen eher für Dupilumab als für Op.

Schwindelursache: Massagepistole lässt Otholiten tanzen

Update HNO

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Graphical Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Neu im Fachgebiet HNO

Betalaktam-Allergie: praxisnahes Vorgehen beim Delabeling

Eingreifen von Umstehenden rettet vor Erstickungstod

Real-World-Daten sprechen eher für Dupilumab als für Op.

Schwindelursache: Massagepistole lässt Otholiten tanzen

Update HNO