Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures

Author:

Austin Thomas R1,Fink Howard A2ORCID,Jalal Diana I345,Törnqvist Anna E6ORCID,Buzkova Petra7,Barzilay Joshua I8,Lu Tianyuan91011ORCID,Carbone Laura1213ORCID,Gabrielsen Maiken E14,Grahnemo Louise6ORCID,Hveem Kristian1415,Jonasson Christian14,Kizer Jorge R161718,Langhammer Arnulf1519,Mukamal Kenneth J20,Gerszten Robert E20,Nethander Maria621,Psaty Bruce M12223,Robbins John A24,Sun Yan V2526,Skogholt Anne Heidi14,Åsvold Bjørn Olav142728,Valderrabano Rodrigo J2930,Zheng Jie3132333435,Richards J Brent9113637383940ORCID,Coward Eivind14,Ohlsson Claes641

Affiliation:

1. Cardiovascular Health Research Unit, University of Washington , Seattle, WA, 98195 , United States

2. Geriatric Research Education and Clinical Center, VA Health Care System , Minneapolis, MN, 56401 , United States

3. Division of Nephrology , Department of Internal Medicine, , Iowa City, IA, 52242 , United States

4. Carver College of Medicine , Department of Internal Medicine, , Iowa City, IA, 52242 , United States

5. Iowa City VA Medical Center , Iowa City, IA, 52246 , United States

6. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg , 413 45, Gothenburg , Sweden

7. Department of Biostatistics, University of Washington , Seattle, WA, 98115 , United States

8. Division of Endocrinology, Kaiser Permanente of Georgia , Atlanta, GA, 30339 , United States

9. Lady Davis Institute for Medical Research, Jewish General Hospital , Montreal, Quebec, H3T 1E2 , Canada

10. Quantitative Life Sciences Program, McGill University , Montreal, Quebec, H3G 0B1 , Canada

11. 5 Prime Sciences Inc , Montreal, Quebec, H3Y 2W4 , Canada

12. Charlie Norwood VAMC , Augusta, GA, 30901 , United States

13. Department of Medicine, Medical College of Georgia, Augusta University , Augusta, GA, 30912 , United States

14. Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology , 7491, Trondheim , Norway

15. HUNT Research Centre, NTNU , 7600, Levanger , Norway

16. Cardiology Section, San Francisco VA Health Care System , San Francisco, CA, 94121 , United States

17. Department of Medicine , Epidemiology and Biostatistics, , San Francisco, CA, 94158 , United States

18. University of California San Francisco , Epidemiology and Biostatistics, , San Francisco, CA, 94158 , United States

19. Levanger Hospital, Nord-Trøndelag Hospital Trust , 7600, Levanger , Norway

20. Department of Medicine, Beth Israel Deaconess Medical Center , Brookline, MA, 2446 , United States

21. Bioinformatics and Data Center, Sahlgrenska Academy, University of Gothenburg , 413 90, Gothenburg , Sweden

22. Departments of Medicine , Epidemiology, and Health Systems and Population Health, , Seattle, WA, 98195 , United States

23. University of Washington , Epidemiology, and Health Systems and Population Health, , Seattle, WA, 98195 , United States

24. Department of Medicine, University of California , Davis, CA, 95817 , United States

25. Department of Epidemiology , Rollins School of Public Health, , Atlanta, GA, 30322 , United States

26. Emory University , Rollins School of Public Health, , Atlanta, GA, 30322 , United States

27. Department of Endocrinology , Clinic of Medicine, St. Olavs Hospital, , 7491, Trondheim , Norway

28. Trondheim University Hospital , Clinic of Medicine, St. Olavs Hospital, , 7491, Trondheim , Norway

29. Research Program in Men’s Health , Aging and Metabolism, Harvard Medical School, , Boston, MA, 2130 , United States

30. Brigham and Women’s Hospital , Aging and Metabolism, Harvard Medical School, , Boston, MA, 2130 , United States

31. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Jiao Tong University School of Medicine, Ruijin Hospital , Shanghai, 200025 , China

32. Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China , Shanghai Key Laboratory for Endocrine Tumor, , Shanghai, 200025 , China

33. Shanghai National Clinical Research Center for Metabolic Diseases, Shanghai Digital Medicine Innovation Center, Shanghai Jiao Tong University School of Medicine, Ruijin Hospital , Shanghai Key Laboratory for Endocrine Tumor, , Shanghai, 200025 , China

34. MRC Integrative Epidemiology Unit (IEU) , Bristol Medical School, , Bristol, BS8 2BN , United Kingdom

35. University of Bristol, Oakfield House , Bristol Medical School, , Bristol, BS8 2BN , United Kingdom

36. Department of Human Genetics, McGill University , Montreal, Quebec , Canada

37. Department of Epidemiology , Biostatistics, and Occupational Health, , Montreal, Quebec , Canada

38. McGill University , Biostatistics, and Occupational Health, , Montreal, Quebec , Canada

39. Department of Medicine, McGill University , Montreal, Quebec, H4A 3J1 , Canada

40. Department of Twin Research, King’s College London , London, SE1 7EH , United Kingdom

41. Department of Drug Treatment, Region Västra Götaland, Sahlgrenska University Hospital , 413 45, Gothenburg , Sweden

Abstract

Abstract Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10−5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

Funder

Swedish Research Council

Swedish government and the county councils

ALF-agreement

Lundberg Foundation

Novo Nordisk Foundation

Knut and Alice Wallenberg Foundation

National Heart, Lung, and Blood Institute

National Institute of Neurological Disorders and Stroke

National Institute on Aging

Publisher

Oxford University Press (OUP)

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