Plasma proteins and risk of developing Addison’s disease: a two-sample two-way Mendelian randomization study_West China Medical Journal

Authors：

LI Yanan , LIU Bin ,  MAO Yingying

School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P. R. China;

Corresponding?author：

MAO Yingying, Email: myy@zcmu.edu.cn

Keywords：

Addison’s disease; plasma protein; autoimmune disease; genome-wide association study; Mendelian randomization

DOI：

10.7507/1002-0179.202509278

Video：

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Objective To explore the association between plasma proteins and the risk of Addison’s disease using the Mendelian randomization (MR) method. Methods Plasma protein quantitative trait loci data from the deCODE cohort, along with genome-wide association study summary statistics for Addison’s disease comprising 1 223 cases and 4 097 controls from Sweden and Norway, were analyzed in a two-sample two-way MR framework. The primary causal inference was performed using inverse variance weighting, with MR-Egger regression, weighted median, and maximum likelihood methods employed as sensitivity analyses to assess the robustness of the findings. To mitigate reverse causality, MR analysis was conducted with Addison’s disease as the exposure factor and plasma proteins as the outcome variables. Results A total of 105 plasma protein closely associated with Addison’s disease were included in the forward study. Among them, sialic acid binding Ig like lectin 5, poly ADP-ribose polymerase, ectonucleotide pyrophosphatase/phosphodiesterase family member 5, butyrophilin subfamily 3 member A3, collagen type Ⅺ alpha 2 chain (COL11A2) and calsyntenin-1 still exhibited certain associations after multiple corrections (P<0.05). In the reverse study, only COL11A2 closely associated with Addison’s disease [odds ratio=0.98, 95% confidence interval (0.96, 1.00), P=0.026]. Conclusions This research discovers that sialic acid binding Ig like lectin 5, poly ADP-ribose polymerase, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 significantly enhance the risk of Addison’s disease, whereas butyrophilin subfamily 3 member A3, COL11A2, and calsyntenin-1 decrease the risk of Addison’s disease. Moreover, there is a potential reverse causal relationship between Addison’s disease and COL11A2.

Citation： LI Yanan, LIU Bin, MAO Yingying. Plasma proteins and risk of developing Addison’s disease: a two-sample two-way Mendelian randomization study. West China Medical Journal, 2026, 41(5): 785-791. doi: 10.7507/1002-0179.202509278 Copy

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2.	Almeida MQ. Genetic diagnosis of primary adrenal insufficiency in children: a paradigm change. J Endocr Soc, 2021, 5(9): bvab117.
3.	Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults. J Endocrinol Invest, 2019, 42(12): 1407-1433.
4.	Wolff ASB, Kucuka I, Oftedal BE. Autoimmune primary adrenal insufficiency -current diagnostic approaches and future perspectives. Front Endocrinol (Lausanne), 2023, 14: 1285901.
5.	Olafsson AS, Sigurjonsdottir HA. Increasing prevalence of addison disease: results from a nationwide study. Endocr Pract, 2016, 22(1): 30-35.
6.	Conrad N, Misra S, Verbakel JY, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet, 2023, 401(10391):1878-1890.
7.	Anderson NL, Polanski M, Pieper R, et al. The human plasma proteome: a nonredundant list developed by combination of four separate sources. Mol Cell Proteomics, 2004, 3(4): 311-326.
8.	Sun BB, Maranville JC, Peters JE, et al. Genomic atlas of the human plasma proteome. Nature, 2018, 558(7708): 73-79.
9.	Fichna M, ?urawek M, Budny B, et al. Elevated serum RANTES chemokine levels in autoimmune Addison disease. Pol Arch Intern Med, 2018, 128(4): 216-221.
10.	Palomares O, Elewaut D, Irving PM, et al. Regulatory T cells and immunoglobulin E: a new therapeutic link for autoimmunity?. Allergy, 2022, 77(11): 3293-3308.
11.	Mitchell AL, Macarthur KD, Gan EH, et al. Association of autoimmune Addison’s disease with alleles of STAT4 and GATA3 in European cohorts. PLoS One, 2014, 9(3): e88991.
12.	Smith GD, Ebrahim S. Data dredging, bias, or confounding. BMJ, 2002, 325(7378): 1437-1438.
13.	Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 2008, 27(8): 1133-1163.
14.	Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J, 2023, 44(47): 4913-4924.
15.	Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
16.	Ferkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet, 2021, 53(12): 1712-1721.
17.	Eriksson D, R?yrvik EC, Aranda-Guillén M, et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat Commun, 2021, 12(1): 959.
18.	Su Y, Zhang Y, Chai Y, et al. Autoimmune diseases and their genetic link to bronchiectasis: insights from a genetic correlation and Mendelian randomization study. Front Immunol, 2024, 15: 1343480.
19.	Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
20.	Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
21.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
22.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
23.	Zhou L, Gao H, Zhang J, et al. Metabolic syndrome and cancer risk: a two-sample Mendelian randomization study of European ancestry. Int J Surg, 2025, 111(1): 311-321.
24.	Kriegel MA, Lohmann T, Gabler C, et al. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med, 2004, 199(9):1285-1291.
25.	Tsubata T. The ligand interactions of B cell Siglecs are involved in the prevention of autoimmunity to sialylated self-antigens and in the quality control of signaling-competent B cells. Int Immunol, 2023, 35(10): 461-473.
26.	Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol, 2014, 14(10): 653-666.
27.	Qi L, Jiang K, Zhao FF, et al. Identification of therapeutic targets and prognostic biomarkers in the Siglec family of genes in tumor immune microenvironment of sarcoma. Sci Rep, 2024, 14(1): 577.
28.	Bernecker C, Halim F, Haase M, et al. MicroRNA expressions in PMBCs, CD4+, and CD8+ T-cells from patients suffering from autoimmune Addison’s disease. Horm Metab Res, 2013, 45(8): 599-604.
29.	Brady PN, Goel A, Johnson MA. Poly(ADP-Ribose) polymerases in host-pathogen interactions, inflammation, and immunity. Microbiol Mol Biol Rev, 2018, 83(1): e00038-18.
30.	García S, Conde C. The Role of Poly(ADP-ribose) Polymerase-1 in rheumatoid arthritis. Mediators Inflamm, 2015, 2015: 837250.
31.	Tian Q, Zhao H, Ling H, et al. Poly(ADP-Ribose) polymerase enhances infiltration of mononuclear cells in primary Sj?gren’s Syndrome through interferon-induced protein with tetratricopeptide repeats 1-mediated up-regulation of CXCL10. Arthritis Rheumatol, 2020, 72(6): 1003-1012.
32.	Niyazoglu M, Baykara O, Koc A, et al. Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with graves disease and graves ophthalmopathy. Gene, 2014, 547(2): 226-232.
33.	Jog NR, Dinnall JA, Gallucci S, et al. Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. J Immunol, 2009, 182(11): 7297-7306.
34.	Hassa PO, Haenni SS, Buerki C, et al. Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem, 2005, 280(49): 40450-40464.
35.	Rosado MM, Bennici E, Novelli F, et al. Beyond DNA repair, the immunological role of PARP-1 and its siblings. Immunology, 2013, 139(4): 428-437.
36.	Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf), 2001, 54(5): 633-639.
37.	van Doorn CLR, Steenbergen SaM, Walburg KV, et al. Pharmacological Poly (ADP-Ribose) polymerase inhibitors decrease Mycobacterium tuberculosis survival in human macrophages. Front Immunol, 2021, 12: 712021.
38.	Si S, Liu H, Xu L, et al. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome. Genome Med, 2024, 16(1): 84.
39.	Li Z, Zhang M, Chen S, et al. BTN3A3 inhibits clear cell renal cell carcinoma progression by regulating the ROS/MAPK pathway via interacting with RPS3A. Cell Signal, 2023, 112: 110914.
40.	Yamashiro H, Yoshizaki S, Tadaki T, et al. Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol, 2010, 88(4): 757-767.
41.	Jaremka LM, Glaser R, Loving TJ, et al. Attachment anxiety is linked to alterations in cortisol production and cellular immunity. Psychol Sci, 2013, 24(3): 272-279.
42.	Borza R, Salgado-Polo F, Moolenaar WH, et al. Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: tidying up diversity. J Biol Chem, 2022, 298(2): 101526.
43.	Oh S, Yang JY, Park CH, et al. Dieckol reduces muscle atrophy by modulating angiotensin type II type 1 receptor and NADPH oxidase in spontaneously hypertensive rats. Antioxidants (Basel), 2021, 10(10): 1561.
44.	Lawrence EA, Kague E, Aggleton JA, et al. The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis. Philos Trans R Soc Lond B Biol Sci, 2018, 373(1759): 20170335.
45.	S?nmez E, Yan S, Lin MS, et al. MAP4 kinase-regulated reduced CLSTN1 expression in medulloblastoma is associated with increased invasiveness. Sci Rep, 2025, 15(1): 946.

1. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab, 2016, 101(2): 364-389.
2. Almeida MQ. Genetic diagnosis of primary adrenal insufficiency in children: a paradigm change. J Endocr Soc, 2021, 5(9): bvab117.
3. Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults. J Endocrinol Invest, 2019, 42(12): 1407-1433.
4. Wolff ASB, Kucuka I, Oftedal BE. Autoimmune primary adrenal insufficiency -current diagnostic approaches and future perspectives. Front Endocrinol (Lausanne), 2023, 14: 1285901.
5. Olafsson AS, Sigurjonsdottir HA. Increasing prevalence of addison disease: results from a nationwide study. Endocr Pract, 2016, 22(1): 30-35.
6. Conrad N, Misra S, Verbakel JY, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet, 2023, 401(10391):1878-1890.
7. Anderson NL, Polanski M, Pieper R, et al. The human plasma proteome: a nonredundant list developed by combination of four separate sources. Mol Cell Proteomics, 2004, 3(4): 311-326.
8. Sun BB, Maranville JC, Peters JE, et al. Genomic atlas of the human plasma proteome. Nature, 2018, 558(7708): 73-79.
9. Fichna M, ?urawek M, Budny B, et al. Elevated serum RANTES chemokine levels in autoimmune Addison disease. Pol Arch Intern Med, 2018, 128(4): 216-221.
10. Palomares O, Elewaut D, Irving PM, et al. Regulatory T cells and immunoglobulin E: a new therapeutic link for autoimmunity?. Allergy, 2022, 77(11): 3293-3308.
11. Mitchell AL, Macarthur KD, Gan EH, et al. Association of autoimmune Addison’s disease with alleles of STAT4 and GATA3 in European cohorts. PLoS One, 2014, 9(3): e88991.
12. Smith GD, Ebrahim S. Data dredging, bias, or confounding. BMJ, 2002, 325(7378): 1437-1438.
13. Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 2008, 27(8): 1133-1163.
14. Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J, 2023, 44(47): 4913-4924.
15. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
16. Ferkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet, 2021, 53(12): 1712-1721.
17. Eriksson D, R?yrvik EC, Aranda-Guillén M, et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat Commun, 2021, 12(1): 959.
18. Su Y, Zhang Y, Chai Y, et al. Autoimmune diseases and their genetic link to bronchiectasis: insights from a genetic correlation and Mendelian randomization study. Front Immunol, 2024, 15: 1343480.
19. Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
20. Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
21. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
22. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
23. Zhou L, Gao H, Zhang J, et al. Metabolic syndrome and cancer risk: a two-sample Mendelian randomization study of European ancestry. Int J Surg, 2025, 111(1): 311-321.
24. Kriegel MA, Lohmann T, Gabler C, et al. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med, 2004, 199(9):1285-1291.
25. Tsubata T. The ligand interactions of B cell Siglecs are involved in the prevention of autoimmunity to sialylated self-antigens and in the quality control of signaling-competent B cells. Int Immunol, 2023, 35(10): 461-473.
26. Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol, 2014, 14(10): 653-666.
27. Qi L, Jiang K, Zhao FF, et al. Identification of therapeutic targets and prognostic biomarkers in the Siglec family of genes in tumor immune microenvironment of sarcoma. Sci Rep, 2024, 14(1): 577.
28. Bernecker C, Halim F, Haase M, et al. MicroRNA expressions in PMBCs, CD4+, and CD8+ T-cells from patients suffering from autoimmune Addison’s disease. Horm Metab Res, 2013, 45(8): 599-604.
29. Brady PN, Goel A, Johnson MA. Poly(ADP-Ribose) polymerases in host-pathogen interactions, inflammation, and immunity. Microbiol Mol Biol Rev, 2018, 83(1): e00038-18.
30. García S, Conde C. The Role of Poly(ADP-ribose) Polymerase-1 in rheumatoid arthritis. Mediators Inflamm, 2015, 2015: 837250.
31. Tian Q, Zhao H, Ling H, et al. Poly(ADP-Ribose) polymerase enhances infiltration of mononuclear cells in primary Sj?gren’s Syndrome through interferon-induced protein with tetratricopeptide repeats 1-mediated up-regulation of CXCL10. Arthritis Rheumatol, 2020, 72(6): 1003-1012.
32. Niyazoglu M, Baykara O, Koc A, et al. Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with graves disease and graves ophthalmopathy. Gene, 2014, 547(2): 226-232.
33. Jog NR, Dinnall JA, Gallucci S, et al. Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. J Immunol, 2009, 182(11): 7297-7306.
34. Hassa PO, Haenni SS, Buerki C, et al. Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem, 2005, 280(49): 40450-40464.
35. Rosado MM, Bennici E, Novelli F, et al. Beyond DNA repair, the immunological role of PARP-1 and its siblings. Immunology, 2013, 139(4): 428-437.
36. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf), 2001, 54(5): 633-639.
37. van Doorn CLR, Steenbergen SaM, Walburg KV, et al. Pharmacological Poly (ADP-Ribose) polymerase inhibitors decrease Mycobacterium tuberculosis survival in human macrophages. Front Immunol, 2021, 12: 712021.
38. Si S, Liu H, Xu L, et al. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome. Genome Med, 2024, 16(1): 84.
39. Li Z, Zhang M, Chen S, et al. BTN3A3 inhibits clear cell renal cell carcinoma progression by regulating the ROS/MAPK pathway via interacting with RPS3A. Cell Signal, 2023, 112: 110914.
40. Yamashiro H, Yoshizaki S, Tadaki T, et al. Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol, 2010, 88(4): 757-767.
41. Jaremka LM, Glaser R, Loving TJ, et al. Attachment anxiety is linked to alterations in cortisol production and cellular immunity. Psychol Sci, 2013, 24(3): 272-279.
42. Borza R, Salgado-Polo F, Moolenaar WH, et al. Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: tidying up diversity. J Biol Chem, 2022, 298(2): 101526.
43. Oh S, Yang JY, Park CH, et al. Dieckol reduces muscle atrophy by modulating angiotensin type II type 1 receptor and NADPH oxidase in spontaneously hypertensive rats. Antioxidants (Basel), 2021, 10(10): 1561.
44. Lawrence EA, Kague E, Aggleton JA, et al. The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis. Philos Trans R Soc Lond B Biol Sci, 2018, 373(1759): 20170335.
45. S?nmez E, Yan S, Lin MS, et al. MAP4 kinase-regulated reduced CLSTN1 expression in medulloblastoma is associated with increased invasiveness. Sci Rep, 2025, 15(1): 946.

West China Medical Journal

Plasma proteins and risk of developing Addison’s disease: a two-sample two-way Mendelian randomization study

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