Association of APOE Genotypes and Total Apolipoprotein E Levels With Galectin-3 and Cardiovascular Risk in Rheumatoid Arthritis Patients
,
Abstract
Rheumatoid arthritis (RA) defined as a chronic inflammatory disease characterized by painull inflammation of small joints additionally to cardiac disease, probably due to shared pathophysiological pathways and dyslipidemia. The main goal of the presented study is to evaluate the role of the ApoE polymorphisms in Iraqi RA patients and their association with lipid profiles, total ApoE levels, and disease severity markers, including galectin-3 and anti-CCP. A case-control study included 90 RA patients and 90 gender- and healthy controls aged 21 to 70 years with BMI ranging from 18 to 27 kg/m². Fasting serum lipid profiles were analyzed colorimetrically. Total ApoE, ApoE isoforms, anti-CCP, and galectin-3 were quantified by ELISA. Genomic DNA was used to perform ApoE genotyping for the ε2, ε3, and ε4 alleles. RA patients had significantly lower total ApoE levels and markedly higher levels of total cholesterol, LDL, galectin-3, and anti-CCP than controls (P<0.001). The ApoE ε2 allele correlated with reduced cholesterol and LDL-c levels and higher total ApoE levels. In contrast, the ApoE ε4 allele was associated with more severe dyslipidemia, including higher cholesterol and LDL-c levels, as well as increased inflammatory markers, including galectin-3 and anti-CCP, compared with carriers of either ε2 or ε3. ApoE polymorphisms, specifically the ε4 allele, together with elevated galectin-3 levels, are associated with exacerbated dyslipidemia and systemic inflammation in RA, suggesting their potential utility as combined biomarkers for identifying patients with a heightened atherogenic profile who may warrant cardiovascular risk assessment.
1. Chen YM, Chen PK, Chang CK, Lin CC, Chen HH, Lan JL, et al. Association of apolipoprotein E polymorphism with adipokines and cardiovascular disease risk in rheumatoid arthritis patients. Life (Basel) 2020;10:330.
2. Erickson AR, Cannella AC, Mikuls TR. Clinical features of rheumatoid arthritis. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, editors. Kelley and Firestein’s textbook of rheumatology. 10th ed. Philadelphia: Elsevier; 2017;1167-86.
3. Lin YJ, Anzaghe M, Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells 2020;9:880.
4. Mousavi MJ, Jamshidi A, Chopra A, Aslani S, Akhlaghi M, Mahmoudi M. Implications of the noncoding RNAs in rheumatoid arthritis pathogenesis. J Cell Physiol 2019;234:335-47.
5. Innala L, Berglin E, Möller B, Ljung L, Smedby T, Södergren A, et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther 2014;16:R94.
6. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity 2017;46:183-96.
7. Matsushita M, Yamaji KEN, Tamura N. Extra-articular manifestations of rheumatoid arthritis. Juntendo Med J 2020;66:21-6.
8. Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 2015;11:390-400.
9. Meyer PW, Anderson R, Ker JA, Ally MT. Rheumatoid arthritis and risk of cardiovascular disease. Cardiovasc J Afr 2018;29:317-21.
10. Johri N, Varshney S, Gandha S, Maurya A, Mittal P, Jangra S, et al. Association of cardiovascular risks in rheumatoid arthritis patients: management, treatment and future perspectives. Health Sci Rev 2023;8:100108.
11. Hajiesmaeili Y, Tamhankar P, Stranges S, Barra L. Factors associated with incident cardiovascular disease in patients with rheumatoid arthritis: a scoping review. Autoimmun Rev 2024;23:103539.
12. Erum U, Ahsan T, Khowaja D. Lipid abnormalities in patients with rheumatoid arthritis. Pak J Med Sci 2017;33:227-30.
13. Naerr GW, Rein P, Saely CH, Drexel H. Effects of synthetic and biological disease modifying antirheumatic drugs on lipid and lipoprotein parameters in patients with rheumatoid arthritis. Vascul Pharmacol 2016;81:22-30.
14. Pechlaner R, Tsimikas S, Yin X, Willeit P, Baig F, Santer P, et al. Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J Am Coll Cardiol 2017;69:789-800.
15. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener 2022;17:72.
16. Giau VV, Bagyinszky E, An SSA, Kim SY. Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 2015;11:1723-37.
17. Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, et al. The impact of low-frequency and rare variants on lipid levels. Nat Genet 2015;47:589-97.
18. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology 2019;51:165-76.
19. Huebbe P, Rimbach G. Evolution of human apolipoprotein E isoforms: gene structure, protein function and interaction with dietary factors. Ageing Res Rev 2017;37:146-61.
20. Toms TE, Smith JP, Panoulas VF, Blackmore H, Douglas KM, Kitas GD. Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia in rheumatoid arthritis. J Rheumatol 2012;39:218-25.
21. Villeneuve S, Brisson D, Gaudet D. Influence of abdominal obesity on the lipid-lipoprotein profile in apoprotein E2/4 carriers: the effect of an apparent duality. J Lipids 2015;2015:742408.
22. Zanotti I, Pedrelli M, Potì F, Stomeo G, Gomaraschi M, Calabresi L, et al. Macrophage, but not systemic, apolipoprotein E is necessary for macrophage reverse cholesterol transport in vivo. Arterioscler Thromb Vasc Biol 2011;31:74-80.
23. Marais AD, Solomon GA, Blom DJ. Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. Crit Rev Clin Lab Sci 2014;51:46-62.
24. Grant WB. A multicountry ecological study of risk-modifying factors for prostate cancer: apolipoprotein E ε4 as a risk factor and cereals as a risk reduction factor. Anticancer Res 2010;30:189-99.
25. Niiranen TJ, Vasan RS. Epidemiology of cardiovascular disease: recent novel outlooks on risk factors and clinical approaches. Expert Rev Cardiovasc Ther 2016;14:855-69.
26. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: one molecule for an alphabet of diseases, from A to Z. Int J Mol Sci 2018;19:379.
27. Zhang N, Liu Q, Wang D, Wang X, Pan Z, Han B, et al. Multifaceted roles of galectins: from carbohydrate binding to targeted cancer therapy. Biomark Res 2025;13:49.
28. Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta 2006;1760:616-35.
29. Rebeck GW. The role of APOE on lipid homeostasis and inflammation in normal brains. J Lipid Res 2017;58:1493-9.
30. Shinozaki K, Honda T, Yamaji K, Nishijima E, Ichi I, Yamane D. Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells. J Lipid Res 2025;66:100795.
31. Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life 2014;66:616-23.
32. Toribio-Fernández R, Tristão-Pereira C, Silla-Castro JC, Callejas S, Oliva B, Fernandez-Nueda I, et al. Apolipoprotein E-ε2 and resistance to atherosclerosis in midlife: the PESA observational study. Circ Res 2024;134:411-24.
33. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016;94:739-46.
34. Khalil YA, Rabès JP, Boileau C, Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis 2021;328:11-22.
35. Attar SM. Hyperlipidemia in rheumatoid arthritis patients in Saudi Arabia: correlation with C-reactive protein levels and disease activity. Saudi Med J 2015;36:685-91.
36. Fernández-Ortiz AM, Ortiz AM, Pérez S, Toledano E, Abásolo L, González-Gay MA, et al. Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory? Arthritis Res Ther 2020;22:213.
37. Schroeder JT, Adeosun AA, Bieneman AP. Epithelial cell-associated galectin-3 activates human dendritic cell subtypes for pro-inflammatory cytokines. Front Immunol 2020;11:524826.
38. Dos Santos SN, Sheldon H, Pereira JX, Paluch C, Bridges EM, El-Cheikh MC, et al. Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/Notch activation. Oncotarget 2017;8:49484-501.
39. Robinson BS, Arthur CM, Evavold B, Roback E, Kamili NA, Stowell CS, et al. The sweet-side of leukocytes: galectins as master regulators of neutrophil function. Front Immunol 2019;10:1762.
40. Ohshima S, Kuchen S, Seemayer CA, Kyburz D, Hirt A, Klinzing S, et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum 2003;48:2788-95.
41. Papaspyridonos M, McNeill E, de Bono JP, Smith A, Burnand KG, Channon KM, et al. Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction. Arterioscler Thromb Vasc Biol 2008;28:433-40.
42. Anyfanti P, Gkaliagkousi E, Gavriilaki E, Triantafyllou A, Dolgyras P, Galanopoulou V, et al. Association of galectin-3 with markers of myocardial function, atherosclerosis, and vascular fibrosis in patients with rheumatoid arthritis. Clin Cardiol 2019;42:62-8.
43. Tian L, Wang Y, Zhang R. Galectin-3 induces vascular smooth muscle cells calcification via AMPK/TXNIP pathway. Aging (Albany NY) 2022;14:5086-96.
44. Gao Z, Liu Z, Wang R, Zheng Y, Li H, Yang L. Galectin-3 is a potential mediator for atherosclerosis. J Immunol Res 2020;2020:5284728.
2. Erickson AR, Cannella AC, Mikuls TR. Clinical features of rheumatoid arthritis. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, editors. Kelley and Firestein’s textbook of rheumatology. 10th ed. Philadelphia: Elsevier; 2017;1167-86.
3. Lin YJ, Anzaghe M, Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells 2020;9:880.
4. Mousavi MJ, Jamshidi A, Chopra A, Aslani S, Akhlaghi M, Mahmoudi M. Implications of the noncoding RNAs in rheumatoid arthritis pathogenesis. J Cell Physiol 2019;234:335-47.
5. Innala L, Berglin E, Möller B, Ljung L, Smedby T, Södergren A, et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther 2014;16:R94.
6. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity 2017;46:183-96.
7. Matsushita M, Yamaji KEN, Tamura N. Extra-articular manifestations of rheumatoid arthritis. Juntendo Med J 2020;66:21-6.
8. Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol 2015;11:390-400.
9. Meyer PW, Anderson R, Ker JA, Ally MT. Rheumatoid arthritis and risk of cardiovascular disease. Cardiovasc J Afr 2018;29:317-21.
10. Johri N, Varshney S, Gandha S, Maurya A, Mittal P, Jangra S, et al. Association of cardiovascular risks in rheumatoid arthritis patients: management, treatment and future perspectives. Health Sci Rev 2023;8:100108.
11. Hajiesmaeili Y, Tamhankar P, Stranges S, Barra L. Factors associated with incident cardiovascular disease in patients with rheumatoid arthritis: a scoping review. Autoimmun Rev 2024;23:103539.
12. Erum U, Ahsan T, Khowaja D. Lipid abnormalities in patients with rheumatoid arthritis. Pak J Med Sci 2017;33:227-30.
13. Naerr GW, Rein P, Saely CH, Drexel H. Effects of synthetic and biological disease modifying antirheumatic drugs on lipid and lipoprotein parameters in patients with rheumatoid arthritis. Vascul Pharmacol 2016;81:22-30.
14. Pechlaner R, Tsimikas S, Yin X, Willeit P, Baig F, Santer P, et al. Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J Am Coll Cardiol 2017;69:789-800.
15. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener 2022;17:72.
16. Giau VV, Bagyinszky E, An SSA, Kim SY. Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 2015;11:1723-37.
17. Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, et al. The impact of low-frequency and rare variants on lipid levels. Nat Genet 2015;47:589-97.
18. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology 2019;51:165-76.
19. Huebbe P, Rimbach G. Evolution of human apolipoprotein E isoforms: gene structure, protein function and interaction with dietary factors. Ageing Res Rev 2017;37:146-61.
20. Toms TE, Smith JP, Panoulas VF, Blackmore H, Douglas KM, Kitas GD. Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia in rheumatoid arthritis. J Rheumatol 2012;39:218-25.
21. Villeneuve S, Brisson D, Gaudet D. Influence of abdominal obesity on the lipid-lipoprotein profile in apoprotein E2/4 carriers: the effect of an apparent duality. J Lipids 2015;2015:742408.
22. Zanotti I, Pedrelli M, Potì F, Stomeo G, Gomaraschi M, Calabresi L, et al. Macrophage, but not systemic, apolipoprotein E is necessary for macrophage reverse cholesterol transport in vivo. Arterioscler Thromb Vasc Biol 2011;31:74-80.
23. Marais AD, Solomon GA, Blom DJ. Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. Crit Rev Clin Lab Sci 2014;51:46-62.
24. Grant WB. A multicountry ecological study of risk-modifying factors for prostate cancer: apolipoprotein E ε4 as a risk factor and cereals as a risk reduction factor. Anticancer Res 2010;30:189-99.
25. Niiranen TJ, Vasan RS. Epidemiology of cardiovascular disease: recent novel outlooks on risk factors and clinical approaches. Expert Rev Cardiovasc Ther 2016;14:855-69.
26. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: one molecule for an alphabet of diseases, from A to Z. Int J Mol Sci 2018;19:379.
27. Zhang N, Liu Q, Wang D, Wang X, Pan Z, Han B, et al. Multifaceted roles of galectins: from carbohydrate binding to targeted cancer therapy. Biomark Res 2025;13:49.
28. Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta 2006;1760:616-35.
29. Rebeck GW. The role of APOE on lipid homeostasis and inflammation in normal brains. J Lipid Res 2017;58:1493-9.
30. Shinozaki K, Honda T, Yamaji K, Nishijima E, Ichi I, Yamane D. Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells. J Lipid Res 2025;66:100795.
31. Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life 2014;66:616-23.
32. Toribio-Fernández R, Tristão-Pereira C, Silla-Castro JC, Callejas S, Oliva B, Fernandez-Nueda I, et al. Apolipoprotein E-ε2 and resistance to atherosclerosis in midlife: the PESA observational study. Circ Res 2024;134:411-24.
33. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016;94:739-46.
34. Khalil YA, Rabès JP, Boileau C, Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis 2021;328:11-22.
35. Attar SM. Hyperlipidemia in rheumatoid arthritis patients in Saudi Arabia: correlation with C-reactive protein levels and disease activity. Saudi Med J 2015;36:685-91.
36. Fernández-Ortiz AM, Ortiz AM, Pérez S, Toledano E, Abásolo L, González-Gay MA, et al. Effects of disease activity on lipoprotein levels in patients with early arthritis: can oxidized LDL cholesterol explain the lipid paradox theory? Arthritis Res Ther 2020;22:213.
37. Schroeder JT, Adeosun AA, Bieneman AP. Epithelial cell-associated galectin-3 activates human dendritic cell subtypes for pro-inflammatory cytokines. Front Immunol 2020;11:524826.
38. Dos Santos SN, Sheldon H, Pereira JX, Paluch C, Bridges EM, El-Cheikh MC, et al. Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/Notch activation. Oncotarget 2017;8:49484-501.
39. Robinson BS, Arthur CM, Evavold B, Roback E, Kamili NA, Stowell CS, et al. The sweet-side of leukocytes: galectins as master regulators of neutrophil function. Front Immunol 2019;10:1762.
40. Ohshima S, Kuchen S, Seemayer CA, Kyburz D, Hirt A, Klinzing S, et al. Galectin 3 and its binding protein in rheumatoid arthritis. Arthritis Rheum 2003;48:2788-95.
41. Papaspyridonos M, McNeill E, de Bono JP, Smith A, Burnand KG, Channon KM, et al. Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction. Arterioscler Thromb Vasc Biol 2008;28:433-40.
42. Anyfanti P, Gkaliagkousi E, Gavriilaki E, Triantafyllou A, Dolgyras P, Galanopoulou V, et al. Association of galectin-3 with markers of myocardial function, atherosclerosis, and vascular fibrosis in patients with rheumatoid arthritis. Clin Cardiol 2019;42:62-8.
43. Tian L, Wang Y, Zhang R. Galectin-3 induces vascular smooth muscle cells calcification via AMPK/TXNIP pathway. Aging (Albany NY) 2022;14:5086-96.
44. Gao Z, Liu Z, Wang R, Zheng Y, Li H, Yang L. Galectin-3 is a potential mediator for atherosclerosis. J Immunol Res 2020;2020:5284728.
| Files | ||
| Issue | Vol 64 No 5 (2026) | |
| Section | Original Articles | |
| Keywords | ||
| Rheumatoid arthritis Apolipoprotein E Cardiovascular diseases Dyslipidemias Galectin-3 | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Khalil MAA-H, Thanoon QA, Abdulrahman AY. Association of APOE Genotypes and Total Apolipoprotein E Levels With Galectin-3 and Cardiovascular Risk in Rheumatoid Arthritis Patients. Acta Med Iran. 2026;65(5).
