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Contribution of haptoglobin phenotypic variation to the presence of hyperhomocysteinemia in type 2 diabetics with and without angiopathy

European Journal of Clinical Nutrition volume 79, pages 266–272 (2025)Cite this article

Subjects

Abstract

Background/Aim

The genetic polymorphism of haptoglobin (Hp) has been associated with several cardiovascular risk factors, but a possible relationship between Hp phenotypic variation and increased levels of homocysteine (Hcy) and cysteine (Cy) is still unknown. The objective of this study is to evaluate the relationship between the Hp polymorphism and hyperhomocysteinemia (HHcy) and hypercysteinemia (HCy) in type 2 diabetics (T2D) with and without angiopathy (AGP).

Methods

A case-control study was carried out on 293 adults: Group I (GI) - 75 subjects with T2D and AGP; Group II (GII) - 75 subjects with T2D without AGP; Group III (GIII) - 143 controls. Plasma levels of Hcy, Cy and vitamin B6 were measured by high performance liquid chromatography (HPLC) and vitamins B9 and B12 determined by electrochemiluminescence (ECL). The Hp polymorphism was identified by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and peroxidase staining. The results were analyzed in SPSS®, version 26.0 with a significance of 95%.

Results

Mean Hcy concentrations were significantly lower in carriers of the Hp2-2 phenotype (6.14 µM; p = 0.046) compared to the other genotypes. The presence of Hp2-1 is associated with an approximately 3.3 times greater probability of occurrence of HHcy (p = 0.015) and 3.7 times greater probability occurrence of HCy (p = 0.021) in T2D with AGP.

Conclusion

The presence of the Hp2-1 phenotype is associated with the predisposition of HHcy and HCy in individuals with T2D and AGP, possibly through a positive heterosis mechanism. Carriers of the Hp2-2 phenotype appear to have a greater activation of the transsulfuration pathway in the Hcy cycle and consequent protection for its accumulation.

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References

  1. Levy AP, Levy JE, Kalet-Litman S, Miller-Lotan R, Levy NS, Asaf R, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 2007;27:134–40.

    Article  PubMed  CAS  Google Scholar 

  2. Kalmovarin N, Friedrichs WE, O’brien HV, Linehan LA, Bowman BH, Yang F. Extrahepatic expression of plasma protein genes during inflammation. Inflammation. 1991;15:369–79.

    Article  PubMed  CAS  Google Scholar 

  3. Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42:1589–600.

    Article  PubMed  CAS  Google Scholar 

  4. Sadrzadeh SMH, Graf E, Panter SS, Hallaway PE, Eaton JW. Hemoglobin. A biologic fenton reagent. J Biol Chem. 1984;259:14354–6.

    Article  PubMed  CAS  Google Scholar 

  5. Wobeto VPA, Zaccariotto TR, Sonati MF. Polymorphism of human haptoglobin and its clinical importance. Genet. Mol Biol. 2008;31:602–20.

    Article  CAS  Google Scholar 

  6. Farbstein D, Soloveichik YZ, Levy NS, Levy AP. Genetics of Redox Systems and Their Relationship with Cardiovascular Disease. Curr Atheroscler Rep. 2011;13:215–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Esse R, Barroso M, de Almeida IT, Castro R. The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art. Int J Mol. Sci. 2019;20:867.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Koklesova L, Mazurakova A, Samec M, Biringer K, Samuel SM, Büsselberg D, et al. Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J. 2021;12:477–505.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Quaye IK, Ababio G, Amoah AG. Haptoglobin 2-2 phenotype is a risk factor for type 2 diabetes in Ghana. J Atheroscler Thromb. 2006;13:90–4.

    Article  PubMed  Google Scholar 

  10. Melamed-Frank M, Lache O, Enav BI, Szafranek T, Levy NS, Ricklis RM, et al. Structure-function analysis of the antioxidant properties of haptoglobin. Blood. 2001;98:3693–8.

    Article  PubMed  CAS  Google Scholar 

  11. Delanghe JR, Delrue C, Speeckaert R, Speeckaert MM. Unlocking the link between haptoglobin polymorphism and noninfectious human diseases: insights and implications. Crit Rev Clin Lab Sci. 2023;27:1–23.

    Google Scholar 

  12. Naryzny SN, Legina OK. Haptoglobin as a Biomarker. Biochem Mosc Suppl B Biomed Chem. 2021;15:184–98.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Carter K, Worwood M. Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases. Int J Lab Hematol. 2007;29:92–110.

    Article  PubMed  Google Scholar 

  14. Farbstein D, Levy AP. The genetics of vascular complications in diabetes mellitus. Cardiol Clin. 2010;28:477–96.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bale BF, Doneen AL, Vigerust DJ. Precision Healthcare of Type 2 Diabetic Patients Through Implementation of Haptoglobin Genotyping. Front Cardiovasc Med. 2018;16:141.

    Article  Google Scholar 

  16. Roguin A, Koch W, Kastrati A, Aronson D, Schomig A, Levy AP. Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes. Diabetes Care. 2003;26:2628–31.

    Article  PubMed  Google Scholar 

  17. Lioupis C, Barbatis C, Drougou A, Koliaraki V, Mamalaki A, Klonaris C, et al. Association of haptoglobin genotype and common cardiovascular risk factors with the amount of iron in atherosclerotic carotid plaques. Atherosclerosis. 2011;216:131–8.

    Article  PubMed  CAS  Google Scholar 

  18. Kulcsar J, Cogoi B, Karanyi Z, Szabo K, Kovacs K, Olah L, et al. Haptoglobin (2-2) Polymorphism together with elevated homocystein level enhance the risk for subclinical atherosclerosis in type 2 diabetic men. Atherosclerosis. 2015;241:E179–80.

    Article  Google Scholar 

  19. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.

    Article  Google Scholar 

  20. International Physical Activity Questionnaire (IPAQ). 2004. https://drive.google.com/file/d/1WKqWQLjwhaD3uRpPQ9u558wlC22dkrWq/view.

  21. Valente A, Bronze MR, Bicho M, Duarte R, Costa HS. Validation and clinical application of an UHPLC method for simultaneous analysis of total homocysteine and cysteine in human plasma. J Sep Sci. 2012;35:3427–33.

    Article  PubMed  CAS  Google Scholar 

  22. Valente A, Bicho M, Duarte R, Raposo JF, Costa HS. Vitamin B6 status in Portuguese type 2 diabetic patients with and without retinopathy. Public Health Nutr. 2010;13:232.

    Google Scholar 

  23. Linke RP. Typing and subtyping of haptoglobin from native serum using disc gel electrophoresis in alkaline buffer: application to routine screening. Analyt Biochem. 1984;141:55–61.

    Article  PubMed  CAS  Google Scholar 

  24. Bicho MC, Silva AP, Natos A, Silva RM, Bicho MD. Sex steroid hormones influence the risk for cervical cancer: modulation by haptoglobin genetic polymorphism. Cancer Genet Cytogenet. 2009;191:85–9.

    Article  PubMed  CAS  Google Scholar 

  25. Valente A, Marques-Vidal P, Costa HS. An improved and validated high-performance liquid chromatography method for measuring malondialdehyde levels in human serum. Ann Nutr Metabol. 2007;51:284.

    Google Scholar 

  26. Shi X, Sun L, Wang L, Jin F, Sun J, Zhu X, et al. Haptoglobin 2-2 genotype is associated with increased risk of type 2 diabetes mellitus in northern Chinese. Genet Test Mol Biomarkers. 2012;16:563–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mishra S, Siddiqi S, Kashyap A. Nkagrawal. Polymorphism Of Human Haptoglobin and Its Importance In Diabetic Nephropathy. Dig J Nanomater Biostruct. 2010;5:599–603.

    Google Scholar 

  28. Dalan R, Liew H, Goh LL, Gao X, Chew DE, Boehm BO, et al. The haptoglobin 2-2 genotype is associated with inflammation and carotid artery intima-media thickness. Diab Vasc Dis Res. 2016;13:373–6.

    Article  PubMed  CAS  Google Scholar 

  29. Filipek A. Hp1-1 as a Genetic Marker in Diabetes: Measures, Applications, and Correlations. In: Patel, VB, Preedy, VR, editors. Biomarkers in Diabetes. Biomarkers in Disease: Methods, Discoveries and Applications. Cham: Springer; 2022. pp 1–22.

  30. Mokgalaboni K, Mashaba GR, Phoswa WN, Lebelo SL. Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials. Nutr Diabetes. 2024;14:22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Al Fatly M, Mulder MT, van Lennep JR, Blom HJ, Berk KAC. The effect of diet-induced weight loss on circulating homocysteine levels in people with obesity and type 2 diabetes. Nutr J. 2024;23:2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Xu T, Chen S, Yang F, Wang Y, Zhang K, Fu G, et al. The impact of homocysteine on the risk of coronary artery diseases in individuals with diabetes: a Mendelian randomization study. Acta Diabetol. 2021;58:301–7.

    Article  PubMed  CAS  Google Scholar 

  33. Shawki HA, Elzehery R, Shahin M, Abo-Hashem EM, Youssef MM. Evaluation of some oxidative markers in diabetes and diabetic retinopathy. Diabetol Int. 2020;12:108–17.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Banik S, Ghosh A. The association of oxidative stress biomarkers with type 2 diabetes mellitus: A systematic review and meta-analysis. Health Sci Rep. 2021;4:e389.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Froese DS, Fowler B, Baumgartne MR. Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. J Inherit Metab Dis. 2019;42:673–85.

    Article  PubMed  CAS  Google Scholar 

  36. McCaddon A, Miller JW. Homocysteine-a retrospective and prospective appraisal. Front. Nutr. 2023;10:1179807.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Viener HL, Levy AP. Haptoglobin genotype and the iron hypothesis of atherosclerosis. Atherosclerosis. 2011;216:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Comings DE, MacMurray JP. Molecular heterosis: a review. Mol Genet Metab. 2000;71:19–31.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was finanially supported by the research project PIC/IC/82957/2007 from Foundation for Science and Technology (FCT) and by Instituto Nacional de Saúde Doutor Ricardo Jorge, I.P. (Lisboa, Portugal). This study had also the financial support of the FCT for Environmental Health Institute (references UIDB/04295/2020 and UIDP/04295/2020). Ana Valente acknowledges the financial support received from FCT, through the PhD grant (SFRH/BD/16166/2004/5E4M).

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Authors and Affiliations

  1. Ecogenetics and Human Health Research Group, Environmental Health Institute (ISAMB), Associate Laboratory TERRA, Faculty of Medicine (FMUL), University of Lisbon, Avenida Professor Egas Moniz, 1649-028, Lisbon, Portugal

    Isabel Ferreira, Manuel Bicho & Ana Valente

  2. Institute of Scientific Research Bento da Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012, Lisbon, Portugal

    Manuel Bicho

  3. Applied Nutrition Research Group (GENA), Nutrition Lab, Egas Moniz Center for Interdisciplinary Research (CiiEM), Egas Moniz School of Health & Science, Quinta da Granja-Campus Universitário, 2829-511, Monte da Caparica, Portugal

    Ana Valente

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  1. Isabel Ferreira
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Contributions

Conceptualization, MB and AV; methodology, MB and AV; software, AV; validation, IF, MB and AV; formal analysis, AV; investigation, IF, MB and AV; resources, AV; writin the original draft preparation, IF and AV; review and editing, MB and AV; visualization, IF and AV; supervision, MB and AV; project administration, AV. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Ana Valente.

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Ferreira, I., Bicho, M. & Valente, A. Contribution of haptoglobin phenotypic variation to the presence of hyperhomocysteinemia in type 2 diabetics with and without angiopathy. Eur J Clin Nutr 79, 266–272 (2025). https://doi.org/10.1038/s41430-024-01524-7

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