Skip to main content

Advertisement

SpringerLink
Log in

VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has been shown to play a significant role in neovascularization during inflammation in atherosclerotic plaques, formation of collateral vessels to an area of ischemic myocardium and neovascularization at the edges of a myocardial infarction during its repair. Interleukin-4 (IL-4) has important role in immune cell chemotaxis, formation of endothelial cell adhesion molecules and has numerous anti-inflammatory effects which prevent the complications of atherosclerosis, the primary cause of coronary heart disease (CHD). In this study, we have analyzed the effect of 1154 A/G polymorphism of VEGF and 70 bp VNTR polymorphism of intron 3 in IL-4 genes in coronary heart disease (CHD) patients (n = 300) and their age matched controls (n = 300). To analyze polymorphic alleles, ARMS-PCR and RFLP techniques were used. Multiple logistic regression analysis was carried out with statistical software. GG genotype was associated with a decreased risk of development of CHD (OR 0.22, 95% CI 0.12–0.38, P < 0.001). However, A allele showed an increased risk whereas G allele decreased the risk of CHD with diabetes mellitus, hypertension, chronic mental stress and positive familial history of myocardial infarction (MI)/CHD. GG genotype was found to have protective effect with alcohol intake (OR 0.34, 95% CI 0.14–0.82, P < 0.01) and central obesity (OR 0.15, 95% CI 0.04–0.56, P < 0.001). GG genotype of VEGF has also shown significant association with IL-4 (P2P2 and P1P2) genotypes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143

    Article  CAS  PubMed  Google Scholar 

  2. Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y (2000) Association of a T29-C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 101:2783–2787

    CAS  PubMed  Google Scholar 

  3. Clauss M, Gerlach M, Gerlach H, Brett J, Wamg F, Familletti PC, Pan YC, Olander JV, Connolly DT, Stern D (1990) Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172:1535–1545

    Article  CAS  PubMed  Google Scholar 

  4. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343

    CAS  PubMed  Google Scholar 

  5. Grosskrutz CL, Anand-Apte B, Duplaa C, Quinn TP, Terman BI, Zetter B, D’Amore PA (1999) Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res 58:128–136

    Article  Google Scholar 

  6. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD (2001) Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nature Med 7:425–429

    Article  CAS  PubMed  Google Scholar 

  7. Lengstrom KB, Krebs R, Nykanen AI, Tikkanen JM, Sihvola RK, Aaltola EM, Hayry PJ, Wood PJ, Alitalo K, Yla-Herttuala S, Koskinen PK (2002) Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Circulation 105:2524–2530

    Article  Google Scholar 

  8. Zhao Q, Egashira K, Inoue S, Usui M, Kitamoto S, Ni W, Ishibashi M, Hiasa Ki K, Ichiki T, Shibuya M, Takeshita A (2002) Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis. Circulation 105:1110–1115

    Article  CAS  PubMed  Google Scholar 

  9. Asahara T, Bauters C, Kearney M, Pastore C, Bunting S, Rossow S, Ferrara N (1995) Local delivery of vascular endothelial growth factor accelerates re-endothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation 91:2793–2801

    CAS  PubMed  Google Scholar 

  10. Van Belle E, Maillard L, Tio FO, Isner JM (1997) Accelerated endothelialization by local delivery of recombinant human vascular endothelial growth factor reduces in-stent intimal formation. Biochem Biophys Res Comm 235:311–316

    Article  PubMed  Google Scholar 

  11. Tsurumi Y, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, Isner JM (1997) Reciprocal relationship between VEGF and NO in the regulation of endothelial integrity. Nature Med 3:879–886

    Article  CAS  PubMed  Google Scholar 

  12. Vincenti V, Cassano C, Rocchi M, Persico G (1996) Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93:1493–1495

    CAS  PubMed  Google Scholar 

  13. Watson CJ, Webb NJA, Bottomley MJ, Brenchley PEC (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12:1232–1235

    Article  CAS  PubMed  Google Scholar 

  14. Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV (2002) Polymorphisms in vascular endothelial growth factor gene are associated with increased risk of acute rejection in renal transplant recipients. J Am Soc Nephrol 13:260–264

    CAS  PubMed  Google Scholar 

  15. Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV (1999) Novel polymorphisms in the promoter and 59 untranslated regions of the human vascular endothelial growth factor gene. Hum Immunol 60:1245–1249

    Article  CAS  PubMed  Google Scholar 

  16. Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S (2002) A common polymorphism in the 59 untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51:1635–1639

    Article  CAS  PubMed  Google Scholar 

  17. Liao JK (2004) Statins: potent vascular anti-inflammatory agents. Int J Clin Pract 143:41–48

    Article  CAS  Google Scholar 

  18. Aukrust P, Yndestad A, Waehre T, Gullestad L, Halvorsen B, Damas JK (2005) Inflammation in coronary artery disease: potential role for immunomodulatory therapy. Expert Rev Cardiovasc Ther 3:1111–1124

    Article  CAS  PubMed  Google Scholar 

  19. Lefer AM, Ma XL, Weyrich AS, Scalia R (1993) Mechanism of the cardioprotective effect of transforming growth factor beta 1 in feline myocardial ischemia and reperfusion. Proc Natl Acad Sci USA 90:1018–1022

    Article  CAS  PubMed  Google Scholar 

  20. Negoro K, Kinouchi Y, Hiwatashi N, Takahashi S, Takagi S, Satoh J, Shimosegawa T, Toyota T (1999) Crohn’s disease is flanking region of the associated with novel polymorphisms in the tumor necrosis factor gene. Gastroenterology 117:1062–1068

    Article  CAS  PubMed  Google Scholar 

  21. Elkarim RA, Mustafa M, Kivisakk P, Link H, Bakhiet M (1998) Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. Eur J Clin Investig 28:295–299

    Article  CAS  Google Scholar 

  22. Kim HM, Shin HY, Jeong HJ, Kim NS, Chae HJ, Kim HR, Song HJ, Kim KY, Baek SH, Cho KS, Moon BS, Lee YM (2000) Reduced IL-2 but elevated IL-4, IL-6, and IgE serum levels in patients with cerebral infarction during the acute stage. J Mol Neurosci 14:191–196

    Article  PubMed  Google Scholar 

  23. Nanavaty U, Goldstein AD, Levine SJ (2001) Polymorphisms in candidate asthma genes. Am J Med Sci 321:11–16

    Article  CAS  PubMed  Google Scholar 

  24. Bijlsma FJ, Van K, Van H, Jonge E, Tilanus N, Gmelig-Meyling FH, de Weger RA (2002) Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-lymphocytes rather than with interleukin-4 promoter or splice variants. Hum Immunol 63:317–323

    Article  CAS  PubMed  Google Scholar 

  25. Maksymowych WP, Suarez-Almazor ME, Buenviaje H, Cooper BL, Degeus C, Thompson M, Russell AS (2002) HLA and cytokine gene polymorphisms in relation to occurrence of palindromic rheumatism and its progression to rheumatoid arthritis. J Rheumatol 29:2319–2326

    CAS  PubMed  Google Scholar 

  26. Nakayama EE, Meyer L, Iwamoto A, Persoz A, Nagai Y, Rouzioux C, Delfraissy JF, Debre P, McIlroy D, Theodorou I, Shioda T (2003) SEROCO Study Group Protective effect of interleukin-4589T polymorphism on human immunodeficiency virus type 1 disease progression: relationship with virus load. J Infect Dis 185:1183–1186

    Article  Google Scholar 

  27. Bugawan TL, Mirel DB, Valdes AM, Panelo A, Pozzilli P, Erlich HA (2003) Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos. Am J Hum Genet 72:1505–1514

    Article  CAS  PubMed  Google Scholar 

  28. Zee RYL, Cook NR, Cheng S, Reynolds R, Erlich HA, Lindpaintner K, Ridker PM (2004) Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. Hum Mol Genet 13:389–396

    Article  CAS  PubMed  Google Scholar 

  29. Debora SF, Flynt L, Bourgeois K, Panettieri RA, Stephanie A (2006) Interleukin-13 and interleukin-4 induce vascular endothelial growth factor release from airway smooth muscle cells role of vascular endothelial growth factor genotype. Am J Respir Cell Mol Biol 34:213–218

    Article  Google Scholar 

  30. Tsai FJ, Chang CH, Chen CC, Hsia TC, Chen HY, Chen WC (2005) Interleukin-4 gene intron-3 polymorphism is associated with transitional cell carcinoma of the urinary bladder. BJU Int 95:430–435

    Article  Google Scholar 

  31. Field JK, Liloglou T, Xinarianos S, Prime GP, Fielding W, Walshaw JM, Turnbull L (1999) Genetic alterations in bronchial lavage as a potential marker for individuals with a high risk of developing lung cancer. Cancer Res 59:2690–2695

    CAS  PubMed  Google Scholar 

  32. Howell WM, Ali S, Rose-Zerilli MJ, Ye S (2005) VEGF polymorphisms and severity of atherosclerosis. J Med Genet 42:485–490

    Article  CAS  PubMed  Google Scholar 

  33. Mout R, Willemze R, Landegent JE (1991) Repeat polymorphisms in the interleukin-4 gene. Nucl Acids Res 19:3763

    Article  CAS  PubMed  Google Scholar 

  34. Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW (2003) Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res 63:812–816

    CAS  PubMed  Google Scholar 

  35. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J (2003) Inhibition of plaque neovascularization reduces marcrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 100:4736–4741

    Article  CAS  PubMed  Google Scholar 

  36. Ray D, Mishra M, Ralph S, Read I, Davies R, Brenchley P (2004) Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes 53:861–864

    Article  CAS  PubMed  Google Scholar 

  37. Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Haas J, Samonigg H (2003) A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer 106:468–471

    Article  CAS  PubMed  Google Scholar 

  38. Smith KC, Bateman AC, Fussell HM, Howell WM (2004) Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 4:167–173

    Article  Google Scholar 

  39. Jacobs EJ, Feigelson HS, Bain EB, Brady KA, Rodriguez C, Stevens VL, Patel AV (2006) Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort. Breast Cancer Res 8:R22

    Article  PubMed  Google Scholar 

  40. Mccarron SL, Edwards S, Evans PR, Gibbs R, Dearnaley DP, Dowe A, Southgate C, Easton DF, Feles RA, Howell WM (2002) Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res 12:3369–3372

    Google Scholar 

  41. Del Bo R, Scarlato M, Ghezzi S, Maestreni A, Sjolind L, Forsblom C, Wessman M, Groop PH, Comi GP, Bresolin M, Luzi L, Zerbini G (2006) VEGF gene variability and type 1 diabetes: evidence for a protective role. Immunogenetics 58:107–112

    Article  PubMed  Google Scholar 

  42. Yang B, Cross DF, Ollerenshaw M, Millward BA, Demaine AG (2003) Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. J Diabetes Complic 17:1–6

    Article  Google Scholar 

  43. Buracznska M, Ksiazek P, Baranowicz-Gaszczyk I, Jozwiak L (2007) Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetic patients. Nephrol Dial Transpl 22:827–832

    Article  Google Scholar 

  44. Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86:515–581

    Article  CAS  PubMed  Google Scholar 

  45. Chang YH, Huang CN, Wu CY, Shiau MY (2005) Association of interleukin-10 A-592C and T-819C polymorphisms with type 2 diabetes mellitus. Hum Immunol 66:1258–1263

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from Council of Scientific and Industrial Research, Ministry of Human Resource and Development, New Delhi, India. We thank Dr. Gurbir Singh and Dr. G. S. Kalra, Fortis Hospital, Mohali, India for their kind help and co-operation.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Panjab University, Chandigarh, 160014, India

    R. C. Sobti, Nishi Maithil & Hitender Thakur

  2. Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Yashpaul Sharma & K. K. Talwar

Authors
  1. R. C. Sobti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nishi Maithil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hitender Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yashpaul Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. K. Talwar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. C. Sobti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sobti, R.C., Maithil, N., Thakur, H. et al. VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population. Mol Cell Biochem 341, 139–148 (2010). https://doi.org/10.1007/s11010-010-0445-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-010-0445-2

Keywords

Search

Navigation