Skip to main content

ENPP1 121Q functional variant enhances susceptibility to coronary artery disease in South Indian patients with type 2 diabetes mellitus

Molecular and Cellular Biochemistry volume 435, pages 67–72 (2017)Cite this article

Abstract

Insulin resistance is associated with endothelial dysfunction and ensuing cardiovascular diseases in type 2 diabetes mellitus (T2DM) patients. ENPP1 is a key modulator of insulin signaling and its polymorphism, K121Q, increases the potency to competitively inhibit insulin receptor binding. We investigated the association of ENPP1 121Q variant with coronary artery disease (CAD) in patients with and without T2DM in South Indian population. Our study was conducted in 913 subjects: 198 patients with CAD, 284 patients in whom T2DM and CAD co-exists, 160 patients with T2DM and no CAD history, and 271 healthy volunteers. Genotyping was performed using PCR–RFLP and PCR-DNA sequencing. Genotype frequency of ENPP1 121Q was higher in disease groups compared to healthy subjects (p < 0.05). T2DM patients who carried polymorphic AC/CC genotypes were at 12.8-fold enhanced risk to CAD (95% CI 4.97–37.18, p < 0.01). Moreover we observed that 121Q, both in heterozygous and homozygous polymorphic states, was a risk factor for CAD without diabetes (OR 4.15, p < 0.01). 121Q variant was associated with T2DM patients with no CAD history too, but the risk was statistically insignificant after multivariate logistic regression analysis (OR 2.32, p > 0.05). We conclude that ENPP1 121Q variant is associated with increased risk for CAD in patients with T2DM in South Indian population. We also report that 121Q variant of ENPP1 was an independent risk factor for CAD irrespective of diabetic milieu. Factors which enhance insulin resistance increase the risk for onset and progression of coronary atherosclerosis irrespective of a diabetic background.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Abbreviations

CAD:

Coronary artery disease

T2DM:

Type 2 diabetes mellitus

ENPP1:

Ectoenzyme nucleotide pyrophosphate phosphodiesterase/plasma cell glycoprotein 1

FBS:

Fasting blood sugar

HbA1c:

Glycated haemoglobin

PCR–RFLP:

Polymerase chain reaction-restriction fragment length polymorphism

OR:

Odds ratio

CI:

Confidence interval

References

  1. Vijayakumar G, Arun R, Kutty VR (2009) High prevalence of type 2 diabetes mellitus and other metabolic disorders in rural Central Kerala. J Assoc Physicians India 57:563–567

    CAS  PubMed  Google Scholar 

  2. Mohan V, Venkatraman JV, Pradeepa R (2010) Epidemiology of cardiovascular disease in type 2 diabetes: the Indian scenario. J Diabetes Sci Technol 4:158–170

    Article  PubMed  PubMed Central  Google Scholar 

  3. Krishnan MN, Zachariah G, Venugopal K et al (2016) Prevalence of coronary artery disease and its risk factors in Kerala, South India: a community-based cross-sectional study. BMC Cardiovasc Disord 16:12. doi:10.1186/s12872-016-0189-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Mohan V, Deepa R, Rani SS, Premalatha G (2001) Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: the Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 38:682–687

    CAS  Article  PubMed  Google Scholar 

  5. Sousa AG, Selvatici L, Krieger JE, Pereira AC (2011) Association between genetics of diabetes, coronary artery disease, and macrovascular complications: exploring a common ground hypothesis. Rev Diabet Stud 8:230–244. doi:10.1900/RDS.2011.8.230

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hadi HA, Carr CS, Al Suwaidi J (2005) Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 1:183–198

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Goldfine ID, Maddux BA, Youngren JF et al (2008) The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev 29:62–75. doi:10.1210/er.2007-0004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Abate N, Chandalia M, Satija P et al (2005) ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes. Diabetes 54:1207–1213. doi:10.2337/diabetes.54.4.1207

    CAS  Article  PubMed  Google Scholar 

  9. Bacci S, Ludovico O, Prudente S et al (2005) The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction. Diabetes 54:3021–3025. doi:10.2337/diabetes.54.10.3021

    CAS  Article  PubMed  Google Scholar 

  10. Weedon MN, Shields B, Hitman G et al (2006) No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8089 U.K. Caucasians. Diabetes 55:3175–3179. doi:10.2337/db06-0410

    CAS  Article  PubMed  Google Scholar 

  11. Bhatti JS, Bhatti GK, Mastana SS et al (2010) ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes in North Indians. Mol Cell Biochem 345:249–257. doi:10.1007/s11010-010-0579-2

    CAS  Article  PubMed  Google Scholar 

  12. Ali S, Chopra R, Manvati S et al (2013) Replication of type 2 diabetes candidate genes variations in three geographically unrelated Indian population groups. PLoS ONE 8(3):e58881. doi:10.1371/journal.pone.0058881

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Tripathi AK, Shukla S, Dwivedi MK et al (2013) Obesity and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) polymorphism and their association with pathophysiology diabetes type 2 in Central Indian population. J Diabetes Endocrinol 4(2):19–26. doi:10.5897/JDE12.018

    CAS  Google Scholar 

  14. Bacci S, Rizza S, Prudente S et al (2011) The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients. Diabetes 60:1000–1007. doi:10.2337/db10-1300

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Sumi S, Ramachandran S, Kutty VR et al (2015) Nonsynonymous T280M gene variant of CX3CR1 in South Indian population is associated with reduced risk for vascular disease in patients with diabetes mellitus. Curr Res 2:188–192

    Google Scholar 

  16. Buckley MF, Loveland KA, McKinstry WJ et al (1990) Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location. J Biol Chem 265:17506–17511

    CAS  PubMed  Google Scholar 

  17. Sortica DA, Crispim D, Zaffari GP et al (2011) The role of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 in diabetic nephropathy. Arq Bras Endocrinol Metabol 55:677–685. doi:10.1590/S0004-27302011000900002

    Article  PubMed  Google Scholar 

  18. Pizzuti A, Frittitta L, Argiolas A et al (1999) A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes 48:1881–1884. doi:10.2337/diabetes.48.9.1881

    CAS  Article  PubMed  Google Scholar 

  19. Tang ST, Shen XR, Tang HQ et al (2014) Association of the ENPP1 K121Q polymorphism with susceptibility to type 2 diabetes in different populations: evidence based on 40 studies. Endocr J 61:1093–1103. doi:10.1507/endocrj.EJ14-0272

    CAS  Article  PubMed  Google Scholar 

  20. Grarup N, Urhammer SA, Ek J et al (2006) Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects. Diabetologia 49:2097–2104. doi:10.1007/s00125-006-0353-x

    CAS  Article  PubMed  Google Scholar 

  21. Lyon HN, Florez JC, Bersaglieri T et al (2006) Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity. Diabetes 55:3180–3184. doi:10.2337/db06-0407

    CAS  Article  PubMed  Google Scholar 

  22. Murea M, Ma L, Freedman BI (2012) Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud 9:6–22. doi:10.1900/RDS.2012.9.6

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jeong DJ, Lee DG, Kim H-J et al (2010) ENPP1 K121Q genotype not associated with coronary artery calcification in Korean patients with type 2 diabetes mellitus. Korean Diabetes J 34:320–326. doi:10.4093/kdj.2010.34.5.320

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Professor M Radhakrishna Pillai, Director, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram for providing funding and facilities for conducting this study. We also thank Dr. N S Pratapchandran and Dr. K R Santosh for providing patient samples. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Sumi S thankfully acknowledge DST WOS-A (SR/WOS-A/LS-1017/2014(G)) for research fellowship.

Authors’ contributions

SS, SR, and CCK conceived and designed the experiments, MMP, SS, and SR performed the experiments, VRK and ATN performed statistical analysis of data, VRK, AM, CCK provided reagents, materials, analysis tools, SS and SR prepared manuscript, AM and CCK critical review of manuscript. All authors read and approved the final manuscript.

Author information

Author notes

  1. S. Sumi and Surya Ramachandran have contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India

    S. Sumi, Surya Ramachandran, Maulin M. Patel & C. C. Kartha

  2. Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

    V RamanKutty & T. N. Anand

  3. Madras Medical Mission, Chennai, Tamil Nadu, India

    Ajit S Mullasari

Authors
  1. S. Sumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Surya Ramachandran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V RamanKutty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maulin M. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. N. Anand
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ajit S Mullasari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. C. Kartha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. C. Kartha.

Ethics declarations

Conflict of interest

All authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this research article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 227 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sumi, S., Ramachandran, S., RamanKutty, V. et al. ENPP1 121Q functional variant enhances susceptibility to coronary artery disease in South Indian patients with type 2 diabetes mellitus. Mol Cell Biochem 435, 67–72 (2017). https://doi.org/10.1007/s11010-017-3057-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3057-2

Keywords

  • Coronary artery disease
  • Type 2 diabetes mellitus
  • Prevalence
  • Polymorphism
  • ENPP1
  • South India