American Journal of Kidney Diseases
Volume 53, Issue 2 , Pages 273-280 , February 2009

Association of the Q121 Variant of ENPP1 Gene With Decreased Kidney Function Among Patients With Type 2 Diabetes

  • Salvatore De Cosmo, MD

      Affiliations

    • Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
    • Corresponding Author InformationAddress correspondence to Salvatore De Cosmo, MD, Endocrinologia, Scientific Institute “Casa Sollievo della Sofferenza” V le Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy
  • ,
  • Antonio Minenna, MD

      Affiliations

    • Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • ,
  • Yuan-Yuan Zhang, PhD

      Affiliations

    • Joslin Diabetes Center, Boston, MA
  • ,
  • Robert Thompson, MD

      Affiliations

    • Joslin Diabetes Center, Boston, MA
  • ,
  • Giuseppe Miscio, PhD

      Affiliations

    • Research Unit of Diabetes and Endocrine Diseases, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • ,
  • Monica Vedovato, MD

      Affiliations

    • Chair of Metabolic Diseases, University of Padova, Padova, Italy
  • ,
  • Anna Rauseo, MD

      Affiliations

    • Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • ,
  • Alois Saller, MD

      Affiliations

    • Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
  • ,
  • Sandra Mastroianno, MD

      Affiliations

    • Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • ,
  • Fabio Pellegrini, MSc

      Affiliations

    • Research Unit of Diabetes and Endocrine Diseases, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
    • Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, S Maria Imbaro, Italy
  • ,
  • Roberto Trevisan, MD

      Affiliations

    • Unit of Diabetes, Ospedali Riuniti of Bergamo, Bergamo, Italy
  • ,
  • Paola Fioretto, MD

      Affiliations

    • Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
  • ,
  • Alessandro Doria, MD

      Affiliations

    • Joslin Diabetes Center, Boston, MA
  • ,
  • Vincenzo Trischitta, MD

      Affiliations

    • Unit of Endocrinology, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
    • Research Unit of Diabetes and Endocrine Diseases, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
    • CSS-Mendel Institute, Sapienza University, Rome, Italy
    • Department of Clinical Sciences, Sapienza University, Rome, Italy
    • Corresponding Author InformationVincenzo Trischitta, MD, Istituto CSS-Mendel, V le R Margherita 261, 00198 Roma, Italy

Received 18 March 2008 ,Accepted 29 July 2008.

References 

  1. He J, Whelton PK. Epidemiology of end-stage renal disease. In:  Brenner BM,  Kurokawa K editor. International Handbook of Renal Disease. Haslemere, UK: Euromed Communications; 1999;p. 1–14
  2. Muntner P, He J, Hamm L, Loria C, Whelton PK. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol. 2002;13:745–753
  3. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32(suppl 3):S112–S119
  4. Langefeld CD, Beck SR, Bowden DW, et al. Heritability of GFR and albumin in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis. 2004;43:796–800
  5. Placha G, Poznik GD, Dunn J, et al. A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes. Diabetes. 2006;55:3358–3365
  6. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med. 2004;140:167–174
  7. De Cosmo S, Trevisan R, Minenna A, et al. Insulin resistance and the cluster of abnormalities related to the metabolic syndrome are associated with reduced glomerular filtration rate in patients with type 2. Diabetes Care. 2006;29:432–434
  8. Almind K, Doria A, Kahn CR. Putting the genes for type II diabetes on the map. Nat Med. 2001;7:277–279
  9. Maddux BA, Sbraccia P, Kumakura S, et al. Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature. 1995;373:448–451
  10. Costanzo BV, Trischitta V, Di Paola R, et al. The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). Diabetes. 2001;50:831–836
  11. Pizzuti A, Frittitta L, Argiolas A, et al. A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes. 1999;48:1881–1884
  12. Frittitta L, Baratta R, Spampinato D, et al. The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance. J Clin Endocrinol Metab. 2001;86:5888–5891
  13. Kubaszek A, Pihlajamaki J, Karhapaa P, Vauhkonen I, Laakso M. The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia. Diabetes Care. 2003;26:464–467
  14. Abate N, Carulli L, Cabo-Chan A, Chandalia M, Snell PG, Grundy SM. Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab. 2003;88:5927–5934
  15. Gonzalez-Sanchez JL, Martinez-Larrad MT, Fernandez-Perez C, Kubaszek A, Laakso M, Serrano-Rios M. K121Q PC-1 gene polymorphism is not associated with insulin resistance in a Spanish population. Obes Res. 2003;11:603–605
  16. Gu HF, Almgren P, Lindholm E, et al. Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis. Diabetes. 2000;49:1601–1603
  17. McAteer JB, Prudente S, Bacci S, et al. ENPP1 Consortium The ENPP1 K121Q polymorphism is associated with type 2 diabetes in European populations: Evidence from an updated meta-analysis in 42,042 subjects. Diabetes. 2008;57:1125–1130
  18. Endler G, Mannhalter C, Sunder-Plassmann H, et al. The K121Q polymorphism in the plasma cell membrane glycoprotein gene predisposes to early myocardial infarction. J Mol Med. 2002;80:791–795
  19. Bacci S, Ludovico O, Prudente S, et al. 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. 2005;54:3021–3025
  20. De Cosmo S, Argiolas A, Miscio G, et al. A PC-1 aminoacid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria. Diabetes. 2000;49:521–524
  21. Canani LH, Ng DP, Smiles A, Rogus JJ, Warram JH, Krolewski AS. Polymorphism in ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes. Diabetes. 2002;51:1188–1193
  22. Jacobsen P, Grarup N, Tarnow L, Pedersen O, Parving HH. PC-1 amino acid variant (K121Q) has no impact on progression of diabetic nephropathy in type 1 diabetic patients. Nephrol Dial Transplant. 2002;17:1408–1412
  23. De Cosmo S, Trevisan R, Della Vestra M, et al. PC-1 amino acid variant Q121 is associated with a lower glomerular filtration rate in type 2 diabetic patients with abnormal albumin excretion rates. Diabetes Care. 2003;26:2898–2902
  24. Boonyasrisawat W, Eberle D, Bacci S, et al. Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes. Diabetes. 2007;56:499–505
  25. De Cosmo S, Minenna A, Ludovico O, et al. Increased urinary albumin excretion, insulin resistance, and related cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care. 2005;28:910–915
  26. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol. 2000;11:155A;(abstr)
  27. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(suppl 2):S1–S180
  28. Higgins JP, Whitehead A, Turner RM, Omar RZ, Thompson SG. Meta-analysis of continuous outcome data from individual patients. Stat Med. 2001;20:2219–2241
  29. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305
  30. Murussi M, Gross JL, Silveiro SP. Glomerular filtration rate changes in normoalbuminuric and microalbuminuric type 2 diabetic patients and normal individuals: A 10-year follow-up. J Diabetes Complications. 2006;20:210–215
  31. Gaede P, Tarnow L, Vedel P, Parving HH, Pedersen O. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol Dial Transplant. 2004;19:2784–2788
  32. Rossing K, Christensen PK, Hovind P, Tarnowe L, Rossing P, Parving H-H. Progression of nephropathy in type 2 diabetic patients. Kidney Int. 2004;66:1596–1605
  33. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55:1832–1839
  34. Placha G, Canani LH, Warram JH, Krolewski AS. Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis. 2005;12:155–169
  35. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia. 1996;39:1569–1576
  36. Bacci S, Menzaghi C, Di Paola R, et al. The ENPP1 Q121 variant plays a role in the susceptibility to increased pulse pressure. Diabetes. 2008;57(suppl 3):S205A;abstr
  37. Meyre D, Bouatia-Naji N, Tounian A, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet. 2005;37:863–867
  38. Bochenski J, Placha G, Wanic K, et al. New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals. Diabetes. 2006;55:2626–2630
  39. Abate N, Chandalia M, Satija P, et al. ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes. Diabetes. 2005;54:1207–1213
  40. Chudleigh RA, Dunseath G, Evans W, et al. How reliable is estimation of glomerular filtration rate at diagnosis of type 2 diabetes?. Diabetes Care. 2007;30:300–305
  41. Rigalleau V, Lasseur C, Raffaitin C, et al. Normoalbuminuric renal insufficient diabetic patients: A lower risk group. Diabetes Care. 2007;30:2034–2039
  42. Böttcher Y, Körner A, Reinehr T, et al. ENPP1 variants and haplotypes predispose to early onset obesity and impaired glucose and insulin metabolism in German obese children. J Clin Endocrinol Metab. 2006;91:4948–4952
  43. Bochenski J, Placha G, Wanic K, et al. New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals. Diabetes. 2006;55:2626–2630
  44. Lyon HN, Florez JC, Bersaglieri T, et al. Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity. Diabetes. 2006;55:3180–3184
  45. Weedon MN, Shields B, Hitman G, et al. No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians. Diabetes. 2006;55:3175–3179
  46. Meyre D, Bouatia-Naji N, Vatin V, et al. ENPP1 K121Q polymorphism and obesity, hyperglycaemia and type 2 diabetes in the prospective DESIR Study. Diabetologia. 2007;50:2090–2096
  47. Keene KL, Mychaleckyj JC, Smith SG, et al. Association of the distal region of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene with type 2 diabetes in an African American population enriched for nephropathy. Diabetes. 2008;57:1057–1062

 Originally published online as doi:10.1053/j.ajkd.2008.07.040 on October 28, 2008.

PII: S0272-6386(08)01298-5

doi: 10.1053/j.ajkd.2008.07.040

American Journal of Kidney Diseases
Volume 53, Issue 2 , Pages 273-280 , February 2009