Skip to main content

Advertisement

SpringerLink
Log in

Susceptibility gene search for nephropathy and related traits in Mexican–Americans

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican–Americans. Mexican–Americans with type 2 diabetes (T2DM) are three times more likely to develop microalbuminuria, and four times more likely to develop clinical proteinuria compared to non-Hispanic whites. Furthermore, Mexican–Americans have a sixfold increased risk of developing renal failure secondary to T2DM compared to Caucasians. Prevention and better treatment of DN should be a high priority for both health-care organizations and society at large. Pathogenesis of DN is multi-factorial. Familial clustering of DN-related traits in MAs show that DN and related traits are heritable and that genes play a susceptibility role. While, there has been some progress in identifying genes which when mutated influence an individual’s risk, major gene(s) responsible for DN are yet to be identified. Knowledge of the genetic causes of DN is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Self-identification and collaboration among researchers with suitable genomic and clinical data for meta-analyses in Mexican–Americans is critical for progress in replicating/identifying DN risk genes in this population. This paper reviews the approaches and recent efforts made to identify genetic variants contributing to risk for DN and related phenotypes in the Mexican–American population.

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

Similar content being viewed by others

References

  1. Burrows NR, Ki Y, Geiss LS (2010) Incidence of treatment for end-stage renal disease among individuals with diabetes in the US continues to decline. Diabetes Care 33:73–77

    Article  PubMed  Google Scholar 

  2. Palmer ND, Freedman BI (2012) Insights into the genetic architecture of diabetic nephropathy. Curr Diab Rep 12:423–431

    Article  PubMed  Google Scholar 

  3. Ventura H, Piña IL, Lavie CJ (2011) Hypertension and antihypertensive therapy in Hispanics and Mexican Americans living in the United States. Postgrad Med 123:46–57

    Article  PubMed  Google Scholar 

  4. Cusi K, Ocampo GL (2011) Unmet needs in Hispanic/Latino patients with type 2 diabetes mellitus. Am J Med 124:S2–S9

    Article  PubMed  Google Scholar 

  5. Garza R, Medina R, Basu S, Pugh JA (1997) Predictors of the rate of renal function decline in non-insulin-dependent diabetes mellitus. Am J Nephrol 17:59–67

    Article  PubMed  CAS  Google Scholar 

  6. Pugh JA, Medina RA, Cornell JC, Basu S (1995) NIDDM is the major cause of diabetic end-stage renal disease. More evidence from a tri-ethnic community. Diabetes 44:1375–1380

    Article  PubMed  CAS  Google Scholar 

  7. Pugh JA (1996) Diabetic nephropathy and end-stage renal disease in Mexican Americans. Blood Purif 14:286–292

    Article  PubMed  CAS  Google Scholar 

  8. Bhandari K, Duggirala R, Kawalitt I, Arya R et al (2001) Genome-wide search for albuminuria susceptibility genes in Mexican Americans. Diabetes 50:A240–A241

    Google Scholar 

  9. Puppala S, Arya R, Thameem F, Arar NH et al (2007) Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans. Diabetes 56:2818–2828

    Article  PubMed  CAS  Google Scholar 

  10. Arar NH, Voruganti SV, Nath SD, Thameem F et al (2008) A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS. Nephrol Dial Transplant 23:3184–3191

    Article  PubMed  CAS  Google Scholar 

  11. Schelling JR, Abboud HE, Nicholas SB, Family Investigation of Nephropathy and Diabetes Research Group et al (2008) Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 57:235–243

    Article  PubMed  CAS  Google Scholar 

  12. Forsblom CM, Kanninen T, Lehtovitra M, Saloranta C et al (1999) Heritability of albumin excretion rate in families of patients with type II diabetes. Diabetologia 42:1359–1366

    Article  PubMed  CAS  Google Scholar 

  13. Krolewski AS, Poznik GD, Placha G, Canani L et al (2006) A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes. Kidney Int 69:129–136

    Article  PubMed  CAS  Google Scholar 

  14. Kiryluk K (2008) Quantitative genetics of renal function: tackling complexities of the eGFR phenotype in gene mapping studies. Kidney Int 74:1109–1112

    Article  PubMed  CAS  Google Scholar 

  15. Knowler WC, Coresh J, Elston RC, Family Investigation of Nephropathy and Diabetes Research Group (2005) The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. J Diabetes Complications 19:1–9

    Article  PubMed  Google Scholar 

  16. Iyengar SK, Abboud HE, Goddard KA, Family Investigation of Nephropathy and Diabetes Research Group et al (2007) Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 56:1577–1585

    Article  PubMed  CAS  Google Scholar 

  17. Imperatore G, Hanson RL, Pettitt DJ, Kobes S et al (1998) Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47:821–830

    Article  PubMed  CAS  Google Scholar 

  18. Vardarli I, Baier LJ, Hanson RL, Akkoyun I et al (2002) Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23. Kidney Int 62:2176–2183

    Article  PubMed  CAS  Google Scholar 

  19. Bowden DW, Colicigno CJ, Langefeld CD, Sale MM et al (2004) A genome scan for diabetic nephropathy in African Americans. Kidney Int 66:1517–1526

    Article  PubMed  CAS  Google Scholar 

  20. Igo RP Jr, Iyengar SK, Nicholas SB, Goddard KA et al (2011) Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study. Am J Nephrol 33:381–389

    Article  PubMed  Google Scholar 

  21. Kao WH, Klag MJ, Meoni LA, Reich D et al (2008) MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40:1185–1192

    Article  PubMed  CAS  Google Scholar 

  22. Kopp JB, Smith MW, Nelson GW, Johnson RC et al (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175–1184

    Article  PubMed  CAS  Google Scholar 

  23. Freedman BI, Hicks PJ, Bostrom MA, Comeau ME et al (2009) Non-muscle myosin heavy chain 9 gene MYH9 associations in African Americans with clinically diagnosed type 2 diabetes mellitus-associated ESRD. Nephrol Dial Transplant 24:3366–3371

    Article  PubMed  CAS  Google Scholar 

  24. Genovese G, Tonna SJ, Knob AU, Appel GB et al (2010) A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. Kidney Int 78:698–704

    Article  PubMed  Google Scholar 

  25. McDonough CW, Palmer ND, Hicks PJ, Roh BH et al (2011) A genome-wide association study for diabetic nephropathy genes in African Americans. Kidney Int 79:563–572

    Article  PubMed  Google Scholar 

  26. Puppala S, Dodd GD, Fowler S, Arya R et al (2006) A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans. Am J Hum Genet 78:377–392

    Article  PubMed  CAS  Google Scholar 

  27. Lehman DM, Leach RJ, Johnson-Pais T, Hamlington J et al (2006) Evaluation of tight junction protein 1 encoding zona occludens 1 as a candidate gene for albuminuria in a Mexican American population. Exp Clin Endocrinol Diabetes 114:432–437

    Article  PubMed  CAS  Google Scholar 

  28. Thameem F, Puppala S, He X, Arar NH et al (2009) Evaluation of Gremlin1 (GREM1) as a candidate susceptibility gene for albuminuria-related traits in Mexican Americans with type 2 diabetes. Metabolism 58:1496–1502

    Article  PubMed  CAS  Google Scholar 

  29. MacCluer JW, Stern MP, Almasy L, Atwood LA et al (1999) Genetics of atherosclerosis risk factors in Mexican Americans. Nutr Rev 57:S59–S65

    Article  PubMed  CAS  Google Scholar 

  30. Arar N, Nath S, Thameem F, Bauer R et al (2007) Genome-wide scans for microalbuminuria in Mexican Americans: the San Antonio Family Heart Study. Genet Med 9:80–87

    Article  PubMed  CAS  Google Scholar 

  31. Shike T, Gohda T, Tanimoto M, Kobayashi et al (2005) Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice. Nephrol Dial Transplant 20:879–885

    Article  PubMed  CAS  Google Scholar 

  32. Klupa T, Malecki MT, Pezzolesi M, Ji L et al (2000) Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes 49:2212–2216

    Article  PubMed  CAS  Google Scholar 

  33. Permutt MA, Wasson J, Love-Gregory L, Ma J et al (2002) Searching for type 2 diabetes genes on chromosome 20. Diabetes 51:S308–S315

    Article  PubMed  CAS  Google Scholar 

  34. Ryffel GU (2001) Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol 27:11–29

    Article  PubMed  CAS  Google Scholar 

  35. Niehof M, Borlak J (2008) HNF4 alpha and the Ca-channel TRPC1 are novel disease candidate genes in diabetic nephropathy. Diabetes 57:1069–1077

    Article  PubMed  CAS  Google Scholar 

  36. Mooyaart AL, Valk EJ, van Es LA, Bruijn JA et al (2011) Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 54:544–553

    Article  PubMed  CAS  Google Scholar 

  37. Thameem F, Puppala S, Schneider J, Bhandari BK et al (2012) The Gly(972)Arg variant of Human Insulin Receptor Substrate 1 (IRS1) gene is associated with variation in glomerular filtration rate (GFR) likely through impaired insulin receptor signaling. Diabetes 61:2385–2393

    Article  PubMed  CAS  Google Scholar 

  38. Köttgen A, Pattaro C, Böger CA, Fuchsberger C et al (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42:376–384

    Article  PubMed  Google Scholar 

  39. Leak TS, Perlegas PS, Smith SG, Keene KL et al (2009) Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. Ann Hum Genet 73:152–159

    Article  PubMed  CAS  Google Scholar 

  40. Hanson RL, Millis MP, Young NJ, Kobes S et al (2010) ELMO1 variants and susceptibility to diabetic nephropathy in American Indians. Mol Genet Metab 101:383–390

    Article  PubMed  CAS  Google Scholar 

  41. Ahluwalia TS, Lindholm E, Groop LC (2011) Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes. Diabetologia 54:2295–2302

    Article  PubMed  CAS  Google Scholar 

  42. Kim S, Abboud HE, Pahl MV, Tayek J et al (2010) Examination of association with candidate genes for diabetic nephropathy in a Mexican American population. Clin J Am Soc Nephrol 5:1072–1078

    Article  PubMed  CAS  Google Scholar 

  43. Wong C, Kanetsky P, Raj D (2008) Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease. Pediatr Nephrol 23:1037–1051

    Article  PubMed  Google Scholar 

  44. Thameem F, Puppala S, Arar N, Blangero J et al (2008) Genetic polymorphisms in the renin-angiotensin system (RAS) genes and their association analysis with type 2 diabetes and related traits in Mexican Americans. Diabetes Res Clin Pract 79:e14–e16

    Article  PubMed  CAS  Google Scholar 

  45. Thameem F, Voruganti VS, He X, Nath SD et al (2009) Genetic variants in the renin-angiotensin system genes are associated with cardiovascular-renal-related risk factors in Mexican Americans. Hum Genet 124:557–559

    Article  Google Scholar 

  46. Zeng Z, Li L, Zhang Z, Li Y et al (2010) A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy. Hum Genet 127:373–381

    Article  PubMed  CAS  Google Scholar 

  47. Thameem F, Puppala S, Arar NH, Stern MP et al (2008) Endothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans. Diab Vasc Dis Res 5:109–113

    Article  PubMed  Google Scholar 

  48. Nath SD, He X, Voruganti VS, Blangero J et al (2009) The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans. Mol Cell Biochem 331:201–205

    Article  PubMed  CAS  Google Scholar 

  49. Calle R, McCarthy MI, Banerjee P, Zeggini E et al (2006) Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76. Diabetologia 49:2892–2899

    Article  PubMed  CAS  Google Scholar 

  50. Thameem F, Puppala S, Arar NH, Farook VS et al (2008) The Cys(311)Ser polymorphism of paraoxonase 2 (PON2) is associated with albumin-to-creatinine ratio (ACR) in Mexican Americans. Nephrol Dial Transplant 23:416–417

    Article  PubMed  CAS  Google Scholar 

  51. Thameem F, He X, Voruganti VS, Nath SD et al (2009) Evaluation of polymorphisms in paraoxonase 2 (PON2) gene and their association with cardiovascular-renal disease risk in Mexican Americans. Kidney Blood Press Res 32:200–204

    Article  PubMed  CAS  Google Scholar 

  52. Ned RM, Yesupriya A, Imperatore G, Smelser DT et al (2010) Inflammation gene variants and susceptibility to albuminuria in the US population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994. BMC Med Genet 11:155–169

    Article  PubMed  CAS  Google Scholar 

  53. Liberopoulos E, Siamopoulos K, Elisaf M (2004) Apolipoprotein E and renal disease. Am J Kidney Dis 43:223–233

    Article  PubMed  CAS  Google Scholar 

  54. Chu AY, Parekh RS, Astor BC, Coresh J et al (2009) Association of APOE polymorphism with chronic kidney disease in a nationally representative sample: a Third National Health and Nutrition Examination Survey (NHANES III) Genetic Study. BMC Med Genet 10:108

    Article  PubMed  Google Scholar 

  55. Seldin MF, Pasaniuc B, Price AL (2011) New approaches to disease mapping in admixed populations. Nat Rev Genet 12:523–528

    Article  PubMed  CAS  Google Scholar 

  56. Tian C, Hinds DA, Shigeta R, Adler SG et al (2007) A genomewide single-nucleotide-polymorphism panel for Mexican American admixture mapping. Am J Hum Genet 80:1014–1023

    Article  PubMed  CAS  Google Scholar 

  57. Seldin MF, Tian C, Pahl M, The FIND Consortium et al (2008) Identification of chromosomal risk loci for diabetic nephropathy in Mexican-Americans using mapping by admixture linkage disequilibrium: the Family Study of Nephropathy and Diabetes (FIND) Study. JASN 19:57A

    Google Scholar 

  58. Adler S, Pahl M, Abboud H, Nicholas S et al (2010) Mexican-American admixture mapping analyses for diabetic nephropathy in type 2 diabetes mellitus. Semin Nephrol 30:141–149

    Article  PubMed  Google Scholar 

  59. Gibson G (2012) Rare and common variants: twenty arguments. Nat Rev Genet 13:135–145

    Article  PubMed  CAS  Google Scholar 

  60. Wijsman (2012) The role of large pedigrees in an era of high-throughput sequencing. Hum Genet 131:1555–1563

    Article  PubMed  Google Scholar 

  61. Blangero J, Diego VP, Dyer TD, Almeida M et al (2013) A kernel of truth: statistical advances in polygenic variance component models for complex human pedigrees. Adv Genet 81:1–31

    Article  PubMed  CAS  Google Scholar 

  62. Lehman DM, Hamlington J, Hunt KJ, Leach RJ et al (2006) A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family. Diabetes Metab Res Rev 22:331–336

    Article  PubMed  CAS  Google Scholar 

  63. Levey AS, Stevens LA, Schmid CH, Zhang YL et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612

    Article  PubMed  Google Scholar 

  64. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH et al (2012) Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367:20–29

    Article  PubMed  CAS  Google Scholar 

  65. Reddy MA, Natarajan R (2011) Epigenetics in diabetic kidney disease. J Am Soc Nephrol 22:2182–2185

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Grant-in-Aid from the American Heart Association, Carl W. Gottschalk Research Scholar award from the American Society of Nephrology, Norman S. Coplan award from the Satellite Healthcare, San Antonio Area Foundation, and Diabetes Action Research and Education Foundation. This work was also supported by the grants from the National Institute of Diabetes, Digestive and Kidney Diseases (5U01DK085524), VA-Merit Review and the National Center for Research Resources contracts UL1 RR025767 and KL2 RR025766 for the Institute for Integration of Medicine and Science. This work was also supported in part by the National Center for Advancing Translational Science through UCLA CTSI Grant UL1TR000124 and by the National Institute of Diabetes, Digestive, and Kidney Diseases Grants R01 DK071185 and U01 DK57249.

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Farook Thameem, Issa A. Kawalit & Hanna E. Abboud

  2. South Texas Veterans Healthcare System, San Antonio, TX, 78229, USA

    Hanna E. Abboud

  3. Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute, Torrance, CA, 90502, USA

    Sharon G. Adler

  4. Division of Nephrology, Department of Medicine, University of Jordan, Amman, 11942, Jordan

    Issa A. Kawalit

Authors
  1. Farook Thameem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Issa A. Kawalit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharon G. Adler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanna E. Abboud
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farook Thameem.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thameem, F., Kawalit, I.A., Adler, S.G. et al. Susceptibility gene search for nephropathy and related traits in Mexican–Americans. Mol Biol Rep 40, 5769–5779 (2013). https://doi.org/10.1007/s11033-013-2680-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-013-2680-6

Keywords

Search

Navigation