Environmental Health and Preventive Medicine

, Volume 20, Issue 5, pp 354–359

Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region, Sri Lanka

  • Shanika Nanayakkara
  • STMLD Senevirathna
  • Nipuna B. Parahitiyawa
  • Tilak Abeysekera
  • Rohana Chandrajith
  • Neelakanthi Ratnatunga
  • Toshiaki Hitomi
  • Hatasu Kobayashi
  • Kouji H. Harada
  • Akio Koizumi
Regular Article

Abstract

Objectives

The familial clustering observed in chronic kidney disease of uncertain etiology (CKDu) characterized by tubulointerstitial damages in the North Central Region of Sri Lanka strongly suggests the involvement of genetic factors in its pathogenesis. The objective of the present study is to use whole-exome sequencing to identify the genetic variants associated with CKDu.

Methods

Whole-exome sequencing of eight CKDu cases and eight controls was performed, followed by direct sequencing of candidate loci in 301 CKDu cases and 276 controls.

Results

Association study revealed rs34970857 (c.658G > A/p.V220M) located in the KCNA10 gene encoding a voltage-gated K channel as the most promising SNP with the highest odds ratio of 1.74. Four rare variants were identified in gene encoding Laminin beta2 (LAMB2) which is known to cause congenital nephrotic syndrome. Three out of four variants in LAMB2 were novel variants found exclusively in cases.

Conclusion

Genetic investigations provide strong evidence on the presence of genetic susceptibility for CKDu. Possibility of presence of several rare variants associated with CKDu in this population is also suggested.

Keywords

Chronic kidney disease Sri Lanka KCNA10 LAMB2 Genetic susceptibility 

References

  1. 1.
    Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, et al. Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007;72(3):247–59.CrossRefPubMedGoogle Scholar
  2. 2.
    Schieppati A, Remuzzi G. Chronic renal diseases as a public health problem: epidemiology, social, and economic implications. Kidney Int Suppl. 2005;98:S7–10.CrossRefPubMedGoogle Scholar
  3. 3.
    Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet. 2010;42(5):376–84.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Nanayakkara S, Senevirathna ST, Karunaratne U, Chandrajith R, Harada KH, Hitomi T, et al. Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: a cross-sectional study. Environ Health Prev Med. 2012;17(2):109–17.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Athuraliya NT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, Karunaratne U, et al. Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney Int. 2011;80(11):1212–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Jayatilake N, Mendis S, Maheepala P. Mehta FR; CKDu National Research Project Team. Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. BMC Nephrol. 2013;14:180.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Bandara JM, Wijewardena HV, Liyanege J, Upul MA, Bandara JM. Chronic renal failure in Sri Lanka caused by elevated dietary cadmium: trojan horse of the green revolution. Toxicol Lett. 2012;198(1):33–9.CrossRefGoogle Scholar
  8. 8.
    Chandrajith R, Nanayakkara S, Itai K, Aturaliya TN, Dissanayake CB, Abeysekera T, et al. Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution and environmental implications. Environ Geochem Health. 2011;33(3):267–78.CrossRefPubMedGoogle Scholar
  9. 9.
    Wimalawansa SJ. Escalating chronic kidney diseases of multi-factorial origin in Sri Lanka: causes, solutions, and recommendations. Environ Health Prev Med. 2014;19(6):375–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Ileperuma OA, Dharmagunawardhane HA, Herath KPRP. Dissolution of aluminium from sub-standard utensils under high fluoride stress: a possible risk factor for chronic renal failure in the North Central Province. J Natl Sci Found Sri Lanka. 2009;37(3):219–22.Google Scholar
  11. 11.
    Wickremasinghe AR, Peiris-John RJ, Wanigasuriya KP. Chronic kidney disease of unknown aetiology in the North Central Province of Sri Lanka: trying to unravel the mystery. Ceylon Med J. 2011;56(4):143–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R, Hittarage A. Chronic renal failure in North Central Province of Sri Lanka: an environmentally induced disease. Trans R Soc Trop Med Hyg. 2007;101:1013–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Nanayakkara S, Senevirathna S, Abeysekera T, Chandrajith R, Ratnatunga N, Gunarathne E, et al. An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the north central region of Sri Lanka. J Occup Health. 2014;56(1):28–38.CrossRefPubMedGoogle Scholar
  14. 14.
    Casto AM, Feldman MW. Genome-wide association study SNPs in the human genome diversity project populations: does selection affect unlinked SNPs with shared trait associations? PLoS Genet. 2011;7(1):e1001266.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Majewski J, Schwartzentruber J, Lalonde E, Montpetit A, Jabado N. What can exome sequencing do for you? J Med Genet. 2011;48(9):580–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler Transform. Bioinformatics. 2009;25:1754–60.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler Transform. Bioinformatics. 2010;26:589–95.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–303.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001;11(5):863–74.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Liu DJ, Leal SM. A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions. PLoS Genet. 2010;6(10):e1001156.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Dai B, David V, Martin A, Huang J, Li H, Jiao Y, et al. Comparative Transcriptome Analysis Identifying FGF23 Regulated Genes in the Kidney of a Mouse CKD Model. PLoS One. 2012;7(9):e44161.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Liu CT, Garnaas MK, Tin A, Kottgen A, Franceschini N, Peralta CA, et al. Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. PLoS Genet. 2011;7(9):e1002264.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Köttgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet. 2009;41(6):712–7.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Abid A, Khaliq S, Shahid S, Lanewala A, Mubarak M, Hashmi S, et al. A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan. Gene. 2012;502(2):133–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Bostrom MA, Perlegas P, Lu L, Hicks PJ, Hawkins G, Ng MC, et al. Relevance of the ACTN4 Gene in African-Americans with non-diabetic end-stage renal disease. Am J Nephrol. 2012;36(3):252–60.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Putaala H, Soininen R, Kilpeläinen P, Wartiovaara J, Tryggvason K. The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet. 2001;10(1):1–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Thilo F, Liu Y, Loddenkemper C, Schuelein R, Schmidt A, Yan Z, et al. VEGF regulates TRPC6 channels in podocytes. Nephrol Dial Transplant. 2012;27(3):921–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Matejas V, Hinkes B, Alkandari F, Al-Gazali L, Annexstad E, Aytac MB, et al. Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum Mutat. 2010;31(9):992–1002.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Chen YM, Kikkawa Y, Miner JH. A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion. J Am Soc Nephrol. 2011;22(5):849–58.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Mallela J, Yang J, Shariat-Madar Z. Prolylcarboxypeptidase: a cardioprotective enzyme. Int J Biochem Cell Biol. 2009;41(3):477–81.CrossRefPubMedGoogle Scholar
  32. 32.
    Grand T, L’Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T, et al. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat. 2011;32(4):476–83.CrossRefPubMedGoogle Scholar
  33. 33.
    Monnens L, Levtchenko E. Evaluation of the proximal tubular function in hereditary renal Fanconi syndrome. Nephrol Dial Transplant. 2008;23(9):2719–22.CrossRefPubMedGoogle Scholar
  34. 34.
    Servais A, Morinière V, Grünfeld JP, Noël LH, Goujon JM, Chadefaux-Vekemans B, et al. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008;3(1):27–35.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Bisceglia L, Fischetti L, Bonis PD, Palumbo O, Augello B, Stanziale P, et al. Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients. Mol Genet Metab. 2010;99(1):42–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Igarashi T, Inatomi J, Sekine T, Cha SH, Kanai Y, Kunimi M, et al. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 1999;23(3):264–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial. 2007;20(3):229–36.CrossRefPubMedGoogle Scholar
  38. 38.
    Böger CA, Heid IM. Chronic kidney disease: novel insights from genome-wide association studies. Kidney Blood Press Res. 2011;34(4):225–34.CrossRefPubMedGoogle Scholar
  39. 39.
    Lang R, Lee G, Liu W, Tian S, Rafi H, Orias M, et al. KCNA10: a novel ion channel functionally related to both voltage-gated potassium and CNG cation channels. Am J Physiol Renal Physiol. 2000;278(6):F1013–21.PubMedGoogle Scholar
  40. 40.
    Yao X, Tian S, Chan HY, Biemesderfer D, Desir GV. Expression of KCNA10, a voltage-gated K channel, in glomerular endothelium and at the apical membrane of the renal proximal tubule. J Am Soc Nephrol. 2002;13(12):2831–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Köhler R, Ruth P. Endothelial dysfunction and blood pressure alterations in K + -channel transgenic mice. Pflugers Arch. 2010;459(6):969–76.CrossRefPubMedGoogle Scholar
  42. 42.
    Simino J, Shi G, Arnett D, Broeckel U, Hunt SC, Rao DC. Variants on Chromosome 6p22.3 Associated with Blood Pressure in the HyperGEN Study: follow-up of FBPP Quantitative Trait Loci. Am J Hypertens. 2011;24(11):1227–33.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Senevirathna L, Abeysekera T, Nanayakkara S, Chandrajith R, Ratnatunga N, Harada KH, et al. Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya. Sri Lanka. Environ Health Prev Med. 2011;17(3):191–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Chen YM, Zhou Y, Go G, Marmerstein JT, Kikkawa Y, Miner JH. Laminin β2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am SocNephrol. 2013;24(8):1223–33.Google Scholar
  45. 45.
    Chen YM, Kikkawa Y, Miner JH. A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion. J Am Soc Nephrol. 2009;22(5):849–58.CrossRefGoogle Scholar

Copyright information

© The Japanese Society for Hygiene 2015

Authors and Affiliations

  • Shanika Nanayakkara
    • 1
  • STMLD Senevirathna
    • 2
  • Nipuna B. Parahitiyawa
    • 3
  • Tilak Abeysekera
    • 4
  • Rohana Chandrajith
    • 5
  • Neelakanthi Ratnatunga
    • 6
  • Toshiaki Hitomi
    • 7
  • Hatasu Kobayashi
    • 7
  • Kouji H. Harada
    • 7
  • Akio Koizumi
    • 7
  1. 1.Institute of Dental Research, Faculty of DentistryUniversity of SydneySydneyAustralia
  2. 2.School of Computing, Engineering and MathematicsUniversity of Western SydneySydneyAustralia
  3. 3.School of Pathology and Laboratory MedicineThe University of Western AustraliaPerthAustralia
  4. 4.Department of Pharmacology, Faculty of MedicineUniversity of PeradeniyaPeradeniyaSri Lanka
  5. 5.Department of Geology, Faculty of ScienceUniversity of PeradeniyaPeradeniyaSri Lanka
  6. 6.Department of Pathology, Faculty of MedicineUniversity of PeradeniyaPeradeniyaSri Lanka
  7. 7.Department of Health and Environmental Sciences, Graduate School of MedicineKyoto UniversityKyotoJapan

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