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Environmental Health and Preventive Medicine

Published in:

01-09-2015 | Regular Article

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

Authors: Shanika Nanayakkara, STMLD Senevirathna, Nipuna B. Parahitiyawa, Tilak Abeysekera, Rohana Chandrajith, Neelakanthi Ratnatunga, Toshiaki Hitomi, Hatasu Kobayashi, Kouji H. Harada, Akio Koizumi

Published in: Environmental Health and Preventive Medicine | Issue 5/2015

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.

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.CrossRefPubMed

Schieppati A, Remuzzi G. Chronic renal diseases as a public health problem: epidemiology, social, and economic implications. Kidney Int Suppl. 2005;98:S7–10.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

16.

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler Transform. Bioinformatics. 2009;25:1754–60.PubMedCentralCrossRefPubMed

17.

Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler Transform. Bioinformatics. 2010;26:589–95.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

19.

Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001;11(5):863–74.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

31.

Mallela J, Yang J, Shariat-Madar Z. Prolylcarboxypeptidase: a cardioprotective enzyme. Int J Biochem Cell Biol. 2009;41(3):477–81.CrossRefPubMed

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.CrossRefPubMed

33.

Monnens L, Levtchenko E. Evaluation of the proximal tubular function in hereditary renal Fanconi syndrome. Nephrol Dial Transplant. 2008;23(9):2719–22.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

37.

Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial. 2007;20(3):229–36.CrossRefPubMed

38.

Böger CA, Heid IM. Chronic kidney disease: novel insights from genome-wide association studies. Kidney Blood Press Res. 2011;34(4):225–34.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

41.

Köhler R, Ruth P. Endothelial dysfunction and blood pressure alterations in K + -channel transgenic mice. Pflugers Arch. 2010;459(6):969–76.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRef

Title: Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region, Sri Lanka
Authors: Shanika Nanayakkara
STMLD Senevirathna
Nipuna B. Parahitiyawa
Tilak Abeysekera
Rohana Chandrajith
Neelakanthi Ratnatunga
Toshiaki Hitomi
Hatasu Kobayashi
Kouji H. Harada
Akio Koizumi
Publication date: 01-09-2015
Publisher: Springer Japan
Published in: Environmental Health and Preventive Medicine / Issue 5/2015
Print ISSN: 1342-078X
Electronic ISSN: 1347-4715
DOI: https://doi.org/10.1007/s12199-015-0475-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

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