title: 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.
abstract: OBJECTIVE
  Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis.
  
  
  METHODS
  We conducted a social-environmental-and-genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case-series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha-1 microglobulin in urine.
  
  
  CONCLUSIONS
  None of 18 metals measured (μg//) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75-80% of total urinary As was in the form of arsenobetaine, which is non-toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome-wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome-wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 × 10(-9) in quantitative trait locus analysis; p=3.73 × 10(-9) in dichotomous analysis) in SLC13A3 (sodium-dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non-communicable diseases, suggesting their possible influence on CKDu progression.
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University.
authors.forename: Shanika
authors.initials: S
authors.lastname: Nanayakkara
authors.forename: S T M L D
authors.initials: ST
authors.lastname: Senevirathna
authors.forename: Tilak
authors.initials: T
authors.lastname: Abeysekera
authors.forename: Rohana
authors.initials: R
authors.lastname: Chandrajith
authors.forename: Neelakanthi
authors.initials: N
authors.lastname: Ratnatunga
authors.forename: E D L
authors.initials: ED
authors.lastname: Gunarathne
authors.forename: Junxia
authors.initials: J
authors.lastname: Yan
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Eri
authors.initials: E
authors.lastname: Muso
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Komiya
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.forename: Wanyang
authors.initials: W
authors.lastname: Liu
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawatari
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyataka
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000383:Agriculture / Q000706:statistics & numerical data; D000510:Alpha-Globulins / Q000032:analysis / Q000235:genetics*; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D060766:Drinking Water / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000209:etiology* / Q000235:genetics; D016273:Occupational Exposure / Q000009:adverse effects / Q000706:statistics & numerical data; D029363:Organic Anion Transporters, Sodium-Dependent / Q000032:analysis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D012307:Risk Factors; D013188:Sri Lanka / Q000453:epidemiology; D027981:Symporters / Q000032:analysis; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000652:urine; D055815:Young Adult
chemical_list: D000510:Alpha-Globulins; D015415:Biomarkers; D060766:Drinking Water; D047908:Intracellular Signaling Peptides and Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; C568530:SLC13A3 protein, human; D027981:Symporters; D014874:Water Pollutants, Chemical; C016001:alpha-1-microglobulin; D017346:Protein Serine-Threonine Kinases; C441644:TP53RK protein, human