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
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
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DOI：
10.1539/joh.13-0172-oa
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发表时间：
2014-01-01
影响因子：
3
通讯作者：
Koizumi, Akio
中科院分区：
文献类型：
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作者：
Nanayakkara, Shanika;Stmld, Senevirathna;Koizumi, Akio
目的：先前对斯里兰卡中北部地区（NCR）以肾小管间质损伤（CKDu）为特征的病因不明的慢性肾脏疾病的研究支持其发病机制中涉及社会，环境和遗传因素。研究方法：我们对NCR的男性人群进行了社会环境和遗传流行病学研究，以调查遗传和环境因素。我们招募了311名病例系列患者和504名对照候选人。在504名对照候选人中，218名（43%）因存在高血压、蛋白尿、高HbA 1c、高血清肌酐或尿中高α-1微球蛋白而被排除。结果和讨论：在尿中测定的18种金属（微克/升），包括镉，砷和铅，没有显示出显着较高的浓度与对照组相比，在案件。砷形态分析结果表明，75-80%的尿砷以砷甜菜碱的形式存在，砷甜菜碱对人体无毒。饮用水样品中的金属浓度均未超过指导值。进行了全基因组关联研究（GWAS）以确定遗传贡献者。GWAS在SLC 13 A3（钠依赖性二羧酸转运蛋白成员3）的单核苷酸多态性（SNP; rs6066043;在数量性状基因座分析中p=5.23 x 10（-9）;在二分分析中p=3.73 x 10（-9））方面与CKDu产生了全基因组显著关联。该SNP的人群归因分数和比值比分别为50%和2.13。遗传易感性被确定为CKDu的主要危险因素。然而，43%的表面健康的男性人口患有非传染性疾病，这表明他们对CKDu进展的可能影响。
Objectives: 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. Results and Discussion: None of 18 metals measured (mu g/l) 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 x 10(-9) in quantitative trait locus analysis; p=3.73 x 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.