Nanayakkara Shanika, Senevirathna S T M L D, Parahitiyawa Nipuna B, Abeysekera Tilak, Chandrajith Rohana, Ratnatunga Neelakanthi, Hitomi Toshiaki, Kobayashi Hatasu, Harada Kouji H, Koizumi Akio
Institute of Dental Research, Faculty of Dentistry, University of Sydney, Sydney, Australia,
Environ Health Prev Med. 2015 Sep;20(5):354-9. doi: 10.1007/s12199-015-0475-1. Epub 2015 Jun 25.
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.
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.
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.
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.
在斯里兰卡中北部地区以肾小管间质损伤为特征的病因不明的慢性肾脏病（CKDu）中观察到的家族聚集现象强烈提示遗传因素参与其发病机制。本研究的目的是使用全外显子组测序来鉴定与CKDu相关的基因变异。
对8例CKDu病例和8例对照进行全外显子组测序，随后对301例CKDu病例和276例对照的候选位点进行直接测序。
关联研究显示，位于编码电压门控钾通道的KCNA10基因中的rs34970857（c.658G>A/p.V220M）是最有前景的单核苷酸多态性（SNP），优势比最高为1.74。在编码层粘连蛋白β2（LAMB2）的基因中鉴定出4个罕见变异，已知该基因会导致先天性肾病综合征。LAMB2基因的4个变异中有3个是仅在病例中发现的新变异。
遗传学研究为CKDu存在遗传易感性提供了有力证据。也提示了该人群中可能存在几种与CKDu相关的罕见变异。
