Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand.
Division of Medical Genetics Research and Laboratory, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Urolithiasis. 2021 Dec;49(6):521-532. doi: 10.1007/s00240-021-01267-1. Epub 2021 May 26.
An interplay of multiple genetic and environmental factors implicates an incidence of human kidney stone disease (KSD). However, the genetic factors associated with KSD are not completely known or understood. To identify KSD-associated genetic variations among the northeastern Thai patients, a genome-wide association study (GWAS) was conducted. We initially employed genotyping of single nucleotide polymorphism (SNP) using Genome-Wide Human SNP Array 6.0 in 105 patients and in 105 normal control subjects. To overcome the limitation of small sample size, we set forth to analyze SNPs as clusters based on the concept of linkage disequilibrium (LD) and haplotype. Using this analysis, 29 genes were identified. Three candidate SNPs, including rs2039415, rs2274907, and rs3747515, were selected on the basis of haplotype analysis, potentially functional SNPs, and the functions of associated genes. Further genotyping of these SNPs in a larger sample size (altogether 216 patients and 216 control subjects) showed that the candidate SNP rs2274907 remained significantly different between case and control subjects in both genotype frequencies (OR 2.44, 95% CI 1.38-4.30; p = 0.0015) and allele frequencies (OR 1.54, 95% CI 1.17-2.03; p = 0.0021). The non-synonymous SNP rs2274907 (c.326T > A) located in exon 4 of the ITLN1 gene results in a substitution of valine (V) by aspartate (D) at position 109 (p.V109D). This substitution could affect the predicted hydrogen (H)-bonds between lysine (K) 107 and glutamine (Q) 104, which supports its association with KSD in this population.
多种遗传和环境因素的相互作用导致了人类肾结石病 (KSD) 的发生。然而，与 KSD 相关的遗传因素尚不完全清楚。为了在泰国东北部患者中鉴定与 KSD 相关的遗传变异，我们进行了全基因组关联研究 (GWAS)。我们最初使用基因组-wide Human SNP Array 6.0 对 105 名患者和 105 名正常对照进行了单核苷酸多态性 (SNP) 的基因分型。为了克服样本量小的限制，我们着手根据连锁不平衡 (LD) 和单倍型的概念分析 SNP 簇。通过这种分析，鉴定出 29 个基因。基于单倍型分析、潜在功能 SNP 和相关基因的功能，选择了三个候选 SNP，包括 rs2039415、rs2274907 和 rs3747515。在更大的样本量（总共 216 名患者和 216 名对照）中进一步对这些 SNP 进行基因分型表明，候选 SNP rs2274907 在病例和对照组之间的基因型频率（OR 2.44，95%CI 1.38-4.30；p=0.0015）和等位基因频率（OR 1.54，95%CI 1.17-2.03；p=0.0021）均显著不同。位于 ITLN1 基因外显子 4 中的非同义 SNP rs2274907 (c.326T > A) 导致第 109 位缬氨酸 (V) 被天冬氨酸 (D) 取代（p.V109D）。这种取代可能会影响赖氨酸 (K) 107 和谷氨酰胺 (Q) 104 之间预测的氢键，这支持它与该人群中 KSD 的关联。
