Association of Variants inPLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung's Disease in Han Chinese Population
Association of Variants inPLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung's Disease in Han Chinese Population
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中国汉族人群中 PLD1、3p24.1 和 10q11.21 区域变异与先天性巨结肠的关联
DOI：
10.3389/fgene.2020.00738
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发表时间：
2020-07-10
影响因子：
3.7
通讯作者：
Chu, Xun
中科院分区：
文献类型：
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作者：
Niu, Wei-Bo;Bai, Mei-Rong;Chu, Xun
背景和目的：先天性巨结肠症（HSCR）是一种罕见的遗传异质性先天性疾病。最近的一项基于全基因组测序的研究表明，四个新位点的常见变异与HSCR易感性相关，其中包括CASQ 2和PLD 1上的两个内含子变异，以及位于SLC 4A 7和EOMESat 3p24.1之间和10q11.21处的LINC 01518和LOC 283028之间的基因间变异。为了验证这些关联与HSCR的易感性，我们进行了一项病例对照研究，在中国汉族样本集。方法：我们选择了四个先前确定的单核苷酸多态性（SNP）进行复制，沿着标签SNP覆盖四个相关区域。在420例HSCR患者和1，665名健康对照中，共检测了61个SNP。结果：CASQ 2基因区域的14个标签SNPs（包括先前关联的rs 9428225）均未显示与HSCR相关。在SLC 4A 7-EOMES区域3p24.1的24个标签SNP中，rs 2642925 [比值比（OR）= 1.41，95%置信区间（95%CI）= 1.10-1.79;P-additive= 0.007]和先前相关的SNP rs 9851320显示出提示性关联（OR = 1.22，95%CI = 1.01-1.47; P-加性= 0.042）。PLD 1中的一个非同义SNP rs 2287579与HSCR易感性相关（OR = 1.71，95%CI = 1.18-2.46;P-additive= 0.004）。此外，与PLD 1 SNP rs 12632766相关的OR = 1.20，95%CI = 1.01- 1.42，P-Additive= 0.038。在10q11.21的LINC 01518-LOC 283028区域中，三个SNP符合研究范围内的显著性阈值。Rs 17153309是最相关的SNP（OR = 1.60，95%CI = 1.34-1.90; P-加性= 1.13 x 10（-7））。先前关联的SNP rs 1414027也显示出显著关联（OR = 1.43，95%CI = 1.20- 1.70，P-Additive= 3.92 × 10（-5））。10q11.21处的两个相关SNP（rs 1414027和rs624804）是GTEx数据库中消化道组织中的表达数量性状位点。结论：我们的研究结果证实LINC 01518-LOC 283028区域的变异与中国汉族人群的HSCR相关。此外，LINC 01518-LOC 283028区域内SNPs的易感性与邻近基因的表达水平相关。这些结果为HSCR的发病机制提供了新的见解。
Background and Aims:Hirschsprung's disease (HSCR) is a rare genetically heterogeneous congenital disorder. A recent study based on whole genome sequencing demonstrated that common variants at four novel loci, which contained two intronic variants onCASQ2andPLD1, and intergenic variants located betweenSLC4A7andEOMESat 3p24.1, and betweenLINC01518andLOC283028at 10q11.21, were associated with HSCR susceptibility. To validate these associations with HSCR susceptibility, we performed a case-control study in a Han Chinese sample set. Methods:We selected four previously identified single nucleotide polymorphisms (SNPs) for replication, along with tag SNPs to cover the four associated regions. In total, 61 SNPs were genotyped in 420 HSCR patients and 1,665 healthy controls from the Han Chinese population. Results:None of the 14 tag SNPs in theCASQ2gene region, including the previously associated rs9428225, showed an association with HSCR. Among the 24 tag SNPs from theSLC4A7-EOMESregion at 3p24.1, rs2642925 [odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 1.10-1.79;P-Additive= 0.007] and the previously associated SNP rs9851320 showed a suggestive association (OR = 1.22, 95% CI = 1.01-1.47;P-Additive= 0.042). A non-synonymous SNP, rs2287579, inPLD1showed a suggestive association with HSCR susceptibility (OR = 1.71, 95% CI = 1.18-2.46;P-Additive= 0.004). Additionally, the previously associatedPLD1SNP rs12632766 showed a suggestive significance (OR = 1.20, 95% CI = 1.01-1.42,P-Additive= 0.038). In theLINC01518-LOC283028region at 10q11.21, three SNPs meet the study-wide significance threshold. Rs17153309 was the most associated SNP (OR = 1.60, 95% CI = 1.34-1.90;P-Additive= 1.13 x 10(-7)). The previously associated SNP rs1414027 also showed significant association (OR = 1.43, 95% CI = 1.20-1.70,P-Additive= 3.92 x 10(-5)). Two associated SNPs at 10q11.21 (rs1414027 and rs624804) were expression quantitative trait loci in digestive tract tissues from GTEx databases. Conclusions:Our results confirmed that variants of theLINC01518-LOC283028region were associated with HSCR in the Han Chinese population. Additionally, the susceptibility of SNPs in theLINC01518-LOC283028region were associated with the expression levels of nearby genes. These results provide new insight into the pathogenesis of HSCR.