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Abstract：
Leukoaraiosis (LA) is a frequent neuroimaging finding commonly observed on brain MRIs of elderly people with prevalence ranging from 50% to 100%. Multiple susceptibility genes or genetic risk factors for LA have been identified in subjects of European descent. Here, we report the first replication study on several common and novel genetic variations in the Chinese population. In this study, a total of 244 subjects (201 LA patients and 43 controls) were enrolled according to our new and strict definition for LA. Subsequently, 6 genetic variants at 5 genes, rs3744028 in TRIM65, rs1055129 in TRIM47, rs1135889 in FBF1, rs1052053 in PMF1, and rs1801133 (C677T) and rs1801131(A1298C) in MTHFR, were selected for genotyping using polymerase chain reaction (PCR)-based pyrosequencing and restriction fragment length polymorphism (RFLP) together with capillary electrophoresis (CE) and agarose gel electrophoresis. Finally, Pearson\'s χ and multivariate logistic regression tests were used to examine the associations between the genotypes and LA. Among these candidate polymorphisms, except for rs1052053 and rs1801131, rs1135889 (P = 0.012) showed significant associations with LA in the dominant model, and the other 3 SNPs, rs3744028 (P = 0.043), rs1055129 (P = 0.038), and rs1801133 (P = 0.027), showed significant associations with LA in the recessive model. However, these differences no longer remained significant after adjusting for age, gender, hypertension, and diabetes mellitus and applying Bonferroni correction or Sidak correction for multiple testing. These results suggest that the above-mentioned genetic variants are not associated with LA risk. In summary, the study did not replicate the susceptibility of rs3744028, rs1055129, and rs1135889 at the Chr17q25 locus for LA nor did it find any other significant results for rs1052053, rs1801133, and rs1801131 in the Chinese population. It strongly indicated the ethnic differences in the genetics of LA. However, the associations of rs3744028 (TRIM65), rs1055129 (TRIM47), rs1135889 (FBF1), and rs1801133 (MTHFR) with LA before Bonferroni correction and Sidak correction for multiple testing are worth highlighting. Thus, we believe that a genome-wide association study and candidate gene association studies are needed to reassess the previous findings and screen novel risk genes for LA in China.
摘要：
脑白质疏松症（LA）是一种常见的神经影像学发现，通常在老年人的脑MRI上观察到，患病率为50％至100％。已经在欧洲血统的受试者中鉴定了LA的多个易感基因或遗传风险因素。这里,我们报道了中国人群中几种常见和新的遗传变异的首次复制研究。在这项研究中,根据我们对LA的新的严格定义,共纳入了244例受试者(201例LA患者和43例对照).随后，5个基因的6个遗传变异，TRIM65中的rs3744028，TRIM47中的rs1055129，FBF1中的rs1135889，PMF1中的rs1052053，以及MTHFR中的rs1801133（C677T）和rs1801131（A1298C），选择使用基于聚合酶链反应（PCR）的焦磷酸测序和限制性片段长度多态性（RFLP）以及毛细管电泳（CE）和琼脂糖凝胶电泳进行基因分型。最后,使用Pearson的χ和多变量逻辑回归检验来检查基因型与LA之间的关联。在这些候选多态性中，除rs1052053和rs1801131外，rs1135889(P=0.012)在显性模型中与LA显著相关，和其他3个SNP，rs3744028(P=0.043),rs1055129(P=0.038),和rs1801133（P=0.027），在隐性模型中与LA显著相关。然而,调整年龄后，这些差异不再显著，性别,高血压,和糖尿病，并应用Bonferroni校正或Sidak校正进行多次测试。这些结果表明，上述遗传变异与LA风险无关。总之,这项研究没有重复rs3744028,rs1055129和rs1135889在Chr17q25位点对LA的易感性,也没有发现rs1052053,rs1801133和rs1801131在中国人群中的其他显著结果.它强烈表明了洛杉矶遗传学的种族差异。然而,RS3744028（TRIM65）的协会，rs1055129(TRIM47),rs1135889(FBF1),和rs1801133（MTHFR）与LA前Bonferroni校正和Sidak校正的多重测试值得强调。因此，我们认为,需要进行全基因组关联研究和候选基因关联研究,以重新评估先前的发现,并筛选中国LA的新风险基因.
