PDF(Pubmed)
Abstract：
OBJECTIVE: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE.
METHODS: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.
RESULTS: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).
CONCLUSIONS: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.
METHODS: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.
RESULTS: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).
CONCLUSIONS: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.
摘要：
目的：X染色体被认为是SLE的危险因素，这是一种具有显著性别差异的自身免疫性疾病的原型(女性:男性比例约为9:1)。我们的研究旨在探索X染色体遗传变异的关联，并研究X三体在SLE发生发展中的影响。
方法：使用来自泰国（835例SLE患者和2995例对照）和中国人群（1604例SLE患者和3324例对照）的数据进行了X染色体全关联研究。分别在女性和男性中进行关联分析，随后是性别特异性结果的荟萃分析。此外,还检查了SLE女性的X染色体剂量。
结果：我们的分析重复了TMEM187-IRAK1-MECP2、TLR7、PRPS2和GPR173位点与SLE的关联。我们还确定了两个提示与SLE相关的基因座。此外,利用泰国和中国人口之间连锁不平衡的差异，TMEM187中的一个同义变异体被列为可能的因果变异体.这种变体位于免疫相关细胞的活性增强剂中，与TMEM187表达水平降低相关的风险等位基因。更重要的是,我们在2231例SLE女性中的5例（0.22％）中确定了X三体（47，XXX）。频率显着高于女性对照组（0.08％；双侧精确二项检验P=0.002）。
结论：我们的研究证实了X染色体上先前的SLE关联，并确定了两个提示与SLE相关的基因座。更重要的是,我们的研究表明，女性X三体的SLE风险较高。
方法：使用来自泰国（835例SLE患者和2995例对照）和中国人群（1604例SLE患者和3324例对照）的数据进行了X染色体全关联研究。分别在女性和男性中进行关联分析，随后是性别特异性结果的荟萃分析。此外,还检查了SLE女性的X染色体剂量。
结果：我们的分析重复了TMEM187-IRAK1-MECP2、TLR7、PRPS2和GPR173位点与SLE的关联。我们还确定了两个提示与SLE相关的基因座。此外,利用泰国和中国人口之间连锁不平衡的差异，TMEM187中的一个同义变异体被列为可能的因果变异体.这种变体位于免疫相关细胞的活性增强剂中，与TMEM187表达水平降低相关的风险等位基因。更重要的是,我们在2231例SLE女性中的5例（0.22％）中确定了X三体（47，XXX）。频率显着高于女性对照组（0.08％；双侧精确二项检验P=0.002）。
结论：我们的研究证实了X染色体上先前的SLE关联，并确定了两个提示与SLE相关的基因座。更重要的是,我们的研究表明，女性X三体的SLE风险较高。
