Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To d...Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.展开更多
胶原蛋白XI(collagen type XI,COL11)是一种次要胶原,其主要生理功能是调节主要胶原纤维的直径。COL11A1编码前胶原XI A1和成熟胶原XI A1的α1链,通常存在于软骨中,它在肌肉骨骼性疾病中的致病作用已被证实。但作为肿瘤微环境的重要成...胶原蛋白XI(collagen type XI,COL11)是一种次要胶原,其主要生理功能是调节主要胶原纤维的直径。COL11A1编码前胶原XI A1和成熟胶原XI A1的α1链,通常存在于软骨中,它在肌肉骨骼性疾病中的致病作用已被证实。但作为肿瘤微环境的重要成分之一,COL11A1近年来引发越来越多的关注。研究表明,COL11A1可由癌相关成纤维细胞(CAFs)产生,可促进肿瘤上皮间质转化(EMT),是多种癌症发生、发展的重要因素,与肿瘤侵袭、转移、耐药等有关。本文将着重阐述COL11A1在常见消化系统肿瘤恶性进展中的作用及机制,以期对消化道肿瘤的治疗及后续研究方面提供有价值的参考。展开更多
目的:探讨α1-Ⅺ型胶原蛋白基因(COL11A1)突变对胃癌患者生存结局的影响,并分析其分子生物学机制。方法:利用肿瘤基因组图谱(TCGA)中包含体细胞突变数据和随访信息(包括总生存期、无进展生存期和生存结局)的408例胃癌样本进行COL11A1突...目的:探讨α1-Ⅺ型胶原蛋白基因(COL11A1)突变对胃癌患者生存结局的影响,并分析其分子生物学机制。方法:利用肿瘤基因组图谱(TCGA)中包含体细胞突变数据和随访信息(包括总生存期、无进展生存期和生存结局)的408例胃癌样本进行COL11A1突变的单因素生存分析以及其与肿瘤突变负荷(TMB)相关性的Wilcoxon秩和检验。其中包含年龄、性别、临床分期和组织学分级等临床特征的381例样本用于多因素Cox回归和Logistic回归分析。CIBERSORT算法用于评估COL11A1突变型和野生型样本之间肿瘤浸润免疫细胞比例的差异。基因集富集分析(GSEA)用于确定COL11A1突变样本所富集到的分子信号通路。结果:单因素和多因素生存分析表明,相对于野生型患者,COL11A1突变型胃癌患者具有显著延长的总生存期(Log rank test P=0.015;校正P=0.004)和无进展生存期(Log rank test P=0.083;校正P=0.01)。COL11A1突变型患者比野生型患者具有更高的TM B,差异具有统计学意义(P<0.001),校正临床混杂变量和DNA损伤修复基因的突变等因素后,结果仍具有统计学意义(P<0.001)。CIBERSORT结果显示,COL11A1突变患者具有显著更高的CD8 T细胞、M 1巨噬细胞浸润(P<0.001)以及更低的调控性T细胞浸润比例(P=0.018)。GSEA结果表明,免疫激活相关的信号通路能够显著富集到COL11A1突变患者。结论:COL11A1突变的胃癌患者表现出更好的生存结局,可能与该类患者具有更高的TMB以及更好的肿瘤免疫微环境有关。COL11A1基因可能成为胃癌预后以及免疫治疗的重要分子标志物。展开更多
基金supported by the grant from the Youth National Science Foundation of China (No.31100908)
文摘Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.
文摘胶原蛋白XI(collagen type XI,COL11)是一种次要胶原,其主要生理功能是调节主要胶原纤维的直径。COL11A1编码前胶原XI A1和成熟胶原XI A1的α1链,通常存在于软骨中,它在肌肉骨骼性疾病中的致病作用已被证实。但作为肿瘤微环境的重要成分之一,COL11A1近年来引发越来越多的关注。研究表明,COL11A1可由癌相关成纤维细胞(CAFs)产生,可促进肿瘤上皮间质转化(EMT),是多种癌症发生、发展的重要因素,与肿瘤侵袭、转移、耐药等有关。本文将着重阐述COL11A1在常见消化系统肿瘤恶性进展中的作用及机制,以期对消化道肿瘤的治疗及后续研究方面提供有价值的参考。
文摘目的:探讨α1-Ⅺ型胶原蛋白基因(COL11A1)突变对胃癌患者生存结局的影响,并分析其分子生物学机制。方法:利用肿瘤基因组图谱(TCGA)中包含体细胞突变数据和随访信息(包括总生存期、无进展生存期和生存结局)的408例胃癌样本进行COL11A1突变的单因素生存分析以及其与肿瘤突变负荷(TMB)相关性的Wilcoxon秩和检验。其中包含年龄、性别、临床分期和组织学分级等临床特征的381例样本用于多因素Cox回归和Logistic回归分析。CIBERSORT算法用于评估COL11A1突变型和野生型样本之间肿瘤浸润免疫细胞比例的差异。基因集富集分析(GSEA)用于确定COL11A1突变样本所富集到的分子信号通路。结果:单因素和多因素生存分析表明,相对于野生型患者,COL11A1突变型胃癌患者具有显著延长的总生存期(Log rank test P=0.015;校正P=0.004)和无进展生存期(Log rank test P=0.083;校正P=0.01)。COL11A1突变型患者比野生型患者具有更高的TM B,差异具有统计学意义(P<0.001),校正临床混杂变量和DNA损伤修复基因的突变等因素后,结果仍具有统计学意义(P<0.001)。CIBERSORT结果显示,COL11A1突变患者具有显著更高的CD8 T细胞、M 1巨噬细胞浸润(P<0.001)以及更低的调控性T细胞浸润比例(P=0.018)。GSEA结果表明,免疫激活相关的信号通路能够显著富集到COL11A1突变患者。结论:COL11A1突变的胃癌患者表现出更好的生存结局,可能与该类患者具有更高的TMB以及更好的肿瘤免疫微环境有关。COL11A1基因可能成为胃癌预后以及免疫治疗的重要分子标志物。
