■食管肿瘤的发生、发展与激素变化密切相关。这项研究的目的是从遗传角度研究初潮年龄(AAMA)或绝经年龄(AAMO)与良性食道癌(BON)或恶性食道癌(MON)之间的因果关系。
■从IEUOpenGWAS数据库获得暴露(AAMA和AAMO)和结果(BON和MON)的全基因组关联研究(GWAS)汇总数据。我们在他们之间进行了双样本孟德尔随机化(MR)研究。采用逆方差加权(IVW)作为主要分析方法,而Egger先生,加权中位数,简单模式,加权模式是补充方法。最大可能性,惩罚加权中位数,和IVW(固定效应)是验证方法。我们使用Cochran的Q统计量和Rucker的Q统计量来检测异质性。MREgger的截距测试和MR多效性残差和异常值的全局测试(MR-PRESSO)用于检测水平多效性,MR-PRESSO分析的畸变检验用于检测异常值。留一法分析用于检测MR分析是否受单核苷酸多态性(SNP)的影响。此外,使用MR稳健调整轮廓评分(MR-RAPS)方法评估MR分析的稳健性.
■随机效应IVW结果表明,AAMA与BON具有负遗传因果关系(比值比[OR]=0.285[95%置信区间[CI]:0.130-0.523],P=0.002)。加权中位数,最大似然,惩罚加权中位数,和IVW(固定效应)与随机效应IVW一致(P<0.05)。Egger先生,简单模式和加权模式结果显示AAMA与BON无遗传因果关系(P>0.05)。然而,AAMA与MON之间没有因果关系(OR=1.132[95CI:0.621-2.063],P=0.685),AAMO和BON(OR=0.989[95CI:0.755-1.296],P=0.935),或AAMO和MON(OR=1.129[95CI:0.938-1.359],P=0.200)。Egger先生,加权中位数,简单模式,加权模式,最大似然,惩罚加权中位数,和IVW(固定效应)与随机效应IVW一致(P>0.05)。MR分析结果显示无异质性,水平多效性和异常值(P>0.05)。他们不是由一个SNP驱动的,呈正态分布(P>0.05)。
■只有AAMA与BON具有负的遗传因果关系,AAMA和MON之间不存在遗传因果关系,AAMO和BON,或者AAMO和MON.然而,不能排除它们在遗传学之外的其他层面有关联。
The occurrence and development of oesophageal neoplasia (ON) is closely related to hormone changes. The aim of this study was to investigate the causal relationships between age at menarche (AAMA) or age at menopause (AAMO) and benign oesophageal neoplasia (BON) or malignant oesophageal neoplasia (MON) from a genetic perspective.
Genome-wide association study (GWAS) summary data of exposures (AAMA and AAMO) and outcomes (BON and MON) were obtained from the IEU OpenGWAS database. We performed a two-sample Mendelian randomization (MR) study between them. The inverse variance weighted (IVW) was used as the main analysis method, while the MR Egger, weighted median, simple mode, and weighted mode were supplementary methods. The maximum likelihood, penalized weighted median, and IVW (fixed effects) were validation methods. We used Cochran\'s Q statistic and Rucker\'s Q statistic to detect heterogeneity. The intercept test of the MR Egger and global test of MR pleiotropy residual sum and outlier (MR-PRESSO) were used to detect horizontal pleiotropy, and the distortion test of the MR-PRESSO analysis was used to detect outliers. The leave-one-out analysis was used to detect whether the MR analysis was affected by single nucleotide polymorphisms (SNPs). In addition, the MR robust adjusted profile score (MR-RAPS) method was used to assess the robustness of MR analysis.
The random-effects IVW results showed that AAMA had a negative genetic causal relationship with BON (odds ratio [OR] = 0.285 [95% confidence interval [CI]: 0.130-0.623], P = 0.002). The weighted median, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with random-effects IVW (P < 0.05). The MR Egger, simple mode and weighted mode results showed that AAMA had no genetic causal relationship with BON (P > 0.05). However, there were no causal genetic relationships between AAMA and MON (OR = 1.132 [95%CI: 0.621-2.063], P = 0.685), AAMO and BON (OR = 0.989 [95%CI: 0.755-1.296], P = 0.935), or AAMO and MON (OR = 1.129 [95%CI: 0.938-1.359], P = 0.200). The MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with a random-effects IVW (P > 0.05). MR analysis results showed no heterogeneity, the horizontal pleiotropy and outliers (P > 0.05). They were not driven by a single SNP, and were normally distributed (P > 0.05).
Only AAMA has a negative genetic causal relationship with BON, and no genetic causal relationships exist between AAMA and MON, AAMO and BON, or AAMO and MON. However, it cannot be ruled out that they are related at other levels besides genetics.