Qin Yufeng, Ji Juan, Du Guizhen, Wu Wei, Dai Juncheng, Hu Zhibin, Sha Jiahao, Hang Bo, Lu Chuncheng, Xia Yankai, Wang Xinru
State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, China.
Hum Reprod. 2014 Apr;29(4):860-6. doi: 10.1093/humrep/deu013. Epub 2014 Feb 18.
Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)?
Rs1406714 in CHD2, rs2126986 in GNAO1 and rs7226979 in BCL2 were associated with NOA in Han Chinese men at a significant level after multiple testing corrections.
Previous genome-wide association studies (GWASs) have identified three loci for NOA, whereas less attention has been given to those markers that did not exceed the genome-wide significance threshold.
STUDY DESIGN, SIZE, DURATION: We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Imputation and pathway-based approaches can be applied to identify additional causal makers with small effects on NOA. We performed a candidate pathway-based association study using imputed-genotyping data for 24 238 single nucleotide polymorphisms estimated from NOA GWAS. Remarkably, 40 markers were associated with NOA in both imputation analysis and NOA GWAS (Stage 1) after linkage disequilibrium analysis and selected for validation (Stage 2) in another population.
Based on the literature, genes from 11 biological pathways known or hypothesized to be important in spermatogenesis were selected. Combined analysis using directly genotyped data for Stages 1 and 2 revealed that rs1406714 in CHD2 was associated with decreased risk of NOA [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68-0.89, Pmeta = 1.7E-04], whereas rs2126986 in GNAO1 and rs7226979 in BCL2 were both risk makers for NOA (rs2126986: OR = 1.28, 95% CI = 1.15-1.41, Pmeta = 2.3E-06; rs7226979: OR = 1.21, 95% CI = 1.11-1.33, Pmeta = 4.5E-05).
LIMITATIONS, REASONS FOR CAUTION: Our analysis of genes in the pathways studied was not exhaustive.
Our study opens new avenues for the identification of other novel causal markers that are related to NOA. It will also provide a new paradigm for understanding the etiology of male infertility and contribute to the development of targeted therapies.
已知的、被广泛认为会影响精子发生的经典通路中的基因变异，是否会导致非梗阻性无精子症（NOA）的易感性？
在经过多重检验校正后，CHD2基因中的rs1406714、GNAO1基因中的rs2126986和BCL2基因中的rs7226979在汉族男性中与NOA显著相关。
先前的全基因组关联研究（GWAS）已经确定了三个与NOA相关的基因座，而对于那些未超过全基因组显著性阈值的标记则关注较少。
研究设计、规模、持续时间：我们进行了一项两阶段关联研究，包含1653例NOA病例和2329例对照，以研究NOA的易感标记。
参与者/材料、研究环境、方法：可以应用归因和基于通路的方法来识别对NOA有微小影响的其他因果标记。我们使用从NOA的GWAS估计的24238个单核苷酸多态性的归因基因分型数据，进行了一项基于候选通路的关联研究。值得注意的是，在连锁不平衡分析后，40个标记在归因分析和NOA的GWAS（第一阶段）中均与NOA相关，并在另一人群中进行验证（第二阶段）。
根据文献，选择了11条已知或假设在精子发生中起重要作用的生物学通路中的基因。使用第一阶段和第二阶段的直接基因分型数据进行的联合分析显示，CHD2基因中的rs1406714与NOA风险降低相关[比值比（OR）=0.78，95%置信区间（CI）=0.68-0.89，Pmeta=1.7E-04]，而GNAO1基因中的rs2126986和BCL2基因中的rs7226979都是NOA的风险标记（rs2126986：OR=1.28，95%CI=1.15-1.41，Pmeta=2.3E-06；rs7226979：OR=1.21，95%CI=1.11-1.33，Pmeta=4.5E-05）。
局限性、谨慎的原因：我们对所研究通路中的基因分析并不详尽。
我们的研究为识别与NOA相关的其他新型因果标记开辟了新途径。它还将为理解男性不育的病因提供新的范例，并有助于开发靶向治疗方法。
