Polymorphisms in double-strand breaks repair genes are associated with impaired fertility in Chinese population
Polymorphisms in double-strand breaks repair genes are associated with impaired fertility in Chinese population
复制标题
双链断裂修复基因的多态性与中国人群的生育能力受损有关。
DOI：
10.1530/rep-12-0370
复制
发表时间：
2013-05-01
期刊：
影响因子：
3.8
通讯作者：
Wang, Xinru
中科院分区：
文献类型：
--
作者：
Ji, Guixiang;Yan, Lifeng;Wang, Xinru
DNA双链断裂（DSB）修复途径在DNA双链断裂修复中起着关键作用，DSB修复途径基因的遗传变异是多种疾病的潜在危险因素。为了验证DSB基因多态性与男性不育易感性相关的假设，我们检测了来自中国人群为基础的病例对照研究（NJMU Infertility Study）的580例不育患者和580例对照的8个DSB关键基因（XRCC 3、XRCC 2、BRCA 2、RAG 1、XRCC 5、LIG 4、XRCC 4和ATM）的11个单核苷酸多态性。使用OpenArray平台确定基因型，并使用TUNEL测定法检测精子DNA片段化。使用逻辑回归估计调整后的比值比（OR）和95%CI。结果表明，LIG 4 rs 1805388（Ex 2 + 54 C>T，Thr 9 Ile）T等位基因可增加男性不育的易感性（TT基因型调整OR=2.78; 95%CI，1.77-4.36; TC基因型调整OR=1.58; 95%CI，1.77-4.36）。此外，RAG 1 rs 2227973纯合变异基因型GG（A>G，K820 R）与男性不育风险显著增加相关（校正OR，1.44; 95% CI，1.01-2.04）。此外，线性回归分析显示，与普通纯合基因型携带者相比，LIG 4 rs 1805388或RAG 1 rs 2227973变体携带者的精子DNA片段化水平显著较高，而LIG 4 rs 1805388 T等位基因携带者的精子浓度水平也较低。这项研究首次证明，据我们所知，RAG 1 rs 2227973和LIG 4 rs 1805388的功能变体与男性不育的易感性相关。
The DNA double-strand breaks (DSBs) repair pathway plays a critical role in repairing double-strand breaks, and genetic variants in DSBs repair pathway genes are potential risk factors for various diseases. To test the hypothesis that polymorphisms in DSBs genes are associated with susceptibility to male infertility, we examined 11 single nucleotide polymorphisms in eight key DSBs genes (XRCC3, XRCC2, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform, and sperm DNA fragmentation was detected using the TUNEL assay. The adjusted odds ratio (OR) and 95% CI were estimated using logistic regression. The results indicate that LIG4 rs1805388 (Ex2+54C>T, Thr9Ile) T allele could increase the susceptibility to male infertility (adjusted OR=2.78; 95% CI, 1.77-4.36 for TT genotype; and adjusted OR=1.58; 95% CI, 1.77-4.36 for TC genotype respectively). In addition, the homozygous variant genotype GG of RAG1 rs2227973 (A>G, K820R) was associated with a significantly increased risk of male infertility (adjusted OR, 1.44; 95% CI, 1.01-2.04). Moreover, linear regression analysis revealed that carriers of LIG4 rs1805388 or RAG1 rs2227973 variants had a significantly higher level of sperm DNA fragmentation and that T allele carriers of LIG4 rs1805388 also had a lower level of sperm concentration when compared with common homozygous genotype carriers. This study demonstrates, for the first time, to our knowledge, that functional variants of RAG1 rs2227973 and LIG4 rs1805388 are associated with susceptibility to male infertility.