Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
Andrology. 2021 Jul;9(4):1151-1165. doi: 10.1111/andr.13009. Epub 2021 Apr 20.
Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes).
The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns.
We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources.
ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF.
Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.
严重的精子发生失败（SpF）是男性不育最极端的表现，因为它大大降低了精液质量，导致严重少精症（SO，<500 万精子/ml 精液）或非阻塞性无精子症（NOA，精液中完全没有精子而没有阻塞性原因）。
本研究的主要目的是分析伊比利亚人群中先前与汉族人群中的非阻塞性无精子症相关的 6 个单核苷酸多态性（SNP）通过全基因组关联研究（GWAS）的影响，并确定它们在特定 SpF 模式发展中的可能功能相关性。
我们对 674 名伊比利亚不育男性（包括 480 名 NOA 和 194 名 SO 患者）和 1058 名匹配的无影响对照进行了 GWAS 相关变体 PRMT6-rs12097821、PEX10-rs2477686、CDC42BPA-rs3000811、IL17A-rs13206743、ABLIM1-rs7099208 和 SOX5-rs10842262 的基因分型。通过逻辑回归模型评估它们与 SpF、SO、NOA 和不同的 NOA 表型的关联，并通过综合分析公共资源来定义它们的功能相关性。
ABLIM1-rs7099208 在加性（OR=0.86，p=0.036）和显性模型（OR=0.78，p=0.026）下与 SpF 相关。CDC42BPA-rs3000811 小等位基因频率在与剩余的 NOA 病例相比，显示生殖细胞成熟阻滞（MA）的 NOA 患者亚组中明显增加，该亚组为隐性模型（OR=4.45，p=0.044）。PEX10-rs2477686 SNP 在加性模型下与睾丸精子提取（TESE）结果呈负相关（OR=1.32，p=0.034）。功能注释分析表明，这些变体影响附近基因的睾丸特异性表达，并且 lincRNA 可能在 SpF 中发挥作用。
我们的数据支持先前在亚洲人中报道的三个与非阻塞性无精子症相关的风险变体（ABLIM1-rs7099208、CDC42BPA-rs3000811 和 PEX10-rs2477686）与伊比利亚欧洲血统人群中不同的 SpF 表现有关，这可能是通过影响基因表达和 lincRNA 失调。
