title: A genome-wide association study of mitochondrial DNA in Chinese men identifies two risk single nucleotide substitutions for idiopathic oligoasthenospermia.
abstract: Mitochondrial DNA (mtDNA) is believed to be both the source and target of reactive oxygen species (ROS), and mtDNA genetic alterations have been reported to be associated with molecular defects in the oxidative phosphorylation (OXPHOS) system. In order to investigate the potentially susceptible mtDNA genetic variants to oligoasthenospermia, we conducted a two-stage study in 921 idiopathic infertile men with oligoasthenospermia and 766 healthy controls using comprehensive molecular analysis. In the screen stage, we used next generation sequencing (NGS) in 233 cases and 233 controls to screen oligoasthenospermia susceptible mitochondrial genetic variants. In total, seven variants (C5601T, T12338C, A12361G, G13928C, A15235G, C16179T and G16291A) were screened to be potentially associated with idiopathic oligoasthenospermia. In the validation stage, we replicated these variants in 688 cases and 533 healthy controls using SNPscan. Our results demonstrated that the genetic alteration of C16179T was associated with idiopathic male infertility (odds ratio (OR) 3.10, 95% CI 1.41-6.79) (p=3.10×10(-3)). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that C16179T was associated with both low sperm count and motility, with ORs of 4.18 (95% CI 1.86-9.40) (p=1.90×10(-4)) and 3.17 (95% CI 1.40-7.16) (p=3.50×10(-3)), respectively. Additionally, A12361G was found to be associated with low sperm count, with an OR of 3.30 (95% CI 1.36-8.04) (p=5.50×10(-3)). These results indicated that C16179T influenced both the process of spermatogenesis and sperm motility, while A12361G may just only participate in the process of spermatogenesis. Further investigation in larger populations and functional characterizations are needed to validate our findings.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Miaofei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Shoulin
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zuomin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China. Electronic address: dengshun_miao@yahoo.com.cn.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China. Electronic address: xrwang@njmu.edu.cn.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D044466:Asian People; D053627:Asthenozoospermia / Q000235:genetics*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009845:Oligospermia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial
keywords: Genetic variant; Haplogroup; Mitochondrial DNA; Oligoasthenospermia