title: Genetic variants in nitric oxide synthase genes and the risk of male infertility in a Chinese population: a case-control study.
abstract: BACKGROUND
  In recent years, oxidative stress has been studied extensively as a main contributing factor to male infertility. Nitric Oxide, a highly reactive free radical gas, is potentially detrimental to sperm function and sperm DNA integrity at high levels. Thus, the aim of this study was to investigate the associations between five polymorphisms in nitric oxide synthase genes (NOSs) and the risk of male infertility and sperm DNA damage as well.
  
  
  METHODS
  Genotypes were determined by the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8-hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using unconditional logistic regression.
  
  
  RESULTS
  Our results revealed a statistically significant difference between the cases and controls in both genotypic distribution (P<0.001) and allelic frequency (P = 0.021) only for the NOS3 rs1799983 SNP. Multivariate logistic regression analyses revealed that rs1799983 was associated with a borderline significantly increased risk of male infertility (GT vs. GG: adjusted OR = 1.30, 95% CI: 1.00-1.70; GT+TT vs. GG: adjusted OR = 1.34, 95% CI: 1.03-1.74; P trend = 0.020). Moreover, NOS3 rs1799983 was positively associated with higher levels of sperm DNA fragmentation (β = 0.223, P = 0.044). However, the other 4 polymorphisms (NOS1 rs2682826, NOS1 rs1047735, NOS2 rs2297518, and NOS2 rs10459953) were not found to have any apparent relationships with male infertility risk.
  
  
  CONCLUSIONS
  Of five NOS gene polymorphisms investigated in the present study, we found NOS3 rs1799983 might cause oxidative sperm DNA damage, thereby contributing to male infertility.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology/Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yan
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Guo
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Shengmin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Jining
authors.initials: J
authors.lastname: Liu
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Shenghu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Shi
authors.affiliation: Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, Ministry of Environmental Protection, Nanjing, China.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology/Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Gu
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011379:Prognosis; D013094:Spermatozoa / Q000737:chemistry / Q000201:enzymology*; D055815:Young Adult
chemical_list: C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III