Hum. Reprod. Advance Access published online on August 9, 2008
Human Reproduction, doi:10.1093/humrep/den277
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Tumor necrosis factor-alpha –308 polymorphism in infertile men with altered sperm production or motility
1 INSERM, U407, Oullins, F-69921 France; Université Lyon I, Lyon, F-69921 France 2 Service d'Histologie Embryologie Cytogénétique & Biologie de la Reproduction, Centre Hospitalier Poissy–St Germain en Laye, and UFR Paris, Ile de France Ouest, 78303 Poissy, France 3 Service de Radioanalyses, Hôpital Neuro-Cardiologique, 69677 Bron, France 4 Institut Rhonalpin, Clinique Sainte-Thérèse, 69500 Bron, France 5 Pôle RhôneAlpin de BioInformatique (PRABI), Centre Hospitalier Lyon-Sud, Pierre-Bénite, F-69495 France 6 Pole Gynécologie Obstétrique Reproduction Endocrinologie (GORE), Hôpital de l'Archet 2, Nice, F-06200 France
7 Correspondence address. Bâtiment Universitaire Archimed, Inserm U895, équipe 5, C3M, 151 Route St Antoine Ginestière, BP2 3094, 06204 Nice, cedex 3; Tel: +33 4 92 03 64 56; Fax: +33 4 92 03 64 40; E-mail: benahmed.m{at}chu-nice.fr
BACKGROUND: One of the most well-documented cytokines suspected as a hazard to male fertility is tumor necrosis factor-
(TNF). Genetic factors such as single-nucleotide polymorphisms (SNPs) in the TNF gene cluster impact TNF levels. Our objective was to establish the potential involvement of –308 TNF SNP in male infertility risk.
METHODS: In 684 infertile male patients undergoing an intracytoplasmic sperm injection procedure, we used allele-specific polymerase chain reaction (PCR) and PCR-RFLP to investigate the distribution of the guanine (G)-to-adenosine (A) substitution at position –308 in the promoter region of the TNF gene.
RESULTS: An increased frequency of the –308 TNF A allele was found in patients with low sperm count of testicular origin [P = 0.002; odds ratio (OR) = 2.93] or with normal production count but altered sperm motility (P = 0.003; OR = 2.32), compared with a patient group with normal sperm count and quality (morphology and motility). In patients with low sperm count exhibiting TNF A allele, compared with those with G allele, an alteration in hormonal balance was observed with increased inhibin B levels and subsequent reduced FSH plasma levels, leading to an FSH/inhibin B ratio roughly half as high (from 0.07 ± 0.01 in TNFA versus 0.13 ± 0.02 in TNFG allele groups, P < 0.0001).
CONCLUSION: As the –308 TNF A allele has been associated with an increased expression/production of TNF, the potential use of therapies based on inhibition of TNF activities could represent possible therapeutic opportunities for patients with low sperm count (i.e. primary testicular dysfunction) or with altered sperm motility.
Key words:
tumor necrosis factor-/infertility/polymorphism
These authors contributed equally to this paper. Submitted on February 9, 2006; resubmitted on March 28, 2008; accepted on April 24, 2008.