title: BCL2 Ala43Thr is a functional variant associated with protection against azoospermia in a Han-Chinese population.
abstract: Apoptosis is very common during various stages of mammalian germ cell development and differentiation, and the BCL2 gene is one of the most important apoptotic regulators. Although its genetic variants are reported to be involved in cancers and autoimmune diseases, little information is available regarding BCL2 polymorphisms in male spermatogenesis. In the present study, single nucleotide polymorphisms (SNPs) in coding regions of the BCL2 gene were examined in a hospital-based, case-control study including 198 infertile patients with idiopathic azoospermia and 183 fertile controls. Subsequently, a functional study was conducted for comparison of paclitaxel-induced cytotoxicity and apoptosis between the BCL2 variant and the wild type in vitro. Three SNPs were found in exon 2--A21G (rs1801018), G127A (rs1800477), and C300T (rs61733416)--with the latter first reported in the Han-Chinese population. The frequency of G127A (GA+AA) genotype was significantly lower in azoospermic, infertile men compared to the age-matched controls (P = 0.01). This genotype may confer a lower risk of azoospermia (adjusted odd ratio [OR] = 0.448, 95% confidence interval = 0.226-0.889). In addition, HeLa cells expressing the BCL2 Ala43Thr (G127A), similar to the control cells, were more sensitive to paclitaxel-induced cytotoxicity and apoptosis than those expressing wild-type BCL2. Consistently, the cleaved PARP and p-BCL2 proteins were subsequently increased after paclitaxel treatment, as also predicted by the bioinformatics analysis. Considering the decreased antiapoptotic function of BCL2, these results suggest that the Ala43Thr variant is associated with protection against azoospermia in the Han-Chinese population.
authors.affiliation: Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Hui-Yuan
authors.initials: HY
authors.lastname: Lu
authors.forename: Yan-Kai
authors.initials: YK
authors.lastname: Xia
authors.forename: Hui-Bin
authors.initials: HB
authors.lastname: Dong
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Gu
authors.forename: Zi-Yin
authors.initials: ZY
authors.lastname: Li
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Chen
authors.forename: Xin-Ru
authors.initials: XR
authors.lastname: Wang
authors.forename: Shou-Lin
authors.initials: SL
authors.lastname: Wang
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D053713:Azoospermia / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D016009:Chi-Square Distribution; D002681:China; D004247:DNA / Q000737:chemistry / Q000235:genetics; D019254:Genes, bcl-2; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013091:Spermatogenesis / Q000235:genetics* / Q000502:physiology; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004247:DNA; D017239:Paclitaxel