BCL2 Ala43Thr is a functional variant associated with protection against azoospermia in a Han-Chinese population.
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.
Ma
Jun
J
Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, People's Republic of China.
Lu
Hui-Yuan
HY
Xia
Yan-Kai
YK
Dong
Hui-Bin
HB
Gu
Ai-Hua
AH
Li
Zi-Yin
ZY
Li
Zhong
Z
Chen
Ai-Min
AM
Wang
Xin-Ru
XR
Wang
Shou-Lin
SL
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
D000972:Antineoplastic Agents, Phytogenic; D004247:DNA; D017239:Paclitaxel