Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
J Sex Med. 2010 Aug;7(8):2729-38. doi: 10.1111/j.1743-6109.2009.01641.x. Epub 2010 Jan 6.
Hypospadias is a common congenital anomaly caused by incomplete fusion of urethral folds. Development of the urethra and external genital system in the male fetus is an androgen-dependent process. In this regard, enzymes 17 β-hydroxysteroid dehydrogenase type 3 (17 β HSD3, encoded by HSD17B3) and steroid 5 α-reductase type 2 (encoded by SRD5A2) play crucial roles.
To investigate the possible associations between common polymorphisms in HSD17B3 as well as well-known V89L polymorphism in SRD5A2 and risk of hypospadias.
A case-control study was performed between 1999 and 2005. There were 89 Japanese boys with hypospadias and 291 newborn controls. We genotyped HSD17B3-1999T>C, +10A>G, +20A>G, +139G>A (V31I), +913G>A (G289S), and SRD5A2+336G>C (V89L) polymorphisms by allelic discrimination assay. We measured mRNA expression of the wildtype G289 allele and the mutant S289 allele of the HSD17B3 gene in the transfected human fetal kidney HEK293 cells.
Assessment of hypospadias including its severity and HSD17B3 and SRD5A2 genes using DNA blood samples: allele and genotype distribution of single nucleotide polymorphisms in these two genes in cases and controls.
In our study, the risk of hypospadias was significantly higher in subjects carrying homozygous HSD17B3+913A (289S) alleles (odds ratio [OR]: 3.06; 95% confidence interval [CI]: 1.38-6.76). The risk of severe hypospadias was much higher in these subjects (OR: 3.93; 95% CI: 1.34-11.49). The mRNA expression levels of HSD17B3 G289 were higher than those of HSD17B3 S289 mutant (P < 0.001). In addition, the risk of severe hypospadias increased in boys carrying the SRD5A2+336C (89L) allele (OR: 3.19; 95% CI: 1.09-9.36).
These results suggest that the HSD17B3 G289S polymorphism may be a potential risk modifier for hypospadias. Our findings provide evidence that a certain genotype related to androgen production may potentiate risk of hypospadias.
尿道下裂是一种常见的先天性异常，是由于尿道褶皱不完全融合引起的。男性胎儿尿道和外生殖器系统的发育是一个雄激素依赖的过程。在这方面，酶 17β-羟甾脱氢酶 3 型（17βHSD3，由 HSD17B3 编码）和甾体 5α-还原酶 2 型（由 SRD5A2 编码）起着至关重要的作用。
研究 HSD17B3 常见多态性以及 SRD5A2 中众所周知的 V89L 多态性与尿道下裂风险之间的可能关联。
1999 年至 2005 年间进行了病例对照研究。共有 89 名日本男孩患有尿道下裂和 291 名新生儿对照。我们通过等位基因鉴别检测法对 HSD17B3-1999T>C、+10A>G、+20A>G、+139G>A（V31I）、+913G>A（G289S）和 SRD5A2+336G>C（V89L）多态性进行了基因分型。我们在转染的人胎儿肾 HEK293 细胞中测量了 HSD17B3 基因野生型 G289 等位基因和突变型 S289 等位基因的 mRNA 表达。
使用 DNA 血样评估尿道下裂（包括其严重程度）和 HSD17B3 和 SRD5A2 基因：这些两个基因在病例和对照组中的单核苷酸多态性的等位基因和基因型分布。
在我们的研究中，携带纯合 HSD17B3+913A（289S）等位基因的受试者发生尿道下裂的风险显著增加（比值比[OR]：3.06；95%置信区间[CI]：1.38-6.76）。这些受试者发生严重尿道下裂的风险要高得多（OR：3.93；95% CI：1.34-11.49）。HSD17B3 G289 的 mRNA 表达水平高于 HSD17B3 S289 突变体（P<0.001）。此外，携带 SRD5A2+336C（89L）等位基因的男孩发生严重尿道下裂的风险增加（OR：3.19；95% CI：1.09-9.36）。
这些结果表明，HSD17B3 G289S 多态性可能是尿道下裂的潜在风险修饰因子。我们的发现提供了证据，表明与雄激素产生相关的特定基因型可能会增加尿道下裂的风险。
