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J Urol. 2012 Oct;188(4 Suppl):1450-5. doi: 10.1016/j.juro.2012.03.047. Epub 2012 Aug 17.

Genome-wide DNA methylation profiling of CpG islands in hypospadias.

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Department of Urology, University of California, San Francisco, California 94158, USA.



Hypospadias is one of the most frequent genital malformations in the male newborn, and results from abnormal penile and urethral development. The etiology of hypospadias remains largely unknown despite intensive investigations. Fetal androgens have a crucial role in genital differentiation. Recent studies have suggested that molecular mechanisms that underlie the effects of androgens on the fetus may involve disruption of epigenetic programming of gene expression during development. We assessed whether epigenetic modification of DNA methylation is associated with hypospadias in a case-control study of 12 hypospadias and 8 control subjects.


Genome-wide DNA methylation profiling was performed on the study subjects using the Illumina Infinium® HumanMethylation450 BeadChip, which enables the direct investigation of methylation status of more than 485,000 individual CpG sites throughout the genome. The methylation level at each CpG site was compared between cases and controls using the t test and logistic regression.


We identified 14 CpG sites that were associated with hypospadias with p <0.00001. These CpG sites were in or near the SCARB1, MYBPH, SORBS1, LAMA4, HOXD11, MYO1D, EGFL7, C10orf41, LMAN1L and SULF1 genes. Two CpG sites in SCARB1 and MYBPH genes remained statistically significant after correction for multiple testing (p = 2.61 × 10(-09), p(corrected) = 0.008; p = 3.06 × 10(-08), p(corrected) = 0.02, respectively).


To our knowledge this is the first study to investigate hypospadias using a unique and novel epigenetic approach. Our findings suggest DNA methylation patterns are useful in identifying new genes such as SCARB1 and MYBPH that may be involved in the etiology of hypospadias.

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