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Asian Journal of Andrology (2012) 14, 766–772; doi:10.1038/aja.2012.27; published online 14 May 2012
A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes
Sheela Sathyanarayana1,2, Shanna H Swan3, Federico M Farin4, Hui-Wen Wilkerson4, Michael Bamshad1,5, Richard Grady6, Chuan Zhou1,2 and Stephen M Schwartz7,8
1 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
2 Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA 98105, USA
3 Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
4 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
5 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
6 Division of Pediatric Urology, Seattle Children's Hospital, Seattle, WA 98105, USA
7 Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
8 Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Correspondence: Dr S Sathyanarayana, (sheela.sathyanarayana@seattlechildrens.org)
Received 10 November 2011; Revised 10 February 2012; Accepted 19 February 2012
Advance online publication 14 May 2012.
| Abstract |
Single nucleotide polymorphisms (SNPs) in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities. However, no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance (AGD), anoscrotal distance (ASD) and penile width (PW). We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families. We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates. We found that the rs2077647 G allele, located in the coding region of estrogen receptor alpha (ESR1), was associated with a shorter AGD (P=0.02; −7.3 mm, 95% confidence interval (CI): −11.6 to −3.1), and the rs10475 T allele, located in the 3′ untranslated region of activating transcription factor 3 (ATF3), was associated with a shorter ASD (−4.3 mm, 95% CI: −7.2 to −1.4), although this result was not significant (P=0.07) after controlling for multiple comparisons. We observed no association between PW and the SNPs tested. Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD, although the significance of the association was marginal. Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hypospadias and cryptorchidism.
Keywords: gene; hypospadias; male; phenotype; polymorphism; reproductive |
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