AbstractBACKGROUNDRecent findings suggest that a specific haplotype, including five single nucleotide polymorphisms (SNPs) in the 3′‐terminal region of the estrogen receptor α gene (ESR1), is associated with the risk for cryptorchidism, but results have been conflicting in different populations. The goal of this study was to further define the association between this specific ESR1 haplotype and the risk for nonsyndromic cryptorchidism in a multiracial American population including Caucasian, African American, and Asian American subjects.METHODSApplied Biosystems TaqMan SNP Genotyping Assays were used to identify the genotypes of the five SNPs in ESR1 in 152 nonsyndromic cryptorchidism cases and 160 healthy controls.RESULTSFor the five SNPs, there were no significant differences in genotype frequencies between cases and controls. The four estimated haplotypes at the 3′ region of ESR1 gene were also not associated with the occurrence of cryptorchidism, but the haplotype AGATC was associated with the severity of cryptorchidism. SNP12 (rs6932902) in ESR1 was not associated with cryptorchidism per se, but was associated with increasing severity of cryptorchidism. Severe cases were more likely to have GG genotype (93%) than moderate (54%) cases (p = .04), and this association was in recessive mode (p = .02). The allele distribution of this SNP was also significantly different between moderate and severe cases: 97% of severe cases had the G allele while only 76% of moderate cases had the G allele (p = .03).CONCLUSIONSSNP12 in ESR1 is not associated with the occurrence of cryptorchidism but is associated with the severity of cryptorchidism. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.