Purpose: Nipple aspiration fluid (NAF) is a non-invasively-acquired biosample that can provide a window into the breast environment, but NAF yield is highly variable. Its determinants must be better understood for studies of breast cancer risk. The wet earwax phenotype was identified as one determinant of NAF yield in the 1970s, and is linked to single nucleotide polymorphisms (SNPs) in the ATP-binding cassette transporter gene ABCC11. We have investigated this, as well as SNPs in the prolactin (PRL) and prolactin receptor (PRLR) genes, in relation to NAF yield. Methods: DNA was extracted from white blood cells of 557 NAF yielders and 359 non-yielders, and was used to genotype ABCC11 (rs17822931), PRL (rs849870, rs849872, rs849886, rs2244502, rs1341239), and PRLR (rs37364, rs34024951, rs1610218, rs9292575, rs7718468) using Taqman genotyping assay. The association between NAF yield and each single SNP was analyzed using logistic regression adjusting for age, race, and menopausal status. Results: ABCC11 rs17822931 showed a negative association with NAF yield [odds ratio (OR) 0.66, 95 % confidence interval (CI) 0.49–0.88; p = 0.004]. The PRL rs849870 and the haplotype combination with other SNPs showed a marginal association with NAF yield. In addition, the years since last birth also showed negative association with NAF yielding (OR 0.98, 95 % CI 0.96–0.99; p = 0.001). The combination of the years since last birth with ABCC11 SNP revealed significant interaction between reproductive factor and genetic factor. Conclusions: Our results confirmed the association between NAF yield and earwax phenotype through ABCC11 genotype. Combined with the recency of last birth, ABCC11 genotype should be considered in the design of studies utilizing NAF as a biosample.
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