Polymorphic variations in exon 10 of the luteinizing hormone receptor: functional consequences and associations with breast cancer.

Polymorphic variation of the LHR gene may affect receptor function and accordingly may influence ovarian steroid hormone action, including steroid hormone-dependent clinical outcome. The functional effects of two single nucleotide polymorphisms (SNPs), i.e. LHR 291Asn/Ser (rs12470652) and 312Ser/Asn (rs2293275) in the biologically interesting exon 10 of the LHR gene are described. Furthermore, ethnic diversity in allele frequencies and genotype distributions of both SNPs was determined. In addition associations with breast cancer were studied in 751 breast cancer patients. In vitro transfection studies revealed altered glycosylation status and increased receptor sensitivity for the 291Ser LHR variant. No functional consequences were observed for the 312SerAsn LHR SNP. The LHR 312Asn allele was slightly more often present in two independent breast cancer patient cohorts as compared to controls (OR=1.15; p=0.03 and 1.26; p=0.001, respectively). In conclusion, although functional changes of the LHR 291Ser candidate allele were observed, no associations with breast cancer were found, while the LHR 312Asn allele can be regarded as a weak breast cancer risk allele.