Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis

Osteoporosis is a common disease with multiple environmental and genetic risk factors involved. Using a marker-by-marker approach, the role of different estrogen-related genes has been analyzed in different populations, but most of these studies ignore the complex multigenic nature of human osteoporosis. Looking for markers related to osteoporosis, we have analyzed five single nucleotide polymorphisms located in genes related to the estrogen pathway, Follicle Stimulating Hormone Receptor (FSHR) gene, the CYP19 aromatase (CYP19A1) gene, the Estrogen Receptor alpha (ESR1) gene, the Estrogen Receptor beta (ESR2) gene and the Nuclear Receptor Interacting Protein 1 (NRIP1) gene in 265 unrelated postmenopausal women. We have obtained nominal P values for the NRIP1 Gly75Gly and ESR2 *39A > G markers (P = 0.013 and P = 0.02 respectively), but no gene seems to be associated after multiple test corrections. Reanalysis of this study using 437 postmenopausal women confirmed our results and only detect marginal effects for ESR2 marker (P = 0.045). By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P = 0.003). We detected two digenic genotypes involving ESR2-NRIP1 and ESR2-ESR1 genes strongly associated with osteoporosis (P = 0.007). Replication of multilocus studies using 437 patients confirmed the detected interactions (P < 0.01). We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis. Our results reaffirm the polygenic nature and the genetic complexity of osteoporosis trait adding a new candidate gene (NRIP1) for association studies of bone-related traits.