The RIZ Pro704 insertion-deletion polymorphism, bone mineral density and fracture risk: the Rotterdam study

Estrogens play a major role in the maintenance of bone and bone strength, and they exert their effects via estrogen receptors. Recently, an estrogen receptor alpha (ESR1) specific co-activator, retinoblastoma-interacting zinc-finger protein (RIZ1, 1p36), was shown to strongly enhance ESR1 function in vitro. The same study showed that a Proline insertion-deletion polymorphism at amino acid position 704 (Pro704 ins/del) in the RIZ1 gene was associated with heel BMD in young Swedish women. We tested the relation between the RIZ1 Pro704 ins/del polymorphism and BMD and fracture risk in Caucasian elderly men and women of the Rotterdam study. We also examined whether estradiol levels (measured in a subset) or genetic variation in ESR1 influenced this relation. In 2424 men and 3517 women from the Rotterdam study, RIZ1 genotypes were determined and associations with BMD (lumbar spine and femoral neck) and fracture risk were analysed. We recorded 374 vertebral fractures at baseline and during 6.4+/-0.4 (SD) years of follow-up, and 1219 incident non-vertebral fractures during 7.4+/-3.3 (SD) years of follow-up. The allele frequency of the Pro704 insertion was 41%, the genotype distribution was in Hardy-Weinberg Equilibrium (P=0.94). We found no association of this polymorphism with BMD or fracture risk. Stratification for gender, estradiol levels or interaction with ESR1 risk haplotype did not change these results. In conclusion, in this large study we observed no association of the RIZ1 Pro704 insertion-deletion polymorphism with BMD or fracture risk. This suggests this polymorphism to play a minor role, if any, as a genetic determinant of osteoporosis in elderly subjects.