Esprit Futur : Le Corbusier and José Oubrerie at Saint-Pierre De Firminy, Firminy-Vert, France, 1968–2006

What is the secret mesmerism that death possesses and under the operation of which a modern architect – strident, confident, resolute – becomes rueful, pessimistic, or melancholic?1 Five years before Le Corbusier’s death at sea in 1965, the architect reluctantly agreed to adopt the project for L’Église Saint-Pierre de Firminy in Firminy-Vert (1960–2006), following the death of its original architect, André Sive, from leukemia in 1958.2 Le Corbusier had already developed, in 1956, the plan for an enclave in the new “green” Firminy town, which included his youth and culture center and a stadium and swimming pool; the church and a “boîte à miracles” near the youth center were inserted into the plan in the ’60s. (Le Corbusier was also invited, in 1962, to produce another plan for three Unités d’Habitation outside Firminy-Vert.) The Saint-Pierre church should have been the zenith of the quartet (the largest urban concentration of works by Le Corbusier in Europe, and what the architect Henri Ciriani termed Le Corbusier’s “acropolis”3) but in the early course of the project, Le Corbusier would suffer the diocese’s serial objections to his vision for the church – not unlike the difficulties he experienced with Notre Dame du Haut at Ronchamp (1950–1954) and the resistance to his proposed monastery of Sainte-Marie de la Tourette (1957–1960). In 1964, the bishop of Saint-Étienne requested that Le Corbusier relocate the church to a new site, but Le Corbusier refused and the diocese subsequently withdrew from the project. (With neither the approval, funds, nor the participation of the bishop, by then the cardinal archbishop of Lyon, the first stone of the church was finally laid on the site in 1970.) Le Corbusier’s ambivalence toward the project, even prior to his quarrels with the bishop, reveals...

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.