title: Development of a molecular test of Paget's disease of bone.
abstract: Depending on populations, 15 to 40% of patients have a familial form of Paget's disease of bone (PDB), which is transmitted in an autosomal-dominant mode of inheritance with incomplete penetrance. To date, only SQSTM1 gene mutations have been linked to the disease. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in patient non-carriers of SQSTM1 mutations, but they have minor size effects. The current clinical practice guidelines still recommend to measure total serum alkaline phosphatase (sALP) for PDB screening. However, genetic or bone biomarkers alone may lack sensitivity to detect PDB. Thus, the objective of this study was to develop a molecular test of PDB, combining genetic and bone biomarkers, in order to detect PDB, which is frequently asymptomatic. We genotyped 35 SNPs previously associated with PDB in 305 patients, and 292 healthy controls. In addition, serum levels of 14 bone biomarkers were assayed in 51 patients and 151 healthy controls. Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations. First, a combination of five genetic markers gave rise to the highest area under the ROC curve (AUC) with 95% confidence interval [95% CI] of 0.731 [0.688; 0.773], which allowed us to detect 81.5% of patients with PDB. Second, a combination of two bone biomarkers had an AUC of 0.822 [0.726; 0.918], and was present in 81.5% of patients with PDB. Then, the combination of the five genetic markers and the two bone biomarkers increased the AUC up to 0.892 [0.833; 0.951], and detected 88.5% of patients with PDB. These results suggested that an algorithm integrating first a screen for SQSTM1 gene mutations, followed by either a genetic markers combination or a combined genetic and biochemical markers test in patients non-carrier of any SQSTM1 mutation, may detect the PDB phenotype better than biomarkers already available in the clinical practice.
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada; Division of Rheumatology, Department of Medicine, Université Laval, Quebec, QC, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Guay-Bélanger
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Simonyan
authors.affiliation: Département de Médecine Sociale et Préventive, Université Laval, Québec, QC, Canada; Centre de Recherche du Centre Intégré Universitaire de Santé et de Services Sociaux de la Capitale-Nationale, Quebec, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bureau
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Gagnon
authors.affiliation: Department of Biochemistry, CHUM, Montreal, QC, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Albert
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Morissette
authors.affiliation: Columbia University Medical Centre, New York City, NY, USA.
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Siris
authors.affiliation: Pôle Appareil Locomoteur, Service de Rhumatologie B, Hôpital Lariboisière, AP-HP, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Orcel
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada; Division of Rheumatology, Department of Medicine, Université Laval, Quebec, QC, Canada; Department of Rheumatology, CHU de Québec, Quebec, QC, Canada.
authors.forename: Jacques P
authors.initials: JP
authors.lastname: Brown
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada; Division of Rheumatology, Department of Medicine, Université Laval, Quebec, QC, Canada; Department of Rheumatology, CHU de Québec, Quebec, QC, Canada. Electronic address: laetitia.michou@crchudequebec.ulaval.ca.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Michou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010001:Osteitis Deformans / Q000175:diagnosis* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012372:ROC Curve; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D005819:Genetic Markers; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: Area under the ROC curve; Bone biomarkers; Molecular test; Paget's disease of bone; Polymorphisms