Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone.
We performed a genetic association study of rare variants and single nucleotide polymorphisms (SNPs) of UCMA/GRP and OPTN genes, in French-Canadian patients with Paget's disease of bone (PDB) and in healthy controls from the same population. We reproduced the variant found in the UCMA/GRP basal promoter and tested its functionality using in vitro transient transfection assays. Interestingly, this SNP rs17152980 appears to affect the transcription level of UCMA/GRP. In addition, we have identified five rare genetic variants in UCMA/GRP gene, four of them being population-specific, although none were found to be associated with PDB. Six Tag SNPs of UCMA/GRP gene were associated with PDB, particularly the SNP rs17152980 (uncorrected P=3.8 × 10(-3)), although not significant after Bonferroni's correction. More importantly, we replicated the strong and statistically significant genetic association of two SNPs of the OPTN gene, the rs1561570 (uncorrected P=5.7 × 10(-7)) and the rs2095388 (uncorrected P=4.9 × 10(-3)), with PDB. In addition, we identified a very rare variant found to be located close to the basal promoter of the OPTN gene, at -232bp from its distal transcription start site. Furthermore, depending on the type of allele present (G or A), the binding of several important nuclear factors such as the vitamin D or the retinoic acid receptors is predicted to be altered at this position, suggesting a significant effect in the regulation of transcription of the OPTN gene. In conclusion, we identified a functional SNP located in the basal promoter of the UCMA/GRP gene which provided a weak genetic association with PDB. In addition, we replicated the strong genetic association of two already known SNPs of the OPTN gene, with PDB in a founder effect population. We also identified a very rare variant in the promoter of OPTN, and through bioinformatic analysis, identified putative transcription factor binding sites likely to affect OPTN gene transcription.
Department of Medicine, Laval University, CHUQ (CHUL) Research centre and Division of Rheumatology, CHUQ (CHUL), Quebec City, QC, Canada. laetitia.michou@crchul.ulaval.ca
Laëtitia
L
Michou
Natércia
N
Conceição
Jean
J
Morissette
Edith
E
Gagnon
Gabriel
G
Miltenberger-Miltenyi
Ethel S
ES
Siris
Jacques P
JP
Brown
M Leonor
ML
Cancela
D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D010001:Osteitis Deformans / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D035582:Transcription Factor TFIIIA / Q000235:genetics*
D018797:Cell Cycle Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D011506:Proteins; D035582:Transcription Factor TFIIIA; C528959:Ucma protein, human