RESUMO
OBJECTIVE: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families. METHODS: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family. RESULTS: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele. CONCLUSION: A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.
Assuntos
Cromossomos Humanos Par 2/genética , Ligação Genética , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Exoma/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , LinhagemAssuntos
Proteínas da Matriz Extracelular/genética , Predisposição Genética para Doença , Glicoproteínas/genética , Debilidade Muscular/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Substituição de Aminoácidos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Proteína de Matriz Oligomérica de Cartilagem , Criança , Colágeno Tipo IX/genética , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas Matrilinas , Debilidade Muscular/diagnóstico , Osteocondrodisplasias/patologia , Linhagem , RadiografiaAssuntos
Proteínas da Matriz Extracelular/genética , Mutação de Sentido Incorreto/genética , Osteocondrodisplasias/genética , Adolescente , Sequência de Aminoácidos/genética , Proteína de Matriz Oligomérica de Cartilagem , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Éxons/genética , Proteínas da Matriz Extracelular/química , Feminino , Glicoproteínas/genética , Haplótipos/genética , Humanos , Masculino , Proteínas Matrilinas , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Peptídeos/química , Peptídeos/genética , Estrutura Terciária de Proteína/genéticaRESUMO
OBJECTIVE: We sought to determine whether sequence variations in cartilage collagen genes are associated with primary, early-onset osteoarthritis (OA). METHODS: The cartilage collagen genes, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2, were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. In addition, allelic association studies were performed using six to 12 common polymorphisms from each gene by genotyping 72 OA patients and 103 controls. RESULTS: Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations, four in COL11A1, two in COL11A2 and one in COL2A1, were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Co-segregation of a sequence variation and the phenotype was found in all four families available for study. Association analysis failed to identify any common predisposing alleles. CONCLUSIONS: Early-onset OA demonstrates locus and allelic heterogeneity since the identified variations were in three different collagen genes and each of the six probands had a different mutation. It is also possible that some OA cases represent the mild end of the chondrodysplasia phenotypic spectrum. The major susceptibility alleles in this form of OA, however, remain to be identified.