RESUMO
OBJECTIVE: Studies have suggested that polymorphisms or mutations either in the COL2A1 or VDR gene. both on chromosome 12q, are associated with the occurrence of osteoarthritis (OA). We examined linkage and association between the VDR/COL2A1 locus and hand/knee OA in the Framingham Osteoarthritis Study (FOS). METHODS: Hand and knee joints were characterized radiographically in the FOS. An overall score for OA using the standard Kellgren and Lawrence grading scheme was determined, as well as scores for individual features of OA including osteophytes and joint space narrowing. For linkage studies, polymorphic microsatellite markers near the VDR-COL2AI genes on chromosome 12 were tested in a collection of 296 of the largest Framingham Heart Study families and the results analyzed using variance component linkage (SOLAR). For association studies, we characterized the allele status of a subset of subjects at the BsmI site of the VDR gene. RESULTS: Overall, we found no linkage or association between OA and the COL2A1/VDR locus for either knee or hand OA, nor did we find an association or linkage between COL2AI or VDR with any individual radiographic features of OA. CONCLUSION: Despite studies suggesting associations of OA with both COL2A1 and VDR loci, our results suggest that mutations at the COL2A1/VDR locus do not play an important role as a cause of common OA in the population at large.
Assuntos
Cromossomos Humanos Par 12/genética , Colágeno Tipo II/genética , Ligação Genética/genética , Mutação/genética , Osteoartrite/genética , Polimorfismo Genético/genética , Receptores de Calcitriol/genética , Idoso , Mapeamento Cromossômico , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Articulações dos Dedos/metabolismo , Articulações dos Dedos/patologia , Articulações dos Dedos/fisiopatologia , Frequência do Gene/genética , Humanos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Fatores SexuaisRESUMO
Spirometric measures of pulmonary function have been shown to be highly heritable and evidence for major genes influencing forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) have been reported. A genome scan of pulmonary traits in the Framingham Heart Study identified a region on chromosome 6qter with evidence for linkage to FEV1 and the FEV1/FVC ratio. For this study, additional markers were genotyped in the region to refine the location of linkage and test for association. Variance component linkage analysis was performed using GENEHUNTER, and family-based association tests were performed using FBAT. The chromosome 6 telomeric region provided significant evidence of linkage with the additional markers, resulting in a maximum multipoint LOD score of 5.0 for FEV1 at 184.5 cM. LOD scores for FVC and the FEV1/FVC ratio were also above 1.0 in this region. Evidence for association with FEV1 and FVC was observed with D6S281 at 190 cM. The strongest effect was seen with the 224 allele, which was associated with higher levels of FEV1 and FVC in allele carriers compared with those carrying other alleles. This study supports the presence of a gene influencing pulmonary function on the q-terminus of chromosome 6 in the region of 184 cM (D6S503) to 190 cM (D6S281).
Assuntos
Cromossomos Humanos Par 6 , Ligação Genética , Pulmão/fisiologia , Capacidade Vital/fisiologia , Adulto , Alelos , Estudos de Coortes , Feminino , Volume Expiratório Forçado/fisiologia , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo Genético , EspirometriaRESUMO
Prior studies have found cross-sectional lung function to be highly heritable. In the present study, we used a 10-cM genome-wide scan of 1,578 members of 330 families participating in the Framingham Study to test for linkage of genetic markers to level of lung function as determined by spirometry during middle age. At this age, lung function measures may reflect the effects of genes influencing lung growth and development, as well as of those influencing decline in lung function during adulthood. We performed spirometry on 345 members of the Original Cohort and 1,233 members of the Offspring Cohort of the Framingham Study. The effects of age, height, body mass index, and smoking status on spirometric measures were adjusted through linear regression models created separately for men and women in each cohort. Standardized residuals for FEV1, FVC, and the ratio of FEV1 to FVC were obtained from these models. The residual spirometric measures were analyzed for linkage to the genome scan markers through the use of variance component models in the Sequential Oligogenic Linkage Analysis Routines software program. The loci most strongly influencing FEV1 and FVC colocalized on chromosomes 4, 6, and 21. FEV1 was most influenced by the locus on chromosome 6 (logarithm of the odds favoring genetic linkage [LOD] = 2.4), whereas chromosome 21 contained markers with the strongest linkage to FVC (LOD = 2.6).