transforming-growth-factor-alpha and Osteoarthritis--Hip

Osteoarthritis (OA) is a complex degenerative joint disorder, which has contributions from both environmental and genetic factors. Several recent publications have established the connection between hip OA susceptibility and genetic markers within the TGFA gene, however, the relationship of these markers with knee OA has not been elucidated. Therefore, the present study was designed to investigate the potential linkage between common variants of the TGFA gene with knee OA in a large sample of Han Chinese individuals.. We conducted a case-control study, including 338 knee OA patients and 985 unrelated healthy controls using both single nucleotide polymorphism (SNP) markers and haplotype-based analyses to examine the genotypic and allelic distribution of 19 tagging SNPs.. We identified a significant association between the SNP rs2862851 and disease status of knee OA (p = 0.000314, OR = 1.40). Allelic analyses showed that the T allele of this SNP significantly elevated the risks of OA. This result was replicated in genotypic association analyses. In addition, haplotype-based analyses have also identified a strong association signal between one haplotype block, including rs2862851, and the disease status of knee OA (p < 0.00001).. Our findings suggest that the rs2862851 allele of the TGFA gene may significantly contribute to the susceptibility to knee OA in the Han Chinese population.

Topics: Aged; Alleles; Asian People; Biomarkers; Case-Control Studies; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Polymorphism, Single Nucleotide; Risk Factors; Transforming Growth Factor alpha

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Topics: Aged; Aged, 80 and over; Cartilage; Class Ia Phosphatidylinositol 3-Kinase; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Genome-Wide Association Study; Hip Joint; Humans; Male; Middle Aged; Osteoarthritis, Hip; Phosphatidylinositol 3-Kinases; Polymorphism, Single Nucleotide; Receptor, Fibroblast Growth Factor, Type 3; Regulatory Sequences, Nucleic Acid; Transforming Growth Factor alpha; Trehalase