Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Psoriasis is strongly associated with certain human leucocyte-associated antigens, especially HLA-Cw*0602. Patients who are HLA-Cw*0602 positive have been reported to have more active disease and a younger age at disease onset than HLA-Cw6-negative patients. OBJECTIVES: To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients. METHODS: One thousand and six patients with chronic plaque psoriasis were evaluated clinically and HLA-C typed. In addition, 512 unrelated controls were typed for HLA-C. RESULTS: Of the patients 646 (64.2%) were HLA-Cw*0602 positive, and 68 (6.8%) were homozygous for this allele. Heterozygosity was associated with a relative risk of developing psoriasis of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset (mean 15.0 vs. 17.8 years, P = 0.04). However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes or any other clinical parameter recorded. CONCLUSIONS: Homozygosity for the gene in the major histocompatibility complex region has a major additive impact on the risk of developing psoriasis and predisposes to an earlier disease onset, but does not have any marked influence on the phenotype or the severity of the disease

A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.

OBJECTIVE: To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. METHODS: We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10(-7) considered genome-wide significant. RESULTS: The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. CONCLUSION: Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target

Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand

Objective. GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data. Methods. Fourteen teams contributed data onpolymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been. investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB. Results. A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09-1.22]) (P = 9.4 x 10(-7)), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019). Conclusion. Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes

A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.

OBJECTIVE: To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. METHODS: We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values &lt;1 x 10(-7) considered genome-wide significant. RESULTS: The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. CONCLUSION: Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target