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A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.

Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, van der Helm-van Mil AH, Ardlie KG, Amos CI, Criswell LA, Kastner DL, Gregersen PK, Kurreeman FA, Toes RE, Huizinga TW, Seldin MF, Begovich AB - PLoS Genet. (2008)

Bottom Line: Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06).Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN.In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs.

View Article: PubMed Central - PubMed

Affiliation: Celera, Alameda, California, United States of America.

ABSTRACT
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

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Related in: MedlinePlus

Relative risk plotted as a function of the genetic load of three validated RA risk variants in HLA-DRB1, PTPN22 and TRAF1.Individuals are classified according to the number of copies of the HLA-DRB1 shared epitope (0, 1 and 2) (SE-positive HLA-DRB1 alleles found in this sample set were: 0101, 0102, 0401, 0404, 0405, 0408 and 1001), carriage of the W620 PTPN22 missense SNP (TT + CT vs CC) and diplotypes at the TRAF1 SNPs, rs2239657, rs7021880 and rs7021049. The frequency of each combination of markers in cases and controls is highlighted in white (case/control).
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pgen-1000107-g004: Relative risk plotted as a function of the genetic load of three validated RA risk variants in HLA-DRB1, PTPN22 and TRAF1.Individuals are classified according to the number of copies of the HLA-DRB1 shared epitope (0, 1 and 2) (SE-positive HLA-DRB1 alleles found in this sample set were: 0101, 0102, 0401, 0404, 0405, 0408 and 1001), carriage of the W620 PTPN22 missense SNP (TT + CT vs CC) and diplotypes at the TRAF1 SNPs, rs2239657, rs7021880 and rs7021049. The frequency of each combination of markers in cases and controls is highlighted in white (case/control).

Mentions: Given that we have begun to witness the application of associated genetic variants to disease prognosis [42],[43] and thus far we have convincing evidence for three RA-predisposing loci in our studies (HLA-DRB1, PTPN22 and the TRAF1 region), we estimated the risk of RA given genotypes at these three loci under three different possible unconditional RA risk assumptions (i.e. RA disease prevalence values) using Bayes' theorem. In total, there were 18 multi-locus genotype combinations and RA risk was calculated for each combination using data from Sample Set 1 as described in the Materials and Methods. Assuming a 1% RA prevalence, similar to that observed in the white North American general population, the results indicate that individuals with the protective genotype at all three loci (0SE for HLA-DRB1, CC genotype for PTPN22 and the AGT/AGT TRAF1 diplotype) have a substantially reduced predicted risk of RA (0.29% vs. 1%), whereas those individuals in the highest-risk category (HLA-2SE, TT or TC genotype at PTPN22, and the GCG/GCG TRAF1 diplotype), have an estimated RA risk of 13.06% – representing more than a 45-fold increase in risk (Table S3). These data are presented as a 3-D plot in Figure 4 where the lowest risk value has been reset to 1 and the other values normalized accordingly. Approximately 19% of the general population will find themselves in the low-risk multi-locus genotype category and only 0.06% in the high risk group. In contrast, when the disease prevalence is increased to 30%, as might be observed in high-risk groups such as an early arthritis clinic, the range of risk drops to 7.88-fold, with the posterior probability of RA calculated to be 11% for the lowest-risk genotype combination and increasing to 86.4% in the highest risk category (Table S3).


A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.

Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, van der Helm-van Mil AH, Ardlie KG, Amos CI, Criswell LA, Kastner DL, Gregersen PK, Kurreeman FA, Toes RE, Huizinga TW, Seldin MF, Begovich AB - PLoS Genet. (2008)

Relative risk plotted as a function of the genetic load of three validated RA risk variants in HLA-DRB1, PTPN22 and TRAF1.Individuals are classified according to the number of copies of the HLA-DRB1 shared epitope (0, 1 and 2) (SE-positive HLA-DRB1 alleles found in this sample set were: 0101, 0102, 0401, 0404, 0405, 0408 and 1001), carriage of the W620 PTPN22 missense SNP (TT + CT vs CC) and diplotypes at the TRAF1 SNPs, rs2239657, rs7021880 and rs7021049. The frequency of each combination of markers in cases and controls is highlighted in white (case/control).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481282&req=5

pgen-1000107-g004: Relative risk plotted as a function of the genetic load of three validated RA risk variants in HLA-DRB1, PTPN22 and TRAF1.Individuals are classified according to the number of copies of the HLA-DRB1 shared epitope (0, 1 and 2) (SE-positive HLA-DRB1 alleles found in this sample set were: 0101, 0102, 0401, 0404, 0405, 0408 and 1001), carriage of the W620 PTPN22 missense SNP (TT + CT vs CC) and diplotypes at the TRAF1 SNPs, rs2239657, rs7021880 and rs7021049. The frequency of each combination of markers in cases and controls is highlighted in white (case/control).
Mentions: Given that we have begun to witness the application of associated genetic variants to disease prognosis [42],[43] and thus far we have convincing evidence for three RA-predisposing loci in our studies (HLA-DRB1, PTPN22 and the TRAF1 region), we estimated the risk of RA given genotypes at these three loci under three different possible unconditional RA risk assumptions (i.e. RA disease prevalence values) using Bayes' theorem. In total, there were 18 multi-locus genotype combinations and RA risk was calculated for each combination using data from Sample Set 1 as described in the Materials and Methods. Assuming a 1% RA prevalence, similar to that observed in the white North American general population, the results indicate that individuals with the protective genotype at all three loci (0SE for HLA-DRB1, CC genotype for PTPN22 and the AGT/AGT TRAF1 diplotype) have a substantially reduced predicted risk of RA (0.29% vs. 1%), whereas those individuals in the highest-risk category (HLA-2SE, TT or TC genotype at PTPN22, and the GCG/GCG TRAF1 diplotype), have an estimated RA risk of 13.06% – representing more than a 45-fold increase in risk (Table S3). These data are presented as a 3-D plot in Figure 4 where the lowest risk value has been reset to 1 and the other values normalized accordingly. Approximately 19% of the general population will find themselves in the low-risk multi-locus genotype category and only 0.06% in the high risk group. In contrast, when the disease prevalence is increased to 30%, as might be observed in high-risk groups such as an early arthritis clinic, the range of risk drops to 7.88-fold, with the posterior probability of RA calculated to be 11% for the lowest-risk genotype combination and increasing to 86.4% in the highest risk category (Table S3).

Bottom Line: Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06).Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN.In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs.

View Article: PubMed Central - PubMed

Affiliation: Celera, Alameda, California, United States of America.

ABSTRACT
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

Show MeSH
Related in: MedlinePlus