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Yoko Nagai, Tadashi Imanishi, RAvariome: a genetic risk variants database for rheumatoid arthritis based on assessment of reproducibility between or within human populations, Database, Volume 2013, 2013, bat073, https://doi.org/10.1093/database/bat073
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Abstract
Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease of the joints and is caused by both genetic and environmental factors. In the past six years, genome-wide association studies (GWASs) have identified many risk variants associated with RA. However, not all associations reported from GWASs are reproduced when tested in follow-up studies. To establish a reliable set of RA risk variants, we systematically classified common variants identified in GWASs by the degree of reproducibility among independent studies. We collected comprehensive genetic associations from 90 papers of GWASs and meta-analysis. The genetic variants were assessed according to the statistical significance and reproducibility between or within nine geographical populations. As a result, 82 and 19 single nucleotide polymorphisms (SNPs) were confirmed as intra- and inter-population-reproduced variants, respectively. Interestingly, majority of the intra-population-reproduced variants from European and East Asian populations were not common in two populations, but their nearby genes appeared to be the components of common pathways. Furthermore, a tool to predict the individual’s genetic risk of RA was developed to facilitate personalized medicine and preventive health care. For further clinical researches, the list of reliable genetic variants of RA and the genetic risk prediction tool are provided by open access database RAvariome.
Database URL: http://hinv.jp/hinv/rav/
Introduction
Rheumatoid arthritis (RA; MIM180300) is a common autoimmune disease characterized by the chronic inflammation of the bones and joints. Several epidemiological studies reported that RA prevalence varies among different populations (1). In North America and Northern Europe, the estimated prevalence of RA is 0.5–1.1%, but in Southern Europe, a lower prevalence of 0.3–0.7% has been reported. In East Asia, RA prevalence in the urban areas of Japan and Taiwan is 1.04% and 0.93%, respectively, but that in mainland China ranges from 0.2% to 0.37% (2, 3). Twin studies on RA have led to a heritability estimate for RA of 65% in the Finnish study and 53% in the UK study, and genetic factors account for an estimated 60% of the disease risk (4).
Large numbers of association studies have been conducted, and numerous single nucleotide polymorphisms (SNPs), genes and chromosomal regions have been reported to be associated with RA. Several SNP-trait association databases provide information about RA-associated loci, including the NHGRI Catalog of Published Genome-Wide Association Studies (GWASs) (5), GWASdb (6), GWAS Central (7), HuGE Navigator (8) and PharmGKB (9). On the other hand, some databases have been developed to provide detailed genetic information of a specific disease, e.g. AlzGene (http://www.alzgene.org/) for Alzheimer’s disease, CADgene (http://www.bioguo.org/CADgene/) for coronary artery disease and GOLD.db (https://gold.tugraz.at/) for lipid-associated disorders. There are a few databases focusing on autoimmune diseases; type 1 diabetes database T1Dbase (http://www.t1dbase.org) and Lymphoproliferative syndrome database ALPSbase (http://research.nhgri.nih.gov/ALPS/).
As the first human genetic variation database for RA, RAvariome aims to provide a reliable set of RA risk variants that was systematically assessed according to its reproducibility. Candidate gene association studies and GWASs are known to be vulnerable to a range of errors and biases, especially those arising from differences in the experimental and study designs (10). These problems are reflected in equivocal or inconsistent results and may lead researchers to design inappropriate follow-up studies or medical applications. Accordingly, we have collected association studies comprehensively, classified the studies by ethnicity of subjects, re-evaluated the associations by unified significance level and assessed the associations by population-based reproducibility. All data are publicly available in a regularly updated web database, RAvariome. Additionally, an online tool for predicting the genetic risk of RA for an individual was developed to support further analysis for preventive intervention of genetic RA risk carrier.
Collection and Extraction of Data
We collected 153 English-language literatures from the NHGRI catalog and HuGE Navigator and the automatic paper recommendation system PubMedScan (http://medals.jp/pubmedscan/) (Figure 1). Then, manual screening of their abstracts excluded articles about other autoimmune diseases, pharmacogenomics and gene environment studies. After filtering, 90 literatures about GWASs, fine mapping studies and meta-analyses were kept for further reading. Not only statistically significant but also statistically not significant association results, ethnicity of subjects, the country where subjects were recruited, the total number of cases and controls, the analysis platform and the study design were extracted manually from full text, tables or supplementary data. The association results of human genetic variants included SNPs, HLA alleles, copy number variations and variable number of tandem repeats markers. Finally, 7730 association results were stored in a database.
The results of statistical tests in original literatures were re-evaluated according to the following criteria. We determined two kinds of significance levels for GWAS that assayed genome-wide SNPs and for follow-up study, such as meta-analysis, that assayed only few SNPs of interest. For a GWAS, if the corresponding P-value was <5.0 × 10−8, the result of the statistical analysis was judged as significant evidence of strong association, and P-value between 1.0 × 10−5 and 5.0 × 10–8 was judged as significant evidence of moderate association. Associations with P > 1.0 × 10−5 were judged as not significant. For follow-up study, associations were judged as ‘strong’ for P < 0.01, ‘moderate’ for P-value between 0.01 and 0.05 and ‘not significant’ for P > 0.05. Exceptionally, a meta-analysis of GWAS result and combined analysis of GWAS and replication results were judged by genome-wide significance threshold. According to our significance level, 5970 associations were classified as statistically not significant, and 1760 associations were classified as either strong or moderate associations.
Confirmation of Reproducibility of RA Risk Variants
To confirm reproducibility of genetic associations based on a geographical information, all associations including non-significant results were grouped by the following nine populations; European (including European American, European Australian, European New Zealander, West European, North European, South European and East European), East Asian (including South-East Asian), West Asian, South Asian, South American, Central American, North African, South African and African American. Because many follow-up studies of previous GWAS researches were conducted, the representative association for the variant in each geographical population was selected from the result of a study of the largest number of case subjects. Out of 6740 representative associations, 1296 were statistically significant and remained for further reproducibility assessment. Notably, 34 variants reached significant level in small-scale studies, but were not confirmed by larger studies.
The genetic associations were classified into two classes based on reproducibility between or within population. To assess reproducibility of an association between different populations, the variants that was reproduced by independent representative associations were identified. A genetic variant that showed opposite direction of association between different populations was excluded. Accordingly, 40 representative associations of 19 variants located in 12 loci were confirmed as ‘inter-population reproduced’ based on independent studies of different populations such as African American, Central American, East Asian, European, South American, South Asian and West Asian (Table 1).
Related genes . | SNP-allele . | P-value . | Genotyping coverage . | OR . | Case/control numbers . | Population . | References . |
---|---|---|---|---|---|---|---|
APOM | rs805297-A | 6.65e-005 | Selected | 1.40 | 578/711 | East Asian | Hu HJ, Exp Mol Med, 2011 (11) |
rs805297-A | 1.49e-016 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
CCR6 | rs3093023-A | 2.1e-017 | GW | 1.27 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs3093023-A | 1.5e-011 | GW | 1.12 | 12 307/28 975 | European | Stahl EA, Nat. Genet, 2010 (14) | |
CTLA4, ICOS | rs231775-G | 0.01 | Selected | 1.45 | 199/199 | Central American | Li X, J Clin Immunol, 2012 (15) |
rs231775-G | 0.002 | Selected (Meta) | 1.18 | 2734/1441 | East Asian | Li X, J Clin Immunol, 2012 (15) | |
rs231775 | 0.009 | Selected (Meta) | 1.07 | 6160/6684 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
HLA-DRB1 | rs13192471-G | 1.9e-058 | GW | 1.97 | 2303/3380 | East Asian | Kochi Y, Nat. Genet, 2010 (17) |
rs13192471-G | 6.7e-016 | Selected | 2.16 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs2157337-C | 2.6e-118 | GW | 1.99 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs2157337-C | 1e-299 | GW | 2.50 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs2516049-C | 3.6e-031 | GW | 2.18 | 874/855 | East Asian | Terao C, PLoS One, 2011 (19) | |
rs2516049-C | 1.64e-042 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs6457617-T | 3.44e-076 | GW | 1861/2938 | European | WTCCC, Nature, 2007 (20) | ||
rs6457617-A | 1.6e-009 | Selected | 1.48 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs660895-G | 5.83e-053 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs660895-G | 2.56e-005 | Selected | 1.52 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6910071-G | 1e-299 | GW | 2.88 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs6910071 | 0.04 | Selected | 1.27 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IKZF3a | rs2872507-G | 0.006 | Selected | 0.79 | 440/795 | African American | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2872507-G | 0.003 | Selected | 0.91 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) | |
rs2872507-A | 9.4e-007 | GW | 1.09 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
IL2, IL21 | rs13119723-G | 6.8e-007 | GW | 0.88 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) |
rs13119723-G | 0.008 | Selected | 0.75 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6822844 | 5.89e-008 | Selected (Meta) | 0.88 | 12953/13370 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
rs6822844 | 0.019 | Selected | 0.61 | 354/368 | South American | Maiti AK, Arthritis Rheum, 2010 (22) | |
IL2RA | rs2104286 | 2.48e-05 | Selected (Meta) | 0.91 | 10 112/10 450 | European | Plant D, Ann Rheum Dis, 2010 (16) |
rs2104286-G | 0.00019 | Selected | 0.73 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IL6 | rs1800795-G | 1e-008 | Selected | 0.074 | 120/168 | East Asian | Lee YH, Inflamm Res, 2012 (23) |
rs1800795-G | 7.4e-005 | Selected | 0.46 | 425/247 | West Asian | Lee YH, Inflamm Res, 2012 (23) | |
OLIG3, TNFAIP3 | rs2230926 | 0.032 | Selected | 1.847 | 148/1513 | African American | Lee YH, Inflamm Res, 2012 (23) |
rs2230926-C | 1.6e-006 | GW | 1.31 | 7069/15 876 | East Asian | Kochi Y, Nat Gen*et, 2010 (17) | |
rs5029937-T | 3.9e-009 | GW | 1.33 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs5029937 | 4.62e-010 | Selected (Meta) | 1.42 | 7731/9403 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
SPRED2 | rs934734-G | 3.2e-007 | GW | 1.19 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs934734-G | 5.3e-010 | GW | 1.13 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
STAT4 | rs7574865-T | 1.8e-006 | GW | 1.17 | 7069/15 876 | East Asian | Kochi Y, Nat Genet, 2010 (17) |
rs7574865 | 2.99e-015 | Selected (Meta) | 1.18 | 14 394/16 131 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
ZEB1a | rs2793108-T | 0.001 | Selected | 1.11 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2793108-C | 0.006 | Selected | 0.84 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) |
Related genes . | SNP-allele . | P-value . | Genotyping coverage . | OR . | Case/control numbers . | Population . | References . |
---|---|---|---|---|---|---|---|
APOM | rs805297-A | 6.65e-005 | Selected | 1.40 | 578/711 | East Asian | Hu HJ, Exp Mol Med, 2011 (11) |
rs805297-A | 1.49e-016 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
CCR6 | rs3093023-A | 2.1e-017 | GW | 1.27 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs3093023-A | 1.5e-011 | GW | 1.12 | 12 307/28 975 | European | Stahl EA, Nat. Genet, 2010 (14) | |
CTLA4, ICOS | rs231775-G | 0.01 | Selected | 1.45 | 199/199 | Central American | Li X, J Clin Immunol, 2012 (15) |
rs231775-G | 0.002 | Selected (Meta) | 1.18 | 2734/1441 | East Asian | Li X, J Clin Immunol, 2012 (15) | |
rs231775 | 0.009 | Selected (Meta) | 1.07 | 6160/6684 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
HLA-DRB1 | rs13192471-G | 1.9e-058 | GW | 1.97 | 2303/3380 | East Asian | Kochi Y, Nat. Genet, 2010 (17) |
rs13192471-G | 6.7e-016 | Selected | 2.16 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs2157337-C | 2.6e-118 | GW | 1.99 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs2157337-C | 1e-299 | GW | 2.50 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs2516049-C | 3.6e-031 | GW | 2.18 | 874/855 | East Asian | Terao C, PLoS One, 2011 (19) | |
rs2516049-C | 1.64e-042 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs6457617-T | 3.44e-076 | GW | 1861/2938 | European | WTCCC, Nature, 2007 (20) | ||
rs6457617-A | 1.6e-009 | Selected | 1.48 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs660895-G | 5.83e-053 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs660895-G | 2.56e-005 | Selected | 1.52 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6910071-G | 1e-299 | GW | 2.88 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs6910071 | 0.04 | Selected | 1.27 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IKZF3a | rs2872507-G | 0.006 | Selected | 0.79 | 440/795 | African American | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2872507-G | 0.003 | Selected | 0.91 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) | |
rs2872507-A | 9.4e-007 | GW | 1.09 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
IL2, IL21 | rs13119723-G | 6.8e-007 | GW | 0.88 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) |
rs13119723-G | 0.008 | Selected | 0.75 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6822844 | 5.89e-008 | Selected (Meta) | 0.88 | 12953/13370 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
rs6822844 | 0.019 | Selected | 0.61 | 354/368 | South American | Maiti AK, Arthritis Rheum, 2010 (22) | |
IL2RA | rs2104286 | 2.48e-05 | Selected (Meta) | 0.91 | 10 112/10 450 | European | Plant D, Ann Rheum Dis, 2010 (16) |
rs2104286-G | 0.00019 | Selected | 0.73 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IL6 | rs1800795-G | 1e-008 | Selected | 0.074 | 120/168 | East Asian | Lee YH, Inflamm Res, 2012 (23) |
rs1800795-G | 7.4e-005 | Selected | 0.46 | 425/247 | West Asian | Lee YH, Inflamm Res, 2012 (23) | |
OLIG3, TNFAIP3 | rs2230926 | 0.032 | Selected | 1.847 | 148/1513 | African American | Lee YH, Inflamm Res, 2012 (23) |
rs2230926-C | 1.6e-006 | GW | 1.31 | 7069/15 876 | East Asian | Kochi Y, Nat Gen*et, 2010 (17) | |
rs5029937-T | 3.9e-009 | GW | 1.33 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs5029937 | 4.62e-010 | Selected (Meta) | 1.42 | 7731/9403 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
SPRED2 | rs934734-G | 3.2e-007 | GW | 1.19 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs934734-G | 5.3e-010 | GW | 1.13 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
STAT4 | rs7574865-T | 1.8e-006 | GW | 1.17 | 7069/15 876 | East Asian | Kochi Y, Nat Genet, 2010 (17) |
rs7574865 | 2.99e-015 | Selected (Meta) | 1.18 | 14 394/16 131 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
ZEB1a | rs2793108-T | 0.001 | Selected | 1.11 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2793108-C | 0.006 | Selected | 0.84 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) |
aConfirmed RA risk loci that were not mentioned in RA reviews (10, 24–27). Related genes, refSNP ID and allele, association P-value, study type to set significance level, OR, sample sizes of case/control, geographical population of samples and references are shown. Genotyping coverage indicated whether the study assayed genome-wide (GW) SNPs or selected SNPs.
Related genes . | SNP-allele . | P-value . | Genotyping coverage . | OR . | Case/control numbers . | Population . | References . |
---|---|---|---|---|---|---|---|
APOM | rs805297-A | 6.65e-005 | Selected | 1.40 | 578/711 | East Asian | Hu HJ, Exp Mol Med, 2011 (11) |
rs805297-A | 1.49e-016 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
CCR6 | rs3093023-A | 2.1e-017 | GW | 1.27 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs3093023-A | 1.5e-011 | GW | 1.12 | 12 307/28 975 | European | Stahl EA, Nat. Genet, 2010 (14) | |
CTLA4, ICOS | rs231775-G | 0.01 | Selected | 1.45 | 199/199 | Central American | Li X, J Clin Immunol, 2012 (15) |
rs231775-G | 0.002 | Selected (Meta) | 1.18 | 2734/1441 | East Asian | Li X, J Clin Immunol, 2012 (15) | |
rs231775 | 0.009 | Selected (Meta) | 1.07 | 6160/6684 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
HLA-DRB1 | rs13192471-G | 1.9e-058 | GW | 1.97 | 2303/3380 | East Asian | Kochi Y, Nat. Genet, 2010 (17) |
rs13192471-G | 6.7e-016 | Selected | 2.16 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs2157337-C | 2.6e-118 | GW | 1.99 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs2157337-C | 1e-299 | GW | 2.50 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs2516049-C | 3.6e-031 | GW | 2.18 | 874/855 | East Asian | Terao C, PLoS One, 2011 (19) | |
rs2516049-C | 1.64e-042 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs6457617-T | 3.44e-076 | GW | 1861/2938 | European | WTCCC, Nature, 2007 (20) | ||
rs6457617-A | 1.6e-009 | Selected | 1.48 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs660895-G | 5.83e-053 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs660895-G | 2.56e-005 | Selected | 1.52 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6910071-G | 1e-299 | GW | 2.88 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs6910071 | 0.04 | Selected | 1.27 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IKZF3a | rs2872507-G | 0.006 | Selected | 0.79 | 440/795 | African American | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2872507-G | 0.003 | Selected | 0.91 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) | |
rs2872507-A | 9.4e-007 | GW | 1.09 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
IL2, IL21 | rs13119723-G | 6.8e-007 | GW | 0.88 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) |
rs13119723-G | 0.008 | Selected | 0.75 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6822844 | 5.89e-008 | Selected (Meta) | 0.88 | 12953/13370 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
rs6822844 | 0.019 | Selected | 0.61 | 354/368 | South American | Maiti AK, Arthritis Rheum, 2010 (22) | |
IL2RA | rs2104286 | 2.48e-05 | Selected (Meta) | 0.91 | 10 112/10 450 | European | Plant D, Ann Rheum Dis, 2010 (16) |
rs2104286-G | 0.00019 | Selected | 0.73 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IL6 | rs1800795-G | 1e-008 | Selected | 0.074 | 120/168 | East Asian | Lee YH, Inflamm Res, 2012 (23) |
rs1800795-G | 7.4e-005 | Selected | 0.46 | 425/247 | West Asian | Lee YH, Inflamm Res, 2012 (23) | |
OLIG3, TNFAIP3 | rs2230926 | 0.032 | Selected | 1.847 | 148/1513 | African American | Lee YH, Inflamm Res, 2012 (23) |
rs2230926-C | 1.6e-006 | GW | 1.31 | 7069/15 876 | East Asian | Kochi Y, Nat Gen*et, 2010 (17) | |
rs5029937-T | 3.9e-009 | GW | 1.33 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs5029937 | 4.62e-010 | Selected (Meta) | 1.42 | 7731/9403 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
SPRED2 | rs934734-G | 3.2e-007 | GW | 1.19 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs934734-G | 5.3e-010 | GW | 1.13 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
STAT4 | rs7574865-T | 1.8e-006 | GW | 1.17 | 7069/15 876 | East Asian | Kochi Y, Nat Genet, 2010 (17) |
rs7574865 | 2.99e-015 | Selected (Meta) | 1.18 | 14 394/16 131 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
ZEB1a | rs2793108-T | 0.001 | Selected | 1.11 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2793108-C | 0.006 | Selected | 0.84 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) |
Related genes . | SNP-allele . | P-value . | Genotyping coverage . | OR . | Case/control numbers . | Population . | References . |
---|---|---|---|---|---|---|---|
APOM | rs805297-A | 6.65e-005 | Selected | 1.40 | 578/711 | East Asian | Hu HJ, Exp Mol Med, 2011 (11) |
rs805297-A | 1.49e-016 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
CCR6 | rs3093023-A | 2.1e-017 | GW | 1.27 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs3093023-A | 1.5e-011 | GW | 1.12 | 12 307/28 975 | European | Stahl EA, Nat. Genet, 2010 (14) | |
CTLA4, ICOS | rs231775-G | 0.01 | Selected | 1.45 | 199/199 | Central American | Li X, J Clin Immunol, 2012 (15) |
rs231775-G | 0.002 | Selected (Meta) | 1.18 | 2734/1441 | East Asian | Li X, J Clin Immunol, 2012 (15) | |
rs231775 | 0.009 | Selected (Meta) | 1.07 | 6160/6684 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
HLA-DRB1 | rs13192471-G | 1.9e-058 | GW | 1.97 | 2303/3380 | East Asian | Kochi Y, Nat. Genet, 2010 (17) |
rs13192471-G | 6.7e-016 | Selected | 2.16 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs2157337-C | 2.6e-118 | GW | 1.99 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs2157337-C | 1e-299 | GW | 2.50 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs2516049-C | 3.6e-031 | GW | 2.18 | 874/855 | East Asian | Terao C, PLoS One, 2011 (19) | |
rs2516049-C | 1.64e-042 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs6457617-T | 3.44e-076 | GW | 1861/2938 | European | WTCCC, Nature, 2007 (20) | ||
rs6457617-A | 1.6e-009 | Selected | 1.48 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs660895-G | 5.83e-053 | GW | 1147/1079 | European | Padyukov L, Ann Rheum Dis, 2011 (12) | ||
rs660895-G | 2.56e-005 | Selected | 1.52 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6910071-G | 1e-299 | GW | 2.88 | 5539/20 169 | European | Stahl EA, Nat Genet, 2010 (14) | |
rs6910071 | 0.04 | Selected | 1.27 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IKZF3a | rs2872507-G | 0.006 | Selected | 0.79 | 440/795 | African American | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2872507-G | 0.003 | Selected | 0.91 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) | |
rs2872507-A | 9.4e-007 | GW | 1.09 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
IL2, IL21 | rs13119723-G | 6.8e-007 | GW | 0.88 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) |
rs13119723-G | 0.008 | Selected | 0.75 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
rs6822844 | 5.89e-008 | Selected (Meta) | 0.88 | 12953/13370 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
rs6822844 | 0.019 | Selected | 0.61 | 354/368 | South American | Maiti AK, Arthritis Rheum, 2010 (22) | |
IL2RA | rs2104286 | 2.48e-05 | Selected (Meta) | 0.91 | 10 112/10 450 | European | Plant D, Ann Rheum Dis, 2010 (16) |
rs2104286-G | 0.00019 | Selected | 0.73 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) | |
IL6 | rs1800795-G | 1e-008 | Selected | 0.074 | 120/168 | East Asian | Lee YH, Inflamm Res, 2012 (23) |
rs1800795-G | 7.4e-005 | Selected | 0.46 | 425/247 | West Asian | Lee YH, Inflamm Res, 2012 (23) | |
OLIG3, TNFAIP3 | rs2230926 | 0.032 | Selected | 1.847 | 148/1513 | African American | Lee YH, Inflamm Res, 2012 (23) |
rs2230926-C | 1.6e-006 | GW | 1.31 | 7069/15 876 | East Asian | Kochi Y, Nat Gen*et, 2010 (17) | |
rs5029937-T | 3.9e-009 | GW | 1.33 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) | |
rs5029937 | 4.62e-010 | Selected (Meta) | 1.42 | 7731/9403 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
SPRED2 | rs934734-G | 3.2e-007 | GW | 1.19 | 4074/16 891 | East Asian | Okada Y, Nat Genet, 2012 (13) |
rs934734-G | 5.3e-010 | GW | 1.13 | 12 307/28 975 | European | Stahl EA, Nat Genet, 2010 (14) | |
STAT4 | rs7574865-T | 1.8e-006 | GW | 1.17 | 7069/15 876 | East Asian | Kochi Y, Nat Genet, 2010 (17) |
rs7574865 | 2.99e-015 | Selected (Meta) | 1.18 | 14 394/16 131 | European | Plant D, Ann Rheum Dis, 2010 (16) | |
ZEB1a | rs2793108-T | 0.001 | Selected | 1.11 | 2414/14 245 | East Asian | Kurreeman FA, Am J Hum Genet, 2012 (21) |
rs2793108-C | 0.006 | Selected | 0.84 | 983/1007 | South Asian | Prasad P, PLoS One, 2012 (18) |
aConfirmed RA risk loci that were not mentioned in RA reviews (10, 24–27). Related genes, refSNP ID and allele, association P-value, study type to set significance level, OR, sample sizes of case/control, geographical population of samples and references are shown. Genotyping coverage indicated whether the study assayed genome-wide (GW) SNPs or selected SNPs.
To assess reproducibility of an association within the particular population, we identified the statistically significant representative association that was reproduced by an independent study of the same population. As a result, associations of 82 variants were confirmed as ‘intra-population reproduced’. Intra-population reproduced variants were only reported in European and East Asian populations (53 SNPs and 29 SNPs, respectively).
Prediction of Genetic RA Risk
To facilitate personalized medicine and preventive health care, a tool to calculate genetic risk of RA for an individual was developed based on confirmed RA risk variants (intra- and inter-population-reproduced variants). To avoid overestimation, if confirmed RA risk variants are closely located to each other, i.e. in the same linkage disequilibrium block, only the genetic variant with a smaller P-value was used as a risk marker of that locus.
RAvariome Web Interface and Usage
To provide our results and a genetic risk prediction tool for researchers and clinicians, a web database RAvariome was developed. By comparing number of literatures and association data with other existing literature-based GWAS databases, RAvariome provides the most comprehensive dataset of associations of RA (Table 2). RAvariome consists of four sections: overview of RA, the list of confirmed RA variants, the collection of reported RA associations and genetic risk prediction tool. In the overview section, the heritability, environmental factors and protective factors of RA are described.
Database . | Condition of literature collection . | Number of literatures . | Condition of data collection . | Number of associations . |
---|---|---|---|---|
RAvariome | RA GWAS and follow-up studies | 90 | All associations described in literature | 7730 |
NHGRI GWAS catalog (5) | GWAS literature | 14a | Associations reached P-values <1.0 × 10−5 | 96a |
HuGE Navigator (8) | GWAS literature | 40a | 84a | |
meta-analysis | 98a | |||
GWASdb (6) | GWAS literature and dataset from GAD | Associations reached P-values <1.0 × 10−3 | 1748b |
Database . | Condition of literature collection . | Number of literatures . | Condition of data collection . | Number of associations . |
---|---|---|---|---|
RAvariome | RA GWAS and follow-up studies | 90 | All associations described in literature | 7730 |
NHGRI GWAS catalog (5) | GWAS literature | 14a | Associations reached P-values <1.0 × 10−5 | 96a |
HuGE Navigator (8) | GWAS literature | 40a | 84a | |
meta-analysis | 98a | |||
GWASdb (6) | GWAS literature and dataset from GAD | Associations reached P-values <1.0 × 10−3 | 1748b |
aThe number for HuGE Navigator and NHGRI GWAS catalog were obtained by searching the term ‘rheumatoid arthritis’ at 12 March 2013. bFor GWASdb, number of data was the result as of July 2012.
Database . | Condition of literature collection . | Number of literatures . | Condition of data collection . | Number of associations . |
---|---|---|---|---|
RAvariome | RA GWAS and follow-up studies | 90 | All associations described in literature | 7730 |
NHGRI GWAS catalog (5) | GWAS literature | 14a | Associations reached P-values <1.0 × 10−5 | 96a |
HuGE Navigator (8) | GWAS literature | 40a | 84a | |
meta-analysis | 98a | |||
GWASdb (6) | GWAS literature and dataset from GAD | Associations reached P-values <1.0 × 10−3 | 1748b |
Database . | Condition of literature collection . | Number of literatures . | Condition of data collection . | Number of associations . |
---|---|---|---|---|
RAvariome | RA GWAS and follow-up studies | 90 | All associations described in literature | 7730 |
NHGRI GWAS catalog (5) | GWAS literature | 14a | Associations reached P-values <1.0 × 10−5 | 96a |
HuGE Navigator (8) | GWAS literature | 40a | 84a | |
meta-analysis | 98a | |||
GWASdb (6) | GWAS literature and dataset from GAD | Associations reached P-values <1.0 × 10−3 | 1748b |
aThe number for HuGE Navigator and NHGRI GWAS catalog were obtained by searching the term ‘rheumatoid arthritis’ at 12 March 2013. bFor GWASdb, number of data was the result as of July 2012.
The page entitled ‘Confirmed RA variants’ provides users a list of genetic variants with the reproducibility class (Figure 2A). The list provides detailed study information of the representative association of the specific variant and the particular geographical population. In this section, users can search the confirmed RA risk variants by the reproducibility class, the geographical population of the subjects, a gene name or refSNP ID.
The page entitled ‘Reported RA associations’ leads users to a list of all statistically significant and statistically not significant associations described in literatures. Users can search association data by study design, geographical population of the subjects, nationality of the subjects, number of subjects and sub-phenotype of cases such as cases with 100% seropositive for rheumatoid factor and/or anti-CCP.
The page entitled ‘Genetic risk predictor’ provides a tool for predicting the genetic risk of RA calculated by the ethnicity and genotypes of an individual (Figure 2B). By choosing a population from either European or East Asian, the confirmed RA risk markers and their common three genotypes are displayed in the list. Users can select one genotype for each risk marker, and selected genotypes will be used for estimation of RGR and GRS. RGR is the index that assumed the risk of average population as baseline. GRS is the index that assumed non-risk allele carrier as baseline and used in basic researches. For example, if genotypes AG for rs3761847, AA for rs2476601 and GA for rs6920220 are selected at the European population, a predicted lifetime risk will be 2.6%, 2.6-fold higher than the prevalence of RA in general European population (1%).
Discussion
RAvariome was developed to provide a list of RA-associated genetic variants with the degree of reproducibility, based on comprehensive re-evaluated results of the genetic association studies. By comparing our results with reviews (10, 24–27) of RA, we found that two loci from inter-population-reproduced variants were not reported in reviews and have been validated in recent meta-analyses (Table 1). Thus, we conclude that our database provides the newest and most reliable genetic risk variants based on the comparative verification.
As the intra-population-reproduced variants were observed only in European and East Asian populations, we used gene set enrichment analysis (32) to discover common functional mechanisms underlying different gene sets confirmed specifically in European and East Asian populations. From inter- and intra-reproduced-variants, 10 genes were confirmed in both European and East Asian populations, although 39 and 30 genes were confirmed only in the European and East Asian populations, respectively. Interestingly, the European and East Asian unique gene sets had the following gene sets in common: genes involved in immune system, gene upregulated by CD40 signaling in Ramos cells, genes upregulated in TK6, WTK1 and NH32 cell lines in response to ionizing radiation, genes modulated in HeLa cells by TNF via NFKB pathway, genes whose promoters are bounded by FOXP3 based on a chromatin immunoprecipitation (ChIP)-chip analysis, genes involved in cytokine signaling in immune system and genes downregulated in freshly isolated CD31− versus the CD31+ counterparts (Table 3). This result suggested that even if the same genes were not reproduced between European and East Asian populations, several pathways were common in both populations.
Description of MSigDB gene set (number of genes in gene set) . | European unique 39 genes . | East Asian unique 30 genes . | ||||
---|---|---|---|---|---|---|
Genes in overlap . | P-value . | FDR q-valuea . | Genes in overlap . | P-value . | FDR q-valuea . | |
Genes involved in Immune System (933) | CD40, HLA-DPB1, IRF5, CD28, IL2, IL2RA, CD226, IL2RB, TNFRSF14, IL6ST, C5, PRKCQ, REL, KIF5A | 3.89E-15 | 2.34E-11 | NFKBIE, IL6, IRF8, IRF4, CSF2, PTPN2 | 8.13E-06 | 2.26E-03 |
Genes upregulated by CD40 (GeneID = 958) signaling in Ramos cells (EBV negative Burkitt lymphoma) (101). | CD40, HLA-DPB1, IRF5, CD58, BATF, TRAF1, SH2B3 | 1.45E-12 | 4.35E-09 | CD83, NFKBIE, ARID5B, IRF4 | 2.54E-07 | 2.18E-04 |
Genes upregulated in TK6, WTK1 and NH32 cell lines (lymphoblast) in response to ionizing radiation (149). | IL2RB, BATF, TRAF1, CCL21, CDK6, PTPN22 | 1.74E-09 | 8.73E-07 | CD83, NFKBIE, IRF4 | 7.01E-05 | 1.11E-02 |
Genes involved in cytokine signaling in immune system (270). | HLA-DPB1, IRF5, IL2, IL2RA, IL2RB, IL6ST | 6.04E-08 | 1.91E-05 | IL6, IRF8, IRF4, CSF2, PTPN2 | 3.05E-07 | 2.29E-04 |
Genes whose promoters are bound by FOXP3 (GeneID = 50943) based a ChIP-chip analysis (491). | CD28, IL2RA, CD226, IL6ST, PRKCQ, PTPN22, ANKRD55 | 8.89E-08 | 2.67E-05 | ETS1, ARID5B, B3GNT2, IRF4, PRKCH, FLI1, EXOC2 | 5.66E-09 | 1.13E-05 |
Genes upregulated in the normal-like subtype of breast cancer (476). | CD40, PRKCQ, HLA-DRA, CD2, CCL21, PTPN22 | 1.66E-06 | 2.68E-04 | IL6, IRF8, FLI1, PDE2A | 1.15E-04 | 1.47E-02 |
Genes upregulated in prostate cancer samples from African-American patients compared with those from the European-American patients. | HLA-DPB1, CD28, HLA-DRA, CD2, PTPN22 | 3.38E-06 | 4.83E-04 | CD83, IRF8, FLI1 | 5.43E-04 | 3.82E-02 |
Genes from common genomic gains observed in a meta-analysis of copy number alterations across a panel of different cancer cell lines and tumor samples (323). | IL2, REL, CDK6, DDX6, AFF3 | 4.91E-06 | 6.29E-04 | IRF4, FLI1, MN1 | 6.79E-04 | 4.39E-02 |
Calcineurin-regulated NFAT-dependent transcription in lymphocytes (47). | IL2, IL2RA, PRKCQ | 6.72E-06 | 8.24E-04 | IRF4, CSF2 | 2.95E-04 | 2.70E-02 |
Genes downregulated in freshly isolated CD31− [GeneID = 5175] (stromal stem cells from adipose tissue) versus the CD31+ (non-stem) counterparts (216). | HLA-DPB1, SH2B3, HLA-DRA, PODXL | 2.36E-05 | 2.49E-03 | PRKCH, FLI1, ANXA3, PDE2A | 5.27E-06 | 1.90E-03 |
Genes modulated in HeLa cells (cervical carcinoma) by TNF [GeneID = 7124] via NFKB pathway (28). | REL, TRAF1 | 2.17E-04 | 1.55E-02 | CD83, NFKBIE, GCH1, IL6 | 1.31E-09 | 7.87E-06 |
Cytokines and inflammatory response (29). | IL2, HLA-DRA | 2.33E-04 | 1.57E-02 | IL6, CSF2 | 1.11E-04 | 1.47E-02 |
Description of MSigDB gene set (number of genes in gene set) . | European unique 39 genes . | East Asian unique 30 genes . | ||||
---|---|---|---|---|---|---|
Genes in overlap . | P-value . | FDR q-valuea . | Genes in overlap . | P-value . | FDR q-valuea . | |
Genes involved in Immune System (933) | CD40, HLA-DPB1, IRF5, CD28, IL2, IL2RA, CD226, IL2RB, TNFRSF14, IL6ST, C5, PRKCQ, REL, KIF5A | 3.89E-15 | 2.34E-11 | NFKBIE, IL6, IRF8, IRF4, CSF2, PTPN2 | 8.13E-06 | 2.26E-03 |
Genes upregulated by CD40 (GeneID = 958) signaling in Ramos cells (EBV negative Burkitt lymphoma) (101). | CD40, HLA-DPB1, IRF5, CD58, BATF, TRAF1, SH2B3 | 1.45E-12 | 4.35E-09 | CD83, NFKBIE, ARID5B, IRF4 | 2.54E-07 | 2.18E-04 |
Genes upregulated in TK6, WTK1 and NH32 cell lines (lymphoblast) in response to ionizing radiation (149). | IL2RB, BATF, TRAF1, CCL21, CDK6, PTPN22 | 1.74E-09 | 8.73E-07 | CD83, NFKBIE, IRF4 | 7.01E-05 | 1.11E-02 |
Genes involved in cytokine signaling in immune system (270). | HLA-DPB1, IRF5, IL2, IL2RA, IL2RB, IL6ST | 6.04E-08 | 1.91E-05 | IL6, IRF8, IRF4, CSF2, PTPN2 | 3.05E-07 | 2.29E-04 |
Genes whose promoters are bound by FOXP3 (GeneID = 50943) based a ChIP-chip analysis (491). | CD28, IL2RA, CD226, IL6ST, PRKCQ, PTPN22, ANKRD55 | 8.89E-08 | 2.67E-05 | ETS1, ARID5B, B3GNT2, IRF4, PRKCH, FLI1, EXOC2 | 5.66E-09 | 1.13E-05 |
Genes upregulated in the normal-like subtype of breast cancer (476). | CD40, PRKCQ, HLA-DRA, CD2, CCL21, PTPN22 | 1.66E-06 | 2.68E-04 | IL6, IRF8, FLI1, PDE2A | 1.15E-04 | 1.47E-02 |
Genes upregulated in prostate cancer samples from African-American patients compared with those from the European-American patients. | HLA-DPB1, CD28, HLA-DRA, CD2, PTPN22 | 3.38E-06 | 4.83E-04 | CD83, IRF8, FLI1 | 5.43E-04 | 3.82E-02 |
Genes from common genomic gains observed in a meta-analysis of copy number alterations across a panel of different cancer cell lines and tumor samples (323). | IL2, REL, CDK6, DDX6, AFF3 | 4.91E-06 | 6.29E-04 | IRF4, FLI1, MN1 | 6.79E-04 | 4.39E-02 |
Calcineurin-regulated NFAT-dependent transcription in lymphocytes (47). | IL2, IL2RA, PRKCQ | 6.72E-06 | 8.24E-04 | IRF4, CSF2 | 2.95E-04 | 2.70E-02 |
Genes downregulated in freshly isolated CD31− [GeneID = 5175] (stromal stem cells from adipose tissue) versus the CD31+ (non-stem) counterparts (216). | HLA-DPB1, SH2B3, HLA-DRA, PODXL | 2.36E-05 | 2.49E-03 | PRKCH, FLI1, ANXA3, PDE2A | 5.27E-06 | 1.90E-03 |
Genes modulated in HeLa cells (cervical carcinoma) by TNF [GeneID = 7124] via NFKB pathway (28). | REL, TRAF1 | 2.17E-04 | 1.55E-02 | CD83, NFKBIE, GCH1, IL6 | 1.31E-09 | 7.87E-06 |
Cytokines and inflammatory response (29). | IL2, HLA-DRA | 2.33E-04 | 1.57E-02 | IL6, CSF2 | 1.11E-04 | 1.47E-02 |
aThe gene set enrichment analysis was performed by computing overlaps between the population unique genes and gene sets of positional (c1), curated (c2) and motif (c3) of MSigDB (32). The MSigDB gene sets listed in left column were significantly enriched in both populations at 5% false discovery rate (FDR) q-value.
Description of MSigDB gene set (number of genes in gene set) . | European unique 39 genes . | East Asian unique 30 genes . | ||||
---|---|---|---|---|---|---|
Genes in overlap . | P-value . | FDR q-valuea . | Genes in overlap . | P-value . | FDR q-valuea . | |
Genes involved in Immune System (933) | CD40, HLA-DPB1, IRF5, CD28, IL2, IL2RA, CD226, IL2RB, TNFRSF14, IL6ST, C5, PRKCQ, REL, KIF5A | 3.89E-15 | 2.34E-11 | NFKBIE, IL6, IRF8, IRF4, CSF2, PTPN2 | 8.13E-06 | 2.26E-03 |
Genes upregulated by CD40 (GeneID = 958) signaling in Ramos cells (EBV negative Burkitt lymphoma) (101). | CD40, HLA-DPB1, IRF5, CD58, BATF, TRAF1, SH2B3 | 1.45E-12 | 4.35E-09 | CD83, NFKBIE, ARID5B, IRF4 | 2.54E-07 | 2.18E-04 |
Genes upregulated in TK6, WTK1 and NH32 cell lines (lymphoblast) in response to ionizing radiation (149). | IL2RB, BATF, TRAF1, CCL21, CDK6, PTPN22 | 1.74E-09 | 8.73E-07 | CD83, NFKBIE, IRF4 | 7.01E-05 | 1.11E-02 |
Genes involved in cytokine signaling in immune system (270). | HLA-DPB1, IRF5, IL2, IL2RA, IL2RB, IL6ST | 6.04E-08 | 1.91E-05 | IL6, IRF8, IRF4, CSF2, PTPN2 | 3.05E-07 | 2.29E-04 |
Genes whose promoters are bound by FOXP3 (GeneID = 50943) based a ChIP-chip analysis (491). | CD28, IL2RA, CD226, IL6ST, PRKCQ, PTPN22, ANKRD55 | 8.89E-08 | 2.67E-05 | ETS1, ARID5B, B3GNT2, IRF4, PRKCH, FLI1, EXOC2 | 5.66E-09 | 1.13E-05 |
Genes upregulated in the normal-like subtype of breast cancer (476). | CD40, PRKCQ, HLA-DRA, CD2, CCL21, PTPN22 | 1.66E-06 | 2.68E-04 | IL6, IRF8, FLI1, PDE2A | 1.15E-04 | 1.47E-02 |
Genes upregulated in prostate cancer samples from African-American patients compared with those from the European-American patients. | HLA-DPB1, CD28, HLA-DRA, CD2, PTPN22 | 3.38E-06 | 4.83E-04 | CD83, IRF8, FLI1 | 5.43E-04 | 3.82E-02 |
Genes from common genomic gains observed in a meta-analysis of copy number alterations across a panel of different cancer cell lines and tumor samples (323). | IL2, REL, CDK6, DDX6, AFF3 | 4.91E-06 | 6.29E-04 | IRF4, FLI1, MN1 | 6.79E-04 | 4.39E-02 |
Calcineurin-regulated NFAT-dependent transcription in lymphocytes (47). | IL2, IL2RA, PRKCQ | 6.72E-06 | 8.24E-04 | IRF4, CSF2 | 2.95E-04 | 2.70E-02 |
Genes downregulated in freshly isolated CD31− [GeneID = 5175] (stromal stem cells from adipose tissue) versus the CD31+ (non-stem) counterparts (216). | HLA-DPB1, SH2B3, HLA-DRA, PODXL | 2.36E-05 | 2.49E-03 | PRKCH, FLI1, ANXA3, PDE2A | 5.27E-06 | 1.90E-03 |
Genes modulated in HeLa cells (cervical carcinoma) by TNF [GeneID = 7124] via NFKB pathway (28). | REL, TRAF1 | 2.17E-04 | 1.55E-02 | CD83, NFKBIE, GCH1, IL6 | 1.31E-09 | 7.87E-06 |
Cytokines and inflammatory response (29). | IL2, HLA-DRA | 2.33E-04 | 1.57E-02 | IL6, CSF2 | 1.11E-04 | 1.47E-02 |
Description of MSigDB gene set (number of genes in gene set) . | European unique 39 genes . | East Asian unique 30 genes . | ||||
---|---|---|---|---|---|---|
Genes in overlap . | P-value . | FDR q-valuea . | Genes in overlap . | P-value . | FDR q-valuea . | |
Genes involved in Immune System (933) | CD40, HLA-DPB1, IRF5, CD28, IL2, IL2RA, CD226, IL2RB, TNFRSF14, IL6ST, C5, PRKCQ, REL, KIF5A | 3.89E-15 | 2.34E-11 | NFKBIE, IL6, IRF8, IRF4, CSF2, PTPN2 | 8.13E-06 | 2.26E-03 |
Genes upregulated by CD40 (GeneID = 958) signaling in Ramos cells (EBV negative Burkitt lymphoma) (101). | CD40, HLA-DPB1, IRF5, CD58, BATF, TRAF1, SH2B3 | 1.45E-12 | 4.35E-09 | CD83, NFKBIE, ARID5B, IRF4 | 2.54E-07 | 2.18E-04 |
Genes upregulated in TK6, WTK1 and NH32 cell lines (lymphoblast) in response to ionizing radiation (149). | IL2RB, BATF, TRAF1, CCL21, CDK6, PTPN22 | 1.74E-09 | 8.73E-07 | CD83, NFKBIE, IRF4 | 7.01E-05 | 1.11E-02 |
Genes involved in cytokine signaling in immune system (270). | HLA-DPB1, IRF5, IL2, IL2RA, IL2RB, IL6ST | 6.04E-08 | 1.91E-05 | IL6, IRF8, IRF4, CSF2, PTPN2 | 3.05E-07 | 2.29E-04 |
Genes whose promoters are bound by FOXP3 (GeneID = 50943) based a ChIP-chip analysis (491). | CD28, IL2RA, CD226, IL6ST, PRKCQ, PTPN22, ANKRD55 | 8.89E-08 | 2.67E-05 | ETS1, ARID5B, B3GNT2, IRF4, PRKCH, FLI1, EXOC2 | 5.66E-09 | 1.13E-05 |
Genes upregulated in the normal-like subtype of breast cancer (476). | CD40, PRKCQ, HLA-DRA, CD2, CCL21, PTPN22 | 1.66E-06 | 2.68E-04 | IL6, IRF8, FLI1, PDE2A | 1.15E-04 | 1.47E-02 |
Genes upregulated in prostate cancer samples from African-American patients compared with those from the European-American patients. | HLA-DPB1, CD28, HLA-DRA, CD2, PTPN22 | 3.38E-06 | 4.83E-04 | CD83, IRF8, FLI1 | 5.43E-04 | 3.82E-02 |
Genes from common genomic gains observed in a meta-analysis of copy number alterations across a panel of different cancer cell lines and tumor samples (323). | IL2, REL, CDK6, DDX6, AFF3 | 4.91E-06 | 6.29E-04 | IRF4, FLI1, MN1 | 6.79E-04 | 4.39E-02 |
Calcineurin-regulated NFAT-dependent transcription in lymphocytes (47). | IL2, IL2RA, PRKCQ | 6.72E-06 | 8.24E-04 | IRF4, CSF2 | 2.95E-04 | 2.70E-02 |
Genes downregulated in freshly isolated CD31− [GeneID = 5175] (stromal stem cells from adipose tissue) versus the CD31+ (non-stem) counterparts (216). | HLA-DPB1, SH2B3, HLA-DRA, PODXL | 2.36E-05 | 2.49E-03 | PRKCH, FLI1, ANXA3, PDE2A | 5.27E-06 | 1.90E-03 |
Genes modulated in HeLa cells (cervical carcinoma) by TNF [GeneID = 7124] via NFKB pathway (28). | REL, TRAF1 | 2.17E-04 | 1.55E-02 | CD83, NFKBIE, GCH1, IL6 | 1.31E-09 | 7.87E-06 |
Cytokines and inflammatory response (29). | IL2, HLA-DRA | 2.33E-04 | 1.57E-02 | IL6, CSF2 | 1.11E-04 | 1.47E-02 |
aThe gene set enrichment analysis was performed by computing overlaps between the population unique genes and gene sets of positional (c1), curated (c2) and motif (c3) of MSigDB (32). The MSigDB gene sets listed in left column were significantly enriched in both populations at 5% false discovery rate (FDR) q-value.
The purpose of open access database RAvariome is to be a standard resource not only for RA researchers but also for RA clinicians and the general public. RAvariome is therefore designed as simple as possible to get confirmed RA genetic risk variants for each geographical population. With ongoing progress in sequencing technology, the number of genetic studies of RA will continue to grow. RAvariome will be periodically updated in concert with progress in RA genetic research and will incorporate a new genetic risk prediction method (33). An open access resource would be valuable to raise the precision of the clinical genetic tests and to develop effective prevention programs of RA based on genetic and population differences among individuals.
Acknowledgements
We thank C. Yamasaki, M. Sera, K. Murakami, Y. Hara and T. Habara for their valuable suggestions and technical support for the database development. We also thank Dr Naoyuki Kamatani and Dr Katsushi Tokunaga for their thoughtful guidance.
Funding
AIST Innovation School to Y.N.; Grant-in-Aid for Scientific Research on Innovative Areas (22133002). Funding for open access charge: Grant-in-Aid for Scientific Research on Innovative Areas (22133002).
Conflict of interest. None declared.
References
Author notes
Citation details: Nagai Y. and Imanishi T. RAvariome: a genetic risk variants database for rheumatoid arthritis based on assessment of reproducibility between or within human populations. Database, Vol. 2013, Article ID bat073, doi:10.1093/database/bat073.