rs394581

Orientation

plus

Stabilized

plus

Geno	Mag	Summary
(C;C)		higher risk of RA in African and Hispanic populations
(T;T)		higher risk of RA in European and Asian populations

Make rs394581(C;T)

Reference

GRCh38 38.1/141

Chromosome

6

Position

159061489

Gene	LOC105378083

is a	snp
is	mentioned by
dbSNP	rs394581
dbSNP (classic)	rs394581
ClinGen	rs394581
ebi	rs394581
HLI	rs394581
Exac	rs394581
Gnomad	rs394581
Varsome	rs394581
LitVar	rs394581
Map	rs394581
PheGenI	rs394581
Biobank	rs394581
1000 genomes	rs394581
hgdp	rs394581
ensembl	rs394581
geneview	rs394581
scholar	rs394581
google	rs394581
pharmgkb	rs394581
gwascentral	rs394581
openSNP	rs394581
23andMe	rs394581
SNPshot	rs394581
SNPdbe	rs394581
MSV3d	rs394581
GWAS Ctlg	rs394581

GMAF

0.2654

Max Magnitude

0

?	(C;C) (C;T) (T;T)	28

rs394581, a SNP cited to be associated with the risk of Rheumatoid Arthritis (RA), is situated on 6q25.3 in the 5' untranslated region of the TAGAP gene [PMID 19898481‎], which encodes the T-cell Activation Rho GTPase activating protein [PMID 22835281]. This gene is highly expressed in immune cells such as B-lymphocytes, T-lymphocytes, dendritic cells, natural killer cells, and monocytes, yet its specific role in immune function is still unclear [PMID 21390051]. Meta-analysis of GWAS in RA with validation in independent samples identified the TAGAP as an RA susceptibility locus [PMID 19898481‎].

Rheumatoid Arthritis and Genetics

RA is an autoimmune disease that is characterized by chronic and systemic inflammation [PMID 11254450]. At least half the variance in RA risk is estimated to be genetic based on family studies [PMID 21390051]. A twin study with nationwide British and Finnish data from both monozygotic and dizygotic twins concluded that there may be a 60% heritability for RA [PMID 10643697].

Study Summaries

A 2009 study took data from a previous meta-analysis of two GWAS data sets which contain 3393 cases and 12462 controls (European). They analyzed 370 SNPs from 179 independent loci with p < 0.001 and identified 22 loci with significant functional connectivity. 22 representative SNPs from these loci were replicated in 7957 cases and 11958 matched controls. They found statistically significant association of the rs394581 SNP with RA risk, reporting T as the risk allele and major allele, and C as the minor allele, with a minor allele odds ratio of 0.89 (p = 5.6E-4) in the discovery set, 0.92 (p = 1.5E-04) in the replication set, and 0.91 (p = 3.8E-07) combined. [PMID 19898481].

A follow-up study published in 2010 with 3962 patients and 3531 controls (European) used conditional logistic regression to investigate whether the effect from rs394581 was independent from the rs182429 SNP, which is in moderate linkage disequilibrium (R^2 = 0.32; D’ = 0.73) with the rs394581. P-value for the rs394581 went up to 0.9 after conditioning on rs182429, which lost statistical significance and implied that the effects found previously for rs394581 may have come from the rs182429 SNP. This study concluded that the association observed with rs394581 has a high probability to be from LD with rs182429. [PMID 20854658]

Another study from 2010 conducted a GWAS meta-analysis with 5539 RA cases and 20169 controls, with replication in an independent set of 6768 cases and 8806 controls (European). It included rs394581 and found minor allele frequency (MAF) of 0.3, odds ratio of 0.91 (95% CI: 0.87 – 0.96), and GWAS p-value of 0.0006. Even though the GWAS p-value could not reach the genome-wide statistically significant value of 5E-08, it was said to be validated by replication in independent samples. [PMID 20453842]

In the same year, another study that looked at the African American population, with 556 cases and 791 controls, found that rs394581 had odds ratio in the opposite direction from the European RA patients. The MAF reported here was 0.47 for patients and 0.43 for controls, with an odds ratio of 1.15 (95% CI: 0.98-1.34). They postulated that possible explanations include different LD structures in the African American vs. European populations or genetic heterogeneity. [PMID 21120996]

In 2011, Chen et al., in a GWAS of 5500 RA cases and 22621 controls (European), found a new TAGAP SNP rs212389 that had 5 orders of magnitude more significant association than rs394581, and was in LD with rs394581 (R^2 = 0.59; D’ = 0.92). This new SNP remained highly significant after conditioning on the rs394581, while conditioning on the new SNP eliminated statistical significance from the rs394581 (P = 0.07). This is an additional study suggesting that the observed association of rs394581 is due to LD. [PMID 21390051]

An interesting study in 2011 tried to use electronic health records with biospecimen data for multiple ethnic groups to obtain similar results as previous GWAS outcomes. With the rs394581 SNP, they found similar results as previous studies (minor allele odds ratio 0.86, 95% CI: 0.75 – 0.99) for the European population with a previous GWAS (OR = 0.91, 95% CI: 0.87 – 0.96). Using EHR for African, Asian, and Hispanic populations, they found odds ratios of 1.35, 0.14 and 1.52 respectively, suggesting that African and Hispanic populations may have opposite association from the European population, and the Asian population has strong association in the same direction as the European population. [PMID 21211616]

In 2011, the rs394581 risk allele was included, among 39 validated genetic risk alleles, in an odds ratio-weighted genetic risk score system for developing RA. The weighting was based on published odds ratio values. The study looked at 542 cases and 551 controls (Caucasian), and found strong predictive power of their genetic risk score for seropositive, erosive RA (RF+ or CCP+), with lower and varying odds ratios for other RA phenotypes, suggesting heterogeneous genetic causality for different RA phenotypes. [PMID 21931699]

In a recent 2013 study, the rs394581 was found to have a zero-inflated negative binomial combined p value of 0.024 during regression analysis for correlation with the Larsen score, which is a measure of bone damage, in RA patients. This suggests that the rs394581 is associated with disease severity in RA. [PMID 23242182]

Conclusion

In summary, even with a few controversial results indicating that the association observed with the rs394581 may be due to LD with other SNPs, overall the majority of studies indicate that this SNP is associated with either the risk of developing RA or disease severity. Studies looking at different populations suggest that the major allele (T) has a higher likelihood of being the risk allele for European and Asian populations, and the minor allele (C) may be the risk allele for African and Hispanic populations.

References

[PMID 19898481] Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

[PMID 22835281] New insights into the genetics of immune responses in rheumatoid arthritis

[PMID 21390051] Fine mapping the TAGAP risk locus in rheumatoid arthritis

[PMID 11254450] A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

[PMID 10643697] Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins

[PMID 20854658] Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease

[PMID 20453842] Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

[PMID 21120996] Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans

[PMID 21211616] Genetic basis of autoantibody positive and negative rheumatoid arthritis risk in a multi-ethnic cohort derived from electronic health records

[PMID 21931699] Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset

[PMID 23242182] Investigation of rheumatoid arthritis genetic susceptibility markers in the early rheumatoid arthritis study further replicates the TRAF1 association with radiological damage

[PMID 22328738] Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.