Epistatic Interaction Between BANK1 and BLK in Rheumatoid Arthritis: Results From a Large Trans-Ethnic Meta-Analysis

Emmanuelle Genin¹, Baptiste Coustet², Yannick Allanore³, Maria Teruel⁴, Arnaud L. Constantin⁵, Shigeto Tohma⁶, O. Vittecoq⁷, Hiroshi Furukawa⁸, Alejandro Balsa⁹, Thierry Schaeverbeke¹⁰, Miguel Angel González-Gay¹¹, Gilles Chiocchia¹², Naoyuki Tsuchiya¹³, Javier Martin¹⁴ and Philippe Dieude¹⁵, ¹INSERM UMR-S946, Paris, France, ²Rheumatology, Université Paris Descartes, Hopital Cochin, Paris, France, ³Rheumatology, Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, ⁴Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain, ⁵Rheumatology, Purpan University Hospital, Toulouse Cedex 9, France, ⁶Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan, ⁷University Hospital, Rouen, France, ⁸Department of Rheumatology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan, ⁹Rheumatology, La Paz Hospital. IdiPaz, Madrid, Spain, ¹⁰Service de Rhumatologie, Groupe Hospitalier Pellegrin, Bordeaux, France, ¹¹Rheumatology, Hospital Universitario Marqués de Valdecilla. IFIMAV, Santander, Spain, ¹²Immunology and Hematology Department, Institut Cochin - INSERM U1016 - CNRS (UMR 8104), Paris, France, ¹³Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ¹⁴Immunology, Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain, ¹⁵Rheumatology, APHP, Hopital Bichat, Paris, France

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: genomics and rheumatoid arthritis (RA)

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: BANK1 and BLK belong to pleiotropic genes and recently a genetic and physical interaction between BANK1 and BLK has been detected in systemic lupus erythematosus. Although BLK has been reproducibly identified as a RA risk factor, conflicting results have been reported regarding the contribution of BANK1 in RA susceptibility. To ascertain the real impact of BANK1 on RA genetic susceptibility we performed a large meta-analysis. In addition, we tested for an epistatic interaction between BLK and BANK1 in RA susceptibility.

Methods: We performed a large trans-ethnic meta-analysis including data from 8,898 RA patients and 15,479 controls genotyped for BANK1 rs10516487 and data from 3,641 RA cases and 3,710 controls genotyped for BANK1 rs3733197. BLK rs13277113 and BANK1 genotypes available from 1,901 RA patients and 1,898 ethnically matched controls coming from France, Spain and Japan were used to test for epistasis by logistic regression analysis.

Results: The meta-analysis provided evidence for an association between RA and BANK1 rs3733197 G risk allele (OR=1.11 95% CI[1.02–1.21], P=0.012). An epistatic interaction between BLK rs13277113 and BANK1 rs3733197 was detected (P_ep=0.037). The association between the BANK1 rs3733197 G risk allele and RA was restricted to individuals carrying the BLK rs13277113 GG genotype: OR=1.21 95%CI[1.04-1.41], P=0.015

Conclusion: This study confirms BANK1 as a RA susceptibility gene and provides for the first time, evidence for epistasis between BLK and BANK1. Our results illustrate the concept of pleiotropic epistatic interaction suggesting that BLK and BANK1 might play a role in RA pathogenesis.

Disclosure:

E. Genin,
None;

B. Coustet,
None;

Y. Allanore,
None;

M. Teruel,
None;

A. L. Constantin,
None;

S. Tohma,

Pfizer Japan,

Eisai,

Chugai Pharmaceutical,

O. Vittecoq,
None;

H. Furukawa,

The work was supported by Research Grants from Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research Grants from Takeda Science Foundation.,

A. Balsa,
None;

T. Schaeverbeke,
None;

M. A. González-Gay,
None;

G. Chiocchia,
None;

N. Tsuchiya,
None;

J. Martin,
None;

P. Dieude,
None.

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