MHC Antigen HLA-DQ6.1 (DQA1*0103/DQB1*0601) Increases

Rheumatoid Arthritis Risk Independent of Shared Epitope

Among IndiansAble Lawrence, Swayam Prakash, Uddalak Bharadwaj, Amita

Aggarwal, Ramnath Misra, and Suraksha Agrawal

SGPGIMS, Lucknow

IRACON 2016 O14

Disclosures: None

MHC Class II antigens DR & DQ

Only β chain of HLA-DR Polymorphic unlike HLA-DQ Kuby, Immunology 7e

HLA-DRB1 Shared Epitope and RA

du Montcel Classification2005

Sophie Tezenas du Montcel, et al. Arthritis Rheum. 2005 Apr;52(4):1063-8

Type Amino Acid(70-74)

Example Risk

S2 QKRAADKRAA

DRB1*0401DRB1*1303

High Risk

S3P QRRAA

RRRAA

DRB1*0101/02DRB1*0404/05/08DRB1*1402DRB1*1001

High Risk

S1 DERAA

QARAA

DRB1*0103DRB1*0402DRB1*1102/03DRB1*1301/02/23DRB1*15xx

Protective

S3D DRRAA DRB1*1101/04DRB1*12xxDRB1*16xx

Protective

SX Other DRB1*03/07/08 Neutral

Shared Epitope (SE)• Amino acids 70-74 Key• Smoking Interaction• Affinity to Citrulline

Loose Ends• DRB1*1501

• Protective in Caucasians• High Risk in Japan

• Strong Linkage with DQA and DQB

Amino Acid CodeA – Ala K - LysR – Arg D - AspQ – Gln E - Glu

HLA-DQw1 comprises DQ5 and DQ6DQB1*05xx/06xx pair only with DQA1*01xx

DQ Instability contributes to Autoimmunity

Miyadera et al J Clin Invest. 2015;125(1):275–291 doi:10.1172/JCI74961l

Results: Shared Epitope genotypes

HLA-DR Shared Epitope Genotypes – High Risk and Low RiskPatients - N (%) Controls N (%)

0 1 2 0 1 2S2 and S3P(High Risk)

95(53.1)

73 (40.8)

11 (6.2)

176 (70.7)

70 (28.1)

3 (1.2)

OR 2.1 (1.5-3)P < 0.001)

S1 and S3D(Low Risk) 75 (41.9) 81

(45.3)23 (12.9)

72 (28.8)

139 (55.6)

39 (15.6)

OR 0.7 (0.52 – 0.94)

P= 0.016)

HLA-DQw1 Association with RA

HLA-DQ1 isotype Association with RAHLA-DQ RA Control OR P

Present Absent Present AbsentDQA1*0104-DQB1*0501 53 128 44 204 1.94

(1.2-3.1) 0.005

DQA1*0103 DQB1*0601 43 138 33 215 2.0

(1.2-3.4)P=0.007

DQA1*0103 DQB1*0603 6 175 21 226

0.37(1.5-.95) 0.035

DQ6.1 Independent AssociationDBA1*0103/DQB1*0601Adjusted Odds Ratio 4.3 (1.7-10.7)

• Commonest Haplotypes • DRB1*15 DQA1*0103 DQB1*0601 (Japan, India)• DRB1*08 DQA1*0103 DQB1*0601 (Australian aborigines)• DRB1*1301 DQA1*0103 DQB1*0601 (Rare)

• Linkage with Protective or neutral HLA-DR alleles make the RA association clear

• Explains the anomalous association of HLA-DRB1*15 in Japanese• HLA-DQ6 associated RA and RA severity in Iraqi Kurds#.

#HLA-DR/DQ Genotypes in KurdPatients with Rheumatoid Arthritis:Relation to Disease ActivityAl-Timimi et al. Journal of Clinical and Diagnostic Research. 2014 May, Vol-8(5): CC01-CC04

DQ6.3 protects from RA(DQA1*0103/DQB1*0603)

• DQ6.3 is usually found in linkage with HLA-DRB1*1301• DRB1*1301 is a protective Shared epitope allele• DQ6.3 protective in Europeans (FINRACO data)

• Explains the robust protection effect of DRB1*1301 relative to other protective alleles

DQA1*0104/DQB1*0501 Not Associated

DQA1*0104/DQB1*0501• In strong Linkage with DRB1*1001, a

high risk S3P allele.• Is Not Expressed on Cell Surface• Stratified analysis powerful in

separating DRB and DQ effects

DQB1*0601 exclusive to AsiaAbsent in Caucasians and AfricansConsistent with European studies that did not find DQ effect

Korea, Australian aboriginals, Fiji, Nauru, Japan

Introgression from archaic hominin?

HLA-DQ6 and Rodent DataCollagen Induced ArthritisDQ double Transgenic Mice• DQ6.3 susceptible• DQ6.1 Protected

• DQ6.3 and 6.1 present peptides differentially. • Collagen not the main

antigen in RA

Pristane Induced ArthritisRats• Susceptibility localises to

RT-1b gene locus• RT-1b related to DQB1• Evidence for antigen

presentation through RT-1b• RT-1b Not associated with

anti-CCP

Conclusion• DQ6.1 (DQA1*0103/DQB1*0601) is independently

associated with Rheumatoid arthritis. • DQ6.1 appears to have a protective effect. • The result is consistent with all extant literature on

HLA-DR and HLA-DQ association in RA• Result explains anomalies in HLA-DR association in

Japanese population.