ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2962

Association of the Toll-like Receptor 4 (TLR4) Gene with Gout

Humaira Rasheed1, Ruth Topless1, Richard Day2, Diluk Kannangara3, Kenneth Williams3, Linda Bradbury4, Matthew Brown5, Catherine Hill6, Susan Lester7, Maureen Rischmueller8, Malcolm Smith9, Mariano Andrés10, Thomas Bardin11, Michael Doherty12, Matthijs Janssen13, Tim Jansen14, Leo Joosten15, Fernando Perez-Ruiz16, Timothy Radstake17, Philip L. Riches18, Ed Roddy19, Anne-Kathrin Tausche20, Lisa K. Stamp21, Nicola Dalbeth22, Frederic Lioté23, Alex So24, Cushla McKinney1 and Tony R. Merriman1, 1Department of Biochemistry, University of Otago, Dunedin, New Zealand, 2Dept of Clin Pharmacology, St. Vincent's Hospital, Sydney, Australia, 3University of New South Wales, Sydney, Australia, 4The University of Queensland, Brisbane, Australia, 5University of Queensland Diamantina Institute, Brisbane, Australia, 6Queen Elizabeth Hospital, Adelaide, Australia, 7Rheumatology Unit, Queen Elizabeth Hospital, Woodville South, Australia, 8Department of Rheumatology, The Queen Elizabeth Hospital, SA, Australia, 9Rheumatology Unit Repatriation, Queen Elizabeth Hospital, Adelaide, Australia, 10Rheumatology Section, Hospital General Universitario de Alicante, Alicante, Spain, 11Clinique de Rhumatologie. Service de Rhumatologie. Centre Viggo Petersen., Hôpital Lariboisière, Paris, France, 12Academic Rheumatology, City Hospital, Nottingham, United Kingdom, 13Department of Rheumatology, Rijnstate Hospital, Arnhem, Netherlands, 14Rheumatology, Radboud University Medical Center, Nijmegen, Netherlands, 15Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands, 16Servicio de Reumatologia, Hospital De Cruces, Baracaldo, Spain, 17University Medical Center Utrecht, Utrecht, Netherlands, 18Centre for Rheumatic Diseases, University of Edinburgh, Edinburgh, United Kingdom, 19Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, United Kingdom, 20Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany, 21University of Otago, Christchurch, New Zealand, 22Department of Medicine, University of Auckland, Auckland, New Zealand, 23UFR médicale, Université Paris Diderot, Paris, France, 24Service De Rhumatologie, CHUV, Lausanne, Switzerland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Metabolic and Crystal Arthropathies II: Mechanisms of Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose: Gout results from innate immune response to monosodium urate (MSU) crystals that form in the context of supersaturation of urate. Identification of genetic risk factors for hyperuricemia and the MSU immune response is therefore important for insight into the etiology of gout. Genome-wide association studies have provided significant insights into the causes of hyperuricemia, however there are no confirmed loci for non-serum urate pathways in gout. Association of rs2149356 in the TLR4 locus with gout was reported in a Chinese sample set (odds ratio TT genotype = 1.88)1. TLR4 triggers innate immune response to endogenous ligands, including MSU crystals. To replicate, we tested rs2149356 for association with gout in 2,501 European and Polynesian cases and 9,105 controls.

Methods: All gout cases were clinically ascertained according to the American Rheumatism Association criteria. European cases (n=1614) were recruited from New Zealand (n=647), by the Eurogout consortium within the European Crystal Network (n=779) and by the Arthritis Genomics Recruitment Initiative in Australasia (AGRIA; n=188). European non-gouty controls (n=8017) were recruited from NZ (n=875) and sourced from the Atherosclerosis Risk in Communities (n=4143) and Framingham Heart (n=2999) studies. There were 872 New Zealand Māori and Pacific Island (Polynesian) cases and 1088 controls.

Genotyping of rs2149356 was done by Taqman in the New Zealand samples and imputed in ARIC and FHS from Affymetrix genome-wide data. Association analysis was done by STATA and adjusted by age, sex and (as appropriate) estimate of Polynesian ancestry.

Results: Using controls unstratified for urate status, there was no evidence for allelic or genotypic association in the European sample sets (Table). However the TT genotype was associated with gout in Polynesians (ORTTgenotype=0.68, P=0.012). Comparison of cases to hyperuricemic controls revealed evidence for association with gout in Europeans (ORTallele=1.26, P=0.005; ORTTgenotype=1.63, P=0.009), but weakened evidence for association in Polynesians (ORTallele= 0.88, P=0.25; ORTTgenotype=0.77, P=0.21).

Conclusion: The previous report of association of TLR4 with gout in Chinese1 was replicated in Europeans with the T allele of rs2149356 conferring risk in both populations. Evidence for association was weaker in Polynesians, with the G-allele conferring risk. The strengthening of association in Europeans using hyperuricemic controls is consistent with a role for this locus in gouty inflammation in the presence of hyperuricemia. Subject to further replication, TLR4 represents the first replicated non-serum urate genetic risk locus identified in gout, and provides support for a role of TLR4 in the etiology of gout.

 

1 Qing et al. Association of TLR4 gene rs2149356 polymorphism with primary gouty arthritis in a case-control study. PLoS One 2013;5:e64845.

 

 

Gout Cases

Control (All)

OR (T allele),

P          

OR (TT genotype), P

 

GG

GT

TT

T

GG

GT

TT

T

European

722

(0.443)

706

(0.433)

201

(0.123)

1108 (0.340)

3773 (0.471)

3408 (0.426)

821

(0.103)

5050 (0.316)

1.13 [1.00-1.28], 0.059

1.26 [0.85-1.67], 0.10

 

 

 

 

 

 

 

 

 

 

 

Polynesian

237

(0.272)

431

(0.494)

204

(0.234)

831

(0.481)

288

 (0.265)

518

 (0.476)

282

(0.259)

1082 (0.497)

0.96 [0.79-1.17],

0.70

0.68 [0.50-0.92], 0.012

 

 

 

 

 

 

 

 

 

 

 

 

Gout Cases

Control (Hyperuricemic)

 

 

European

722

(0.443)

706

(0.433)

201

(0.123)

1108 (0.340)

593 (0.496)

495 (0.414)

108

(0.090)

711 (0.297)

1.26 [1.07-1.47], 0.005

1.63 [1.13-2.34], 0.009

 

 

 

 

 

 

 

 

 

 

 

Polynesian

237

(0.272)

431

(0.494)

204

(0.234)

831

(0.481)

76

 (0.295)

107

 (0.415)

75

(0.291)

257 (0.498)

0.88 [0.72-1.09], 0.25

0.77 [0.52-1.16],

0.21

Disclosure:

H. Rasheed,
None;

R. Topless,
None;

R. Day,
None;

D. Kannangara,
None;

K. Williams,
None;

L. Bradbury,
None;

M. Brown,
None;

C. Hill,
None;

S. Lester,
None;

M. Rischmueller,
None;

M. Smith,
None;

M. Andrés,
None;

T. Bardin,

Novartis, SOBI,

5,

Novartis ,

8;

M. Doherty,

Manarini,

5;

M. Janssen,
None;

T. Jansen,

Abbvie,

2,

UCB,

2,

Abbvie,

5,

AstraZeneca,

5,

UMS,

5,

Janssen Pharmaceutica Product, L.P.,

5,

Menarini,

5,

Novartis Pharmaceutical Corporation,

5,

Pfizer Inc,

5,

Roche Pharmaceuticals,

5,

Abbvie,

8;

L. Joosten,
None;

F. Perez-Ruiz,
None;

T. Radstake,
None;

P. L. Riches,
None;

E. Roddy,
None;

A. K. Tausche,
None;

L. K. Stamp,
None;

N. Dalbeth,

Ardea,

5,

AstraZeneca,

5,

Takeda,

5,

Metabolex,

5,

Menarini,

8,

Savient,

8,

Novartis Pharmaceutical Corporation,

8,

Fonterra,

2,

Novartis Pharmaceutical Corporation,

2,

Ardea,

2,

Fonterra,

9;

F. Lioté,
None;

A. So,
None;

C. McKinney,
None;

T. R. Merriman,
None.

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