Genetic Variation in the TLR5 Locus Is Associated with Anti-TNF Response Among Rheumatoid Arthritis Patients

Jacob Sode^1,2,3, Ulla Vogel⁴, Steffen Bank^5,6, Paal Skytt Andersen⁷, Merete Lund Hetland^8,9, Henning Locht³, Niels H. H. Heegaard^10,11 and Vibeke Andersen^1,5,12,13, ¹Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark, ²Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen S, Denmark, ³Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark, ⁴National Research Centre for the Working Environment, Copenhagen, Denmark, ⁵Medical Department, Viborg Regional Hospital, Viborg, Denmark, ⁶Institute of Human Genetics, University of Aarhus, Aarhus, Denmark, ⁷Microbiology & Infection Control, Statens Serum Institut, Copenhagen S, Denmark, ⁸Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, Denmark, ⁹Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, The Danish Rheumatologic Database (DANBIO), Glostrup Hospital., Copenhagen, Denmark, ¹⁰Department of Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark, ¹¹Department of Clinical Biochemistry & Pharmacology, Odense University Hospital, Odense C, Denmark, ¹²Medical Department, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark, ¹³Odense University Hospital, OPEN (Odense Patient data Explorative Network), Odense, Denmark

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, inflammasome activation, interferons, rheumatoid arthritis (RA) and toll-like receptors

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Therapeutic Strategies, Biomarkers and Predictors of Outcomes in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Genetic Variation in the TLR5 Locus is Associated with Anti-TNF Response among Rheumatoid Arthritis Patients

Background/Purpose:

In a recent study (paper in press) of Danish rheumatoid arthritis (RA) patients we found single nucleotide polymorphisms (SNPs) in the NLRP3 and interferon-γ genes to be associated with response to tumor necrosis factor a inhibitors (anti-TNF). The aim of this study was to extend and corroborate these associations by analyzing a new set of functional polymorphisms in the NLRP3-inflammasome and interferon-γ pathways in RA patients treated with anti-TNF.

Methods:

Twenty-three functional single nucleotide polymorphisms (SNPs) in 14 genes involved in the inflammasome and interferon-gamma pathways were assessed in 538 anti-TNF naive Danish RA patients. Prospectively collected clinical data including functional status (HAQ), patient global score, smoking status, tender and swollen joint counts, treatments, rheumatoid factor (RF) status and C-reative protein (CRP) were obtained from the DANBIO registry. Multivariable logistic regression analyses adjusting for sex, age, HAQ, CRP, baseline disease-modifying anti-rheumatic drugs and RF status were performed to test associations between genotypes and EULAR response—good vs. moderate/none and good/moderate vs. none—at 3–6 months follow-up. ACR50 response was also analyzed to enable comparison with other studies. Subgroup analysis was performed for patients positive for RF (N=407).

Results:

Polymorphisms in IL12B (rs6887695), TLR1 (rs4833095) and TLR5 (rs5744174) were significantly (p<0.05) associated with EULAR response (Table 1). TLR1 rs4833095 was also associated with ACR50 response. None of the associations reached significance when corrected for multiple testing by false discovery rate adjustment.

TLR5 rs5744174 variant C allele is associated with an improved anti-TNF response and maps 71 bp from another polymorphism (no linkage data exists) previously found to be associated with RA anti-TNF response in a Dutch cohort (1) and it has been associated with higher PBMC IFN-γ secretion and altered CCL20 production. TLR1 rs4833095 has been associated with high PBMC TLR1 expression.

Subgroup associations were found for seropositive RA in CARD8 (rs2043211), IL18 (rs187238) and TLR1 (rs4833095) (data not shown) but due to low power these results are preliminary.

Conclusion:

Our results confirm association between a TLR5 locus and EULAR response to anti-TNF treatment. Previous studies suggest that this polymorphism is functional and associated with a phenotype with altered cytokine expression. The associations found for other polymorphisms need validation in a new cohort.

Table 1. Associations between gene variants and anti-TNF treatment response.

			ACR50 response	EULAR response
			yes vs. no	G vs. M/N	G/M vs. N
Gene (SNP)	Genotype	N	Adj. OR (95% CI), P-value	Adj. OR (95% CI), P-value	Adj. OR (95% CI), P-value
TLR1	TT	312
rs4833095	TC	178	1.38 (0.92-2.05), 0.118	1.02 (0.70-1.50), 0.903	1.11 (0.73-1.68), 0.631
	CC	21	3.43 (1.38-8.52), 0.008**	3.11 (1.18-8.19), 0.022*	1.34 (0.47-3.81), 0.584
	TC/CC	199	1.52 (1.04-2.24), 0.031*	1.15 (0.79-1.66), 0.462	1.13 (0.76-1.69), 0.555
TLR5	TT	170
rs5744174	TC	234	1.27 (0.82-1.96), 0.281	1.53 (1.01-2.33), 0.044*	1.17 (0.76-1.81), 0.470
	CC	107	1.40 (0.83-2.36), 0.206	1.89 (1.14-3.13), 0.014*	1.38 (0.80-2.38), 0.247
	TC/CC	341	1.31 (0.87-1.97), 0.192	1.64 (1.11-2.42), 0.013*	1.23 (0.82-1.85), 0.310
IL12B	GG	241
rs6887695	GC	224	1.14 (0.76-1.69), 0.529	0.82 (0.56-1.19), 0.291	0.63 (0.42-0.95), 0.027*
	CC	51	1.44 (0.76-2.73), 0.267	0.87 (0.46-1.64), 0.664	1.68 (0.77-3.67), 0.197
	GC/CC	275	1.19 (0.82-1.73), 0.369	0.83 (0.58-1.18), 0.294	0.74 (0.50-1.09), 0.129

G/M/N: good/moderate/none response

(1) Coenen MJ et al. PLoS One 2010; 5(12):e14326.

Disclosure:

J. Sode,
None;

U. Vogel,
None;

S. Bank,
None;

P. S. Andersen,
None;

M. L. Hetland,
None;

H. Locht,
None;

N. H. H. Heegaard,
None;

V. Andersen,

MSD/Merck,

Janssen Pharmaceutica Product, L.P.,

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