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Abstract Number: 220

A Genome-Wide Association Study Reveals Association of the Transferrin Receptor Locus with Gout

Tony R. Merriman1, Murray Cadzow2, Callum Tanner2, Matthew A. Brown3, Katie Cremin4, Matthijs Janssen5, Tim Jansen6, Leo A. Joosten7, Timothy Radstake8, Philip L. Riches9, Anne-Kathrin Tausche10, Frederic Lioté11, Alex So12,13, Andre M. van Rij2, Gregory T. Jones14, Lisa K. Stamp15, Nicola Dalbeth16 and Cushla McKinney2, 1Biochemistry Dept, PO Box 56, University of Otago, Dunedin, New Zealand, 2University of Otago, Dunedin, New Zealand, 3The University of Queensland Diamantina Institute, Brisbane, Australia, 4Diamantina Institute, University of Queensland, Brisbane, Australia, 5Rheumatology Dept, Ziekenhuis Rijnstate, Arnhem, Netherlands, 6P O Box 581, Haarlem, Netherlands, 7Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 8Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 9Centre for Genomic and Experimental Medicine, Western General Hospital, Edinburgh, United Kingdom, 10Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany, 11Rheumatology Department; Inserm UMR-S606; Paris-Diderot University, hôpital Lariboisiere, Paris, France, 12Service De Rhumatologie, CHUV, Lausanne, Switzerland, 13Department of Rheumatology, CHUV, Lausanne, Switzerland, 14Surgery, University of Otago, Dunedin, New Zealand, 15Medicine, University of Otago, Christchurch, Christchurch, New Zealand, 16Department of Medicine, University of Auckland, Auckland, New Zealand

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: gout

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Session Information

Date: Sunday, November 8, 2015

Session Title: Metabolic and Crystal Arthropathies Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Acute gouty arthritis results from an innate immune response to monosodium urate (MSU) crystals deposited in the joints and soft tissues of hyperuricaemic individuals. Genome-wide association studies (GWAS) have provided insight into the genetic control of urate homeostasis. However there have been very few genetic insights into the pathogenesis of acute gouty arthritis. Key checkpoints are expected to be in MSU crystal formation and immune response. The aim was to conduct a GWAS in gout using the immune-centric Immunochip.

Methods: 456 European patients with gout fulfilling the 1977 ARA gout classification criteria were genotyped with the Immunochip microarray, which contains single nucleotide variants (SNVs) at loci chosen largely on the basis of association with other immune-mediated phenotypes. SNVs out of Hardy Weinberg equilibrium (P<1×10-7) and with minor allele frequency <0.01 were discarded with 139,874 SNVs remaining. The genomic inflation factor was 1.06. Allele frequencies were compared by logistic regression using PLINK software to 1,000 European controls sourced from the 1958 British Birth Cohort. Replication was conducted using Taqman genotyping in 1,190 European cases with gout and 960 NZ controls, with additional data from 11,127 publically-available European controls, and Taqman genotyping of 931 Polynesian cases and 964 controls. For replication, logistic regression analyses were adjusted by age, sex and (for Polynesian) number of self-reported Polynesian grandparents. Replication sample sets were combined by meta-analysis using METAL software. Replication was declared at P<0.01.

Results: Five SNVs with P between 1×10-5 and 6×10-5 from the discovery GWAS were selected for replication (Table). Rs1466085, in the enhancer region 11kb upstream of the transferrin receptor (TFRC), was the only variant to replicate (OR=1.30, P=5×10-5) in a directionally consistent fashion to the discovery GWAS data (OR=1.77, P=3×10-5). Combining the discovery and replication sets yielded P=6.4×10-8 at rs1466085. There was no evidence for association of rs1466085 with serum urate levels in European controls (beta=0.003, P=0.18).

Conclusion: These data, with P=10-5 in both discovery and replication phases, convincingly implicate the region immediately upstream of the transferrin receptor in the etiology of gout in an urate-independent manner. It is important that further genetic fine-mapping and molecular expression experiments are done to confirm TFRC as the causal gene in the region.

Table Association of five genetic variants in the genome-wide (discovery) and replication analyses

Discovery (GWAS)

Replication

Disc and Rep

Nearest gene

Risk allele

MAF case/cont

OR

P

MAF case/cont

OR

P

OR, P

rs117561283

IFNG-AS1

T

0.052/0.024

2.28

6×10-5

EUR

POLY

COMB

0.027/0.021

0.003/0.007

1.32

1.06

1.31

0.062

0.94

0.067

1.57, 1.8×10-4

rs11761178

WBSCR28

A

0.456/0.370

1.43

1×10-5

EUR

POLY

COMB

0.394/0.410

0.775/0.751

0.90

1.01

0.92

0.030

0.91

0.060

–

rs1466085

TFRC

A

0.110/0.066

1.77

3×10-5

EUR

POLY

COMB

0.091/0.068

0.652/0.583

1.29

1.32

1.30

0.0022

0.0094

5×10-5

1.37, 6.4×10-8

rs1887406

ZBTB46

C

0.249/0.176

1.56

4×10-5

EUR

POLY

COMB

0.200/0.191

0.318/0.279

1.02

1.31

1.08

0.69

0.018

0.14

1.18, 4.9×10-4

rs6891250

SORCS2

C

0.176/0.120

1.57

5×10-5

EUR

POLY

COMB

0.125/0.125

0.303/0.315

0.98

0.90

0.96

0.80

0.34

0.45

1.07, 0.22


Disclosure: T. R. Merriman, None; M. Cadzow, None; C. Tanner, None; M. A. Brown, Abbvie, Pfizer, UCB, Wyeth, Leo Pharma, NIAMS, NHMRC, Arthritis Australia, Qld Government, 2,Pfizer, Abbvie, UCB, 5,Pfizer, Abbvie, UCB, 8; K. Cremin, None; M. Janssen, None; T. Jansen, None; L. A. Joosten, None; T. Radstake, None; P. L. Riches, Menarini, 2; A. K. Tausche, None; F. Lioté, None; A. So, None; A. M. van Rij, None; G. T. Jones, None; L. K. Stamp, None; N. Dalbeth, None; C. McKinney, None.

To cite this abstract in AMA style:

Merriman TR, Cadzow M, Tanner C, Brown MA, Cremin K, Janssen M, Jansen T, Joosten LA, Radstake T, Riches PL, Tausche AK, Lioté F, So A, van Rij AM, Jones GT, Stamp LK, Dalbeth N, McKinney C. A Genome-Wide Association Study Reveals Association of the Transferrin Receptor Locus with Gout [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-genome-wide-association-study-reveals-association-of-the-transferrin-receptor-locus-with-gout/. Accessed May 17, 2022.
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