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 So^12,13, 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

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 August 23, 2019.

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