Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Genetic variants in uric acid transporters that control serum urate levels in Europeans have been identified by genome-wide association studies. However there is no evidence for association with the organic anion transporters (OAT) 2-4 (encoded by SLC22A6-A8) and multi-drug resistance protein 4 (MRP4) encoded by ABCC4. The Māori and Pacific (Polynesian) population of New Zealand (NZ) has the highest prevalence of gout worldwide and exhibits lower fractional excretion of uric acid (FEUA) than Europeans. Our aim was to identify genetic variants in the Māori and Pacific SLC22A6-8 and ABCC4 genes that influence the risk of gout.
Methods: 218 hyperuricaemic and 205 normouricaemic individuals, the majority (93%) of whom self-reported >=3 Māori and Pacific grandparents, were resequenced over a total of 24.3 kb of promoter, exon and 3’ and 5’ untranslated region DNA within the four genes. Sequencing was done using Illumina chemistry on a HiSeq 2000 on DNA captured using a custom version of the Roche NimbleGen SeqCap kit. The Genome Analysis Toolkit was used to align reads to the human reference genome and generate variant call files. Replication genotyping for rs4148500was done by Taqman over 284 Western Polynesian (Samoa, Tonga, Niue, Tokelau) gout cases and 174 controls, and 471 Eastern Polynesian (EP: NZ and Cook Island Māori) gout cases and 450 controls (that included 187 Māori gout cases and 170 Māori controls from the area of the Ngati Porou tribe). All replication individuals had >=3 self-reported Māori and/or Pacific grandparents. Logistic regression association analysis was done adjusting by age and sex.
Results: A total of 39 variants with frequency greater than 0.05 were detected with the majority (n=26) in ABCC4. Of these, six variants in ABCC4 significantly associated with hyperuricaemia. The most significantly associated (rs4148500; ORHyperuricaemia=1.76, P=1.6×10-3; monomorphic in Europeans) was also associated with gout in the resequenced sample set (OR=1.86, P=9×10-4) and was therefore genotyped over the replication sample set. Rs4148500 was associated with gout in Western Polynesian (OR=1.47, P=0.026) but not in Eastern Polynesian (OR=1.09, P=0.52) in this sample set. In the combined (resequence plus replication) sample set the minor allele of rs4148500 was associated with reduced FEUA in the combined Polynesians (beta=-0.50, P=3.8×10-3).
Conclusion: We demonstrate for the first time association of ABCC4 with hyperuricaemia, gout and FEUA, providing further support for the proposition of MRP4 as a unidirectional urinary uric acid efflux pump for uric acid. The variant was monomorphic (for the protective major allele) in Europeans and can be regarded as the first report of a genetic factor contributing to the increased risk of gout that is specific to people of Western Polynesian ancestry.
To cite this abstract in AMA style:Merriman TR, Boocock J, Tanner C, Cadzow M, Phipps-Green A, Stamp LK, Dalbeth N, Harre Hindmarsh J, Mount DB, Choi H, Stahl EA. Targeted Deep Resequencing Identifies MRP4/ABCC4 as a Gout Risk Locus in the New Zealand Mä�ori and Pacific Island Populations [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/targeted-deep-resequencing-identifies-mrp4abcc4-as-a-gout-risk-locus-in-the-new-zealand-ma%ef%bf%bdori-and-pacific-island-populations/. Accessed June 7, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeted-deep-resequencing-identifies-mrp4abcc4-as-a-gout-risk-locus-in-the-new-zealand-ma%ef%bf%bdori-and-pacific-island-populations/