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Abstract
Although many genome-wide association studies (GWASs) of hyperuricemia or gout have been reported, the related genetic factors and the mechanisms from hyperuricemia to gouty attack remain unclear. This study aimed to identify genetic factors and pathogenesis of gout from hyperuricemia by genome-wide association study (GWAS). 747 gout patients, 747 hyperuricemia and 2071 age-matched controls were recruited and analyzed with Affymetrix 650 K chip to find the related genetic variants. The functions of the related genes were investigated in an endothelial cell (EC) with urate crystal stimulation. The GWAS results showed 36 SNPs to be strongly associated with gout compared to controls (all p-values < 10−7). Whereas the rs2231142 in ABCG2 gene had significant associations between gout and controls, between gout and hyperuricemia, and between hyperuricemia and controls (all p-values < 10−7), and the ORs were 4.34, 3.37 and 2.15 (all p-values < 0.001) after adjustment of potential confounders, respectively. The cell model showed significantly higher IL-8 release from EC combined with ABCG2 knockdown. We concluded that ABCG2 gene contributed to hyperuricemia but also gout, and that it was involved in the inflammation dysregulation via augmented IL-8 release in EC.
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1 Division of General Internal Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Kaohsiung Medical University, Kaohsiung, Taiwan
3 Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Kaohsiung, Taichung, Taiwan
5 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
6 Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung, Taiwan
7 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan