Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis.

Autor:	Yamashita K; Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.; Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan., Kawasaki A; Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan., Matsushita T; Department of Dermatology, Kanazawa University, Kanazawa, Japan., Furukawa H; Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.; Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan.; Department of Rheumatology, National Hospital Organization Tokyo National Hospital, Kiyose, Japan., Kondo Y; Department of Internal Medicine, University of Tsukuba, Tsukuba, Japan., Okiyama N; Department of Dermatology, University of Tsukuba, Tsukuba, Japan., Nagaoka S; Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan., Shimada K; Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan.; Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan., Sugii S; Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan., Katayama M; Department of Internal Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Japan., Hirohata S; Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan., Okamoto A; Department of Rheumatology, National Hospital Organization Himeji Medical Center, Himeji, Japan., Chiba N; Department of Rheumatology, National Hospital Organization Morioka Medical Center, Morioka, Japan., Suematsu E; Department of Internal Medicine and Rheumatology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan., Setoguchi K; Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan., Migita K; Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan., Sumida T; Department of Internal Medicine, University of Tsukuba, Tsukuba, Japan., Tohma S; Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan.; Department of Rheumatology, National Hospital Organization Tokyo National Hospital, Kiyose, Japan., Hamaguchi Y; Department of Dermatology, Kanazawa University, Kanazawa, Japan., Hasegawa M; Department of Dermatology, University of Fukui, Fukui, Japan., Sato S; Department of Dermatology, University of Tokyo, Tokyo, Japan., Kawaguchi Y; Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan., Takehara K; Department of Dermatology, Kanazawa University, Kanazawa, Japan., Tsuchiya N; Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2020 Nov 01; Vol. 59 (11), pp. 3553-3562.
DOI:	10.1093/rheumatology/keaa306
Abstrakt:	Objective: Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc. Methods: Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR. Results: Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score <10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers. Conclusion: Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc. (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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