Tomohiro Koga1, Shuntaro Sato2, Hiroyuki Mishima3, Kiyoshi Migita4, Yushiro Endo5, Masataka Umeda5, Remi Sumiyoshi5, Fumiaki Nonaka6, Shoichi Fukui5, Shin-Ya Kawashiri5, Naoki Iwamoto5, Kunihiro Ichinose5, Mami Tamai5, Hideki Nakamura5, Tomoki Origuchi5, Yukitaka Ueki7, Junya Masumoto8, Kazunaga Agematsu9, Akihiro Yachie10, Koh-Ichiro Yoshiura3, Katsumi Eguchi7, Atsushi Kawakami5. 1. Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences; and Centre for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan. tkoga@nagasaki-u.ac.jp. 2. Nagasaki University Hospital, Clinical Research Centre, Japan. 3. Department of Human Genetics, Nagasaki University Atomic Bomb Disease Institute, Japan. 4. Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan. 5. Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan. 6. Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences; and Department of Internal Medicine, Sasebo City General Hospital, Sasebo, Japan. 7. Centre for Rheumatic Disease, Sasebo Chuo Hospital, Sasebo, Japan. 8. Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Centre, Toon, Ehime, Japan. 9. Department of Infectious Immunology, Shinshu University, Graduate School of Medicine, Matsumoto, Japan. 10. Department of Paediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan.
Abstract
OBJECTIVES: We aimed to identify the whole nucleotide sequence of the Mediterranean fever (MEFV) gene in familial Mediterranean fever (FMF) and reveal novel single nucleotide variants (SNVs) associated with the susceptibility of FMF. METHODS: SeqCap capturing technique followed by Illumina next-generation sequencing have been used to assess two hundred SNVs in the whole region of MEFV in 266 Japanese patients with FMF and 288 ethnically matched controls. We performed an association analysis using these SNVs to identify genetic variants that predispose to FMF. RESULTS: We identified the two most significant SNVs [rs28940578; M694I in exon 10, odds ratio (OR) = 153, p=2.47×10-21 and rs3743930; E148Q in exon 2, OR = 1.65, p<0.0005]. Stratified analysis identified rs28940578 as a risk allele in typical FMF. Haplotype AG, defined by rs401298 and rs28940578, was the most significant and prevalent among patients with typical FMF compared with controls (22.4% vs. 0%, respectively; OR = 137, p=1.44×10-31). Haplotype GTC, defined by rs11466018, rs224231, and rs401877, was the most significant among patients with typical FMF without the rs28940578 mutation compared with controls (15.9% vs. 6%, respectively; OR = 12.4, p=0.004). CONCLUSIONS: rs28940578 is associated with the highest risk in typical FMF cases. This is consistent with results from previous studies in Japan. We found a novel MEFV gene haplotype that confers susceptibility of FMF among typical FMF without the rs28940578 mutation. There were no relevant SNVs identified in MEFV among the atypical FMF group.
OBJECTIVES: We aimed to identify the whole nucleotide sequence of the Mediterranean fever (MEFV) gene in familial Mediterranean fever (FMF) and reveal novel single nucleotide variants (SNVs) associated with the susceptibility of FMF. METHODS: SeqCap capturing technique followed by Illumina next-generation sequencing have been used to assess two hundred SNVs in the whole region of MEFV in 266 Japanese patients with FMF and 288 ethnically matched controls. We performed an association analysis using these SNVs to identify genetic variants that predispose to FMF. RESULTS: We identified the two most significant SNVs [rs28940578; M694I in exon 10, odds ratio (OR) = 153, p=2.47×10-21 and rs3743930; E148Q in exon 2, OR = 1.65, p<0.0005]. Stratified analysis identified rs28940578 as a risk allele in typical FMF. Haplotype AG, defined by rs401298 and rs28940578, was the most significant and prevalent among patients with typical FMF compared with controls (22.4% vs. 0%, respectively; OR = 137, p=1.44×10-31). Haplotype GTC, defined by rs11466018, rs224231, and rs401877, was the most significant among patients with typical FMF without the rs28940578 mutation compared with controls (15.9% vs. 6%, respectively; OR = 12.4, p=0.004). CONCLUSIONS: rs28940578 is associated with the highest risk in typical FMF cases. This is consistent with results from previous studies in Japan. We found a novel MEFV gene haplotype that confers susceptibility of FMF among typical FMF without the rs28940578 mutation. There were no relevant SNVs identified in MEFV among the atypical FMF group.
Authors: Mikhail Kostik; Ummusen Akca Kaya; Olga V Zhogova; Erdal Sag; Evgeny N Suspitsin; Viktoriya I Nizhnik; Anastasiya V Tumakova; Sergey V Ivanovskiy; Natalia V Lagunova; Yelda Bilginer; Seza Ozen Journal: Turk Arch Pediatr Date: 2022-09