Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease
| Autor: | Yoshiaki Ishigatsubo, Neslihan Abaci, Nobuhisa Mizuki, Ahmet Gül, Gustavo Gutierrez-Cruz, Daniel L. Kastner, Yoonhee Kim, Emire Seyahi, Hidetoshi Inoko, Yilmaz Ozyazgan, Ilknur Tugal-Tutkun, Burak Erer, Atsuhisa Ueda, Baishali Maskeri, Mitsuhiro Takeno, Elaine F. Remmers, Hong-Wei Sun, Akira Meguro, Alexander F. Wilson, Qing Zhou, Colleen Satorius, Duran Ustek, Serdal Ugurlu, Michael J. Ombrello, James C. Mullikin, Yohei Kirino |
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| Rok vydání: | 2013 |
| Předmět: |
Nonsynonymous substitution
Genotype Turkey Familial Mediterranean fever Genome-wide association study DNA Fragmentation Biology Pyrin domain Polymerase Chain Reaction Japan medicine Humans Genetic Predisposition to Disease Genetic association Gene Library Genetics Multidisciplinary Behcet Syndrome Genetic Variation High-Throughput Nucleotide Sequencing PYCARD Sequence Analysis DNA Pyrin Biological Sciences medicine.disease MEFV Familial Mediterranean Fever Toll-Like Receptor 4 Cytoskeletal Proteins Case-Control Studies Genome-Wide Association Study |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 110(20) |
| ISSN: | 1091-6490 |
| Popis: | Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS ( IL10, IL23R , CCR1 , STAT4 , KLRK1 , KLRC1, KLRC2, KLRC3, KLRC4 , and ERAP1 ) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4 ) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R ( P = 6.9 × 10 −5 ), and one gene involved in innate immunity, TLR4 ( P = 8.0 × 10 −4 ), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied ( P = 0.0063–0.045). Furthermore, carriage of the familial Mediterranean fever gene ( MEFV ) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10 −12 ). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis. |
| Databáze: | OpenAIRE |
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