title: Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease.
abstract: 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.
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849, USA.
authors: Yohei
authors: Y
authors: Kirino
authors: Qing
authors: Q
authors: Zhou
authors: Yoshiaki
authors: Y
authors: Ishigatsubo
authors: Nobuhisa
authors: N
authors: Mizuki
authors: Ilknur
authors: I
authors: Tugal-Tutkun
authors: Emire
authors: E
authors: Seyahi
authors: Yilmaz
authors: Y
authors: Özyazgan
authors: Serdal
authors: S
authors: Ugurlu
authors: Burak
authors: B
authors: Erer
authors: Neslihan
authors: N
authors: Abaci
authors: Duran
authors: D
authors: Ustek
authors: Akira
authors: A
authors: Meguro
authors: Atsuhisa
authors: A
authors: Ueda
authors: Mitsuhiro
authors: M
authors: Takeno
authors: Hidetoshi
authors: H
authors: Inoko
authors: Michael J
authors: MJ
authors: Ombrello
authors: Colleen L
authors: CL
authors: Satorius
authors: Baishali
authors: B
authors: Maskeri
authors: James C
authors: JC
authors: Mullikin
authors: Hong-Wei
authors: HW
authors: Sun
authors: Gustavo
authors: G
authors: Gutierrez-Cruz
authors: Yoonhee
authors: Y
authors: Kim
authors: Alexander F
authors: AF
authors: Wilson
authors: Daniel L
authors: DL
authors: Kastner
authors: Ahmet
authors: A
authors: Gül
authors: Elaine F
authors: EF
authors: Remmers
mesh_terms: D001528:Behcet Syndrome / Q000235:genetics*; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D053938:DNA Fragmentation; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000378:metabolism; D015723:Gene Library; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007564:Japan; D016133:Polymerase Chain Reaction; D000071198:Pyrin; D017422:Sequence Analysis, DNA; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014421:Turkey
chemical_list: D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D000071198:Pyrin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: complex genetics; genetic association
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