Direct determination of single nucleotide polymorphism haplotype of NFKBIL1 promoter polymorphism by DNA conformation analysis and its application to association study of chronic inflammatory diseases.
We previously revealed that one of the human leukocyte antigen-linked susceptibility genes for Takayasu's arteritis (TA) was mapped between TNFA and MICB loci and that -63T allele of NFKBIL1, which is between TNFA and MICB loci, was associated with rheumatoid arthritis (RA) in the Japanese population. We have developed a novel typing method based on reference strand-mediated conformation analysis for the upstream sequence of the NFKBIL1 gene, where -422 (T)8/(T)9, -325 C/G, -263 A/G, and -63 T/A polymorphisms were found. Upon the analysis of the patients with TA (n = 84), those with RA (n = 120), and healthy control subjects (n = 217), five common haplotypes named IKBLp*01 through IKBLp*05 were found in the Japanese population. The frequency of IKBLp*03 was significantly increased in the patient with TA (57.1% vs 35.0%, giving an odds ratio of 2.47). In addition, the frequency of IKBLp*01, but not that of other -63T-bearing alleles, was increased in the patients with RA (73.3% vs 58.1%, giving an odds ratio of 1.99), suggesting that the susceptibility to RA was conferred not by -63T alone but by combination of single nucleotide polymorphisms in the NFKBIL1 promoter. A higher promoter activity associated with IKBLp*03 and a lower activity associated with IKBLp*01 may contribute to the susceptibility to TA and RA, respectively.
Shibata
Hiroki
H
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Yasunami
Michio
M
Obuchi
Nobuhisa
N
Takahashi
Megumi
M
Kobayashi
Yasushi
Y
Numano
Fujio
F
Kimura
Akinori
A
D048868:Adaptor Proteins, Signal Transducing; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002908:Chronic Disease; D004247:DNA / Q000737:chemistry; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D009690:Nucleic Acid Conformation; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D013625:Takayasu Arteritis / Q000235:genetics*; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D000949:Histocompatibility Antigens Class II; C120111:NFKBIL1 protein, human; D004247:DNA