PMID- 12509789
OWN - NLM
STAT- MEDLINE
DCOM- 20030318
LR  - 20200824
IS  - 0002-9297 (Print)
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Linking)
VI  - 72
IP  - 2
DP  - 2003 Feb
TI  - Identification of I kappa BL as the second major histocompatibility 
      complex-linked susceptibility locus for rheumatoid arthritis.
PG  - 303-12
AB  - Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a complex 
      etiology in which environmental factors within a genetically susceptible host 
      maneuver the innate and adaptive arms of the immune system toward recognition of 
      autoantigens. This ultimately leads to joint destruction and clinical 
      symptomatology. Despite the identification of a number of disease-susceptibility 
      regions across the genome, RA's major genetic linkage remains with the major 
      histocompatibility complex (MHC), which contains not only the key immune-response 
      class I and class II genes but also a host of other loci, some with potential 
      immunological relevance. Inside the MHC itself, the sole consistent RA 
      association is that with HLA-DRB1, although this does not encode all MHC-related 
      susceptibility. Indeed, in a set of Japanese patients with RA and a control 
      group, we previously reported the presence of a second RA-susceptibility gene 
      within the telomeric human leukocyte antigen (HLA) class III region. Using 
      microsatellites, we narrowed the susceptibility region to 70 kb telomeric of the 
      TNF cluster, known to harbor four expressed genes (I kappa BL, ATP6G, BAT1, and 
      MICB). Here, using numerous single-nucleotide polymorphisms (SNPs) and 
      insertion/deletion polymorphisms, we identify the second RA-susceptibility locus 
      within the HLA region, as the T allele of SNP 96452 (T/A), in the promoter region 
      (position -62) of the I kappa BL gene (P=.0062). This -62T/A SNP disrupts the 
      putative binding motif for the transcriptional repressor, delta EF1, and hence 
      may influence the transcription of I kappa BL, homologous to I kappa B alpha, the 
      latter being a known inhibitor of NF kappa B, which is central to innate 
      immunity. Therefore, the MHC may harbor RA genetic determinants affecting the 
      innate and adaptive arms of the immune system.
FAU - Okamoto, Koichi
AU  - Okamoto K
AD  - Department of Molecular Life Science, Tokai University School of Medicine, 
      Kanagawa, Japan.
FAU - Makino, Satoshi
AU  - Makino S
FAU - Yoshikawa, Yoko
AU  - Yoshikawa Y
FAU - Takaki, Asumi
AU  - Takaki A
FAU - Nagatsuka, Yumie
AU  - Nagatsuka Y
FAU - Ota, Masao
AU  - Ota M
FAU - Tamiya, Gen
AU  - Tamiya G
FAU - Kimura, Akinori
AU  - Kimura A
FAU - Bahram, Seiamak
AU  - Bahram S
FAU - Inoko, Hidetoshi
AU  - Inoko H
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021231
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Alleles
MH  - Arthritis, Rheumatoid/*genetics
MH  - Chromosome Mapping
MH  - Female
MH  - Gene Frequency
MH  - *Genetic Linkage
MH  - *Genetic Predisposition to Disease
MH  - HLA-DR Antigens/genetics
MH  - Humans
MH  - *Major Histocompatibility Complex
MH  - Male
MH  - Microsatellite Repeats
MH  - Polymorphism, Genetic
MH  - Promoter Regions, Genetic
MH  - Tumor Necrosis Factor-alpha/genetics
PMC - PMC379224
EDAT- 2003/01/02 04:00
MHDA- 2003/03/19 04:00
PMCR- 2003/08/01
CRDT- 2003/01/02 04:00
PHST- 2002/08/16 00:00 [received]
PHST- 2002/10/29 00:00 [accepted]
PHST- 2003/01/02 04:00 [pubmed]
PHST- 2003/03/19 04:00 [medline]
PHST- 2003/01/02 04:00 [entrez]
PHST- 2003/08/01 00:00 [pmc-release]
AID - S0002-9297(07)60540-0 [pii]
AID - 024399 [pii]
AID - 10.1086/346067 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2003 Feb;72(2):303-12. doi: 10.1086/346067. Epub 2002 Dec 31.