PMID- 16526951
OWN - NLM
STAT- MEDLINE
DCOM- 20060424
LR  - 20240412
IS  - 1471-2350 (Electronic)
IS  - 1471-2350 (Linking)
VI  - 7
DP  - 2006 Mar 9
TI  - On the Wegener granulomatosis associated region on chromosome 6p21.3.
PG  - 21
AB  - BACKGROUND: Wegener granulomatosis (WG) belongs to the heterogeneous group of 
      systemic vasculitides. The multifactorial pathophysiology of WG is supposedly 
      caused by yet unknown environmental influence(s) on the basis of genetic 
      predisposition. The presence of anti-neutrophil cytoplasmic antibodies (ANCA) in 
      the plasma of patients and genetic involvement of the human leukocyte antigen 
      system reflect an autoimmune background of the disease. Strong associations were 
      revealed with WG by markers located in the major histocompatibility complex class 
      II (MHC II) region in the vicinity of human leukocyte antigen (HLA)-DPB1 and the 
      retinoid X receptor B (RXRB) loci. In order to define the involvement of the 
      6p21.3 region in WG in more detail this previous population-based association 
      study was expanded here to the respective 3.6 megabase encompassing this region 
      on chromosome 6. The RXRB gene was analysed as well as a splice-site variation of 
      the butyrophilin-like (BTNL2) gene which is also located within the respective 
      region. The latter polymorphism has been evaluated here as it appears as a HLA 
      independent susceptibility factor in another granulomatous disorder, sarcoidosis. 
      METHODS: 150-180 German WG patients and a corresponding cohort of healthy 
      controls (n = 100-261) were used in a two-step study. A panel of 94 
      microsatellites was designed for the initial step using a DNA pooling approach. 
      Markers with significantly differing allele frequencies between patient and 
      control pools were individually genotyped. The RXRB gene was analysed for single 
      strand conformation polymorphisms (SSCP) and restriction fragment length 
      polymorphisms (RFLP). The splice-site polymorphism in the BTNL2 gene was also 
      investigated by RFLP analysis. RESULTS: A previously investigated microsatellite 
      (#1.0.3.7, Santa Cruz genome browser (UCSC) May 2004 Freeze localisation: 
      chr6:31257596-34999883), which was used as a positive control, remained 
      associated throughout the whole two-step approach. Yet, no additional evidence 
      for association of other microsatellite markers was found in the entire 
      investigated region. Analysis of the RXRB gene located in the WG associated 
      region revealed associations of two variations (rs10548957 pallelic = 0.02 and 
      rs6531 pallelic = 5.20 x 10-5, OR = 1.88). Several alleles of markers located 
      between HLA-DPB1, SNP rs6531 and microsatellite 1.0.3.7 showed linkage 
      disequilibrium with r2 values exceeding 0.10. Significant differences were not 
      demonstrable for the sarcoidosis associated splice-site variation (rs2076530 
      pallelic = 0.80) in our WG cohort. CONCLUSION: Since a microsatellite flanking 
      the RXRB gene and two intragenic polymorphisms are associated significantly with 
      WG on chromosome 6p21.3, further investigations should be focussed on extensive 
      fine-mapping in this region by densely mapping with additional markers such as 
      SNPs. This strategy may reveal even deeper insights into the genetic 
      contributions of the respective region for the pathogenesis of WG.
FAU - Szyld, Pawel
AU  - Szyld P
AD  - Human Genetics, Ruhr-University, Bochum, Germany. szyld@list.pl
FAU - Jagiello, Peter
AU  - Jagiello P
FAU - Csernok, Elena
AU  - Csernok E
FAU - Gross, Wolfgang L
AU  - Gross WL
FAU - Epplen, Joerg T
AU  - Epplen JT
LA  - eng
PT  - Journal Article
DEP - 20060309
PL  - England
TA  - BMC Med Genet
JT  - BMC medical genetics
JID - 100968552
RN  - 0 (BTNL2 protein, human)
RN  - 0 (Butyrophilins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Retinoid X Receptor beta)
SB  - IM
MH  - Butyrophilins
MH  - Chromosome Mapping
MH  - *Chromosomes, Human, Pair 6
MH  - Granulomatosis with Polyangiitis/*genetics
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Membrane Glycoproteins/*genetics
MH  - Microsatellite Repeats
MH  - Retinoid X Receptor beta/*genetics
PMC - PMC1431512
EDAT- 2006/03/11 09:00
MHDA- 2006/04/25 09:00
PMCR- 2006/03/09
CRDT- 2006/03/11 09:00
PHST- 2005/07/29 00:00 [received]
PHST- 2006/03/09 00:00 [accepted]
PHST- 2006/03/11 09:00 [pubmed]
PHST- 2006/04/25 09:00 [medline]
PHST- 2006/03/11 09:00 [entrez]
PHST- 2006/03/09 00:00 [pmc-release]
AID - 1471-2350-7-21 [pii]
AID - 10.1186/1471-2350-7-21 [doi]
PST - epublish
SO  - BMC Med Genet. 2006 Mar 9;7:21. doi: 10.1186/1471-2350-7-21.