PMID- 11285254
OWN - NLM
STAT- MEDLINE
DCOM- 20010705
LR  - 20220129
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 10
IP  - 8
DP  - 2001 Apr 1
TI  - Conditional linkage disequilibrium analysis of a complex disease superlocus, 
      IDDM1 in the HLA region, reveals the presence of independent modifying gene 
      effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 
      disease loci.
PG  - 881-9
AB  - Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. 
      Its aetiology is underpinned by a major locus, insulin-dependent diabetes 
      mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 
      6p21, and an unknown number of loci of lesser individual effect. In linkage 
      analyses IDDM1 is a single peak, but it is evident that the linkage is caused by 
      allelic variation of three adjacent genes in a 75 kb region, namely the class II 
      genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain 
      all of the HLA association. We investigated, in the founder population of 
      Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region 
      encompassing the whole HLA complex further influence the disease risk, after 
      taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 
      and -DRB1. We generalized the conditional association test, the haplotype method, 
      to detect marker associations that are independent of the main DR/DQ disease 
      associations. Three regions were identified as risk modifiers. These associations 
      were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 
      and -DRB1, but also independent of each other. The individual contributions of 
      these risk modifiers were relatively modest but their combined impact was highly 
      significant. Together, alleles of single nucleotide polymorphisms at the DMB and 
      DOB genes, and the microsatellite locus TNFc, identified approximately 40% of 
      Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach 
      can be applied to any chromosome region involved in the predisposition to complex 
      traits.
FAU - Zavattari, P
AU  - Zavattari P
AD  - Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Via 
      Jenner, Cagliari 09121, Italy.
FAU - Lampis, R
AU  - Lampis R
FAU - Motzo, C
AU  - Motzo C
FAU - Loddo, M
AU  - Loddo M
FAU - Mulargia, A
AU  - Mulargia A
FAU - Whalen, M
AU  - Whalen M
FAU - Maioli, M
AU  - Maioli M
FAU - Angius, E
AU  - Angius E
FAU - Todd, J A
AU  - Todd JA
FAU - Cucca, F
AU  - Cucca F
LA  - eng
GR  - E.0604/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Chromosome Mapping
MH  - Diabetes Mellitus, Type 1/*genetics
MH  - HLA-DQ Antigens/*genetics
MH  - HLA-DQ beta-Chains
MH  - HLA-DR Antigens/*genetics
MH  - HLA-DRB1 Chains
MH  - Humans
MH  - *Linkage Disequilibrium
MH  - Risk Factors
EDAT- 2001/04/04 10:00
MHDA- 2001/07/06 10:01
CRDT- 2001/04/04 10:00
PHST- 2001/04/04 10:00 [pubmed]
PHST- 2001/07/06 10:01 [medline]
PHST- 2001/04/04 10:00 [entrez]
AID - 10.1093/hmg/10.8.881 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2001 Apr 1;10(8):881-9. doi: 10.1093/hmg/10.8.881.