PMID- 24282517
OWN - NLM
STAT- MEDLINE
DCOM- 20150102
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 11
DP  - 2013
TI  - Effects of highly conserved major histocompatibility complex (MHC) extended 
      haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous 
      hemochromatosis patients from three geographically distant areas.
PG  - e79990
LID - 10.1371/journal.pone.0079990 [doi]
LID - e79990
AB  - Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron 
      overload occurring commonly in subjects homozygous for the C282Y mutation in HFE 
      gene localized on chromosome 6p21.3 in linkage disequilibrium with the human 
      leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic 
      expression is variable suggesting the presence of modifying factors. One such 
      genetic factor, a SNP microhaplotype named A-A-T, was recently found to be 
      associated with a more severe phenotype and also with low CD8(+)T-lymphocyte 
      numbers. The present study aimed to test whether the predictive value of the 
      A-A-T microhaplotype remained in other population settings. In this study of 304 
      HH patients from 3 geographically distant populations (Porto, Portugal 65; 
      Alabama, USA 57; Nord-Trondelag, Norway 182), the extended haplotypes involving 
      A-A-T were studied in 608 chromosomes and the CD8(+) T-lymphocyte numbers were 
      determined in all subjects. Patients from Porto had a more severe phenotype than 
      those from other settings. Patients with A-A-T seemed on average to have greater 
      iron stores (p = 0.021), but significant differences were not confirmed in the 3 
      separate populations. Low CD8(+) T-lymphocytes were associated with 
      HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from 
      Nord-Trondelag. Although A-A-T may signal a more severe iron phenotype, this 
      study was unable to prove such an association in all population settings, 
      precluding its use as a universal predictive marker of iron overload in HH. 
      Interestingly, the association between A-A-T and CD8(+) T-lymphocytes, which was 
      confirmed in Porto and Alabama patients, was not observed in Nord-Trondelag 
      patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 
      segregating with HFE/C282Y in the three populations may carry different messages. 
      These findings further strengthen the relevance of HH as a good disease model to 
      search for novel candidate loci associated with the genetic transmission of 
      CD8(+) T-lymphocyte numbers.
FAU - Costa, Monica
AU  - Costa M
AD  - Basic and Clinical Research on Iron Biology (BCRIB), Institute for Molecular and 
      Cell Biology (IBMC), University of Porto, Porto, Portugal.
FAU - Cruz, Eugenia
AU  - Cruz E
FAU - Barton, James C
AU  - Barton JC
FAU - Thorstensen, Ketil
AU  - Thorstensen K
FAU - Morais, Sandra
AU  - Morais S
FAU - da Silva, Berta M
AU  - da Silva BM
FAU - Pinto, Jorge P
AU  - Pinto JP
FAU - Vieira, Cristina P
AU  - Vieira CP
FAU - Vieira, Jorge
AU  - Vieira J
FAU - Acton, Ronald T
AU  - Acton RT
FAU - Porto, Graca
AU  - Porto G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131125
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Genetic Markers)
RN  - 0 (HFE protein, human)
RN  - 0 (Hemochromatosis Protein)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Membrane Proteins)
RN  - 9007-73-2 (Ferritins)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Alabama
MH  - CD8-Positive T-Lymphocytes/*metabolism
MH  - Female
MH  - Ferritins/blood
MH  - Genetic Association Studies
MH  - Genetic Markers
MH  - Geography
MH  - *Haplotypes
MH  - Hemochromatosis/*genetics
MH  - Hemochromatosis Protein
MH  - Histocompatibility Antigens Class I/*genetics
MH  - Humans
MH  - Iron/*metabolism
MH  - Major Histocompatibility Complex/*genetics
MH  - Male
MH  - Membrane Proteins/*genetics
MH  - Norway
MH  - Polymorphism, Single Nucleotide
MH  - Portugal
PMC - PMC3839968
COIS- Competing Interests: The authors declare that they have no conflict of interests. 
      Moreover, although Sandra Morais was partially funded by Roche Pharmaceutics (see 
      Acknowledgments) this funding is a general scholarship program from the Abel 
      Salazar Institute for Biomedical Sciences (ICBAS), University of Porto, 
      supporting research work by medical students, not implicating financial competing 
      interests. This does not alter the authors' adherence to all the PLOS ONE 
      policies on sharing data and materials.
EDAT- 2013/11/28 06:00
MHDA- 2015/01/03 06:00
PMCR- 2013/11/25
CRDT- 2013/11/28 06:00
PHST- 2013/01/22 00:00 [received]
PHST- 2013/10/02 00:00 [accepted]
PHST- 2013/11/28 06:00 [entrez]
PHST- 2013/11/28 06:00 [pubmed]
PHST- 2015/01/03 06:00 [medline]
PHST- 2013/11/25 00:00 [pmc-release]
AID - PONE-D-13-03279 [pii]
AID - 10.1371/journal.pone.0079990 [doi]
PST - epublish
SO  - PLoS One. 2013 Nov 25;8(11):e79990. doi: 10.1371/journal.pone.0079990. 
      eCollection 2013.