A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis

Cruz, Eugénia; Whittington, Chris; Krikler, Samuel; Mascarenhas, Cláudia; Lacerda, Rosa; Vieira, Jorge; Porto, Graça

doi:10.1186/1471-2350-9-97

Cited by 24 publications

(32 citation statements)

References 25 publications

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“…HH patients were all homozygous for the C282Y mutation of the HFE gene. HH patients were genotyped previously, or genotyped in the course of the present study, for three SNPs localized in the following genes: piggyBac transposable element derived 1 (PGBD1), zinc finger protein (ZNF) 193 and ZNF165 [8]. These SNPs are localized in the 6p21.3 region along 500 kb and are approximately 400 kb centromeric to the microsatellite D6S105 at the MHC class I region.…”

Section: Methodsmentioning

confidence: 99%

“…More recently, two conserved haplotypes, defined by three single nucleotide polymorphisms (SNPs) and localized at the 6p21.3 region near the microsatellite D6S105, were described in HH patients homozygous for the C282Y mutation [8]. These conserved haplotypes were shown to be predictors of both CD8 + T lymphocyte numbers and the clinical expression of HH [8]. To our knowledge, the possibility that the reported lymphocyte abnormalities could be explained by a particular subpopulation of cells within the CD8 + T lymphocyte pool has never been addressed previously.…”

Section: Introductionmentioning

confidence: 99%

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Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells

Macedo

Porto

Costa

et al. 2009

Clinical and Experimental Immunology

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SummaryLow CD8 + T lymphocyte numbers have long been described in hereditary haemochromatosis (HH). Recently, two conserved haplotypes localized near the microsatellite D6S105 at the major histocompatibility complex (MHC) class I region were described predicting the clinical expression of HH and the CD8 + T lymphocyte numbers. The A-A-T haplotype was associated with a severe clinical expression of HH and low CD8 + T lymphocyte numbers, while the G-G-G haplotype was associated with a milder clinical expression of HH and high CD8 + T lymphocyte numbers. As CD8 + T lymphocytes are a very heterogeneous population, in this study we analysed the CD8 + subpopulations of naive, central memory (TCM) and effector memory (TEM), and further subsets of CD8 + TEM cells in 47 HH patients and 68 controls. In addition, association studies were conducted between the conserved haplotypes and the CD8 + T cell subpopulations in HH. Variations of the numbers of naive and central memory cells with age were similar between HH patients and controls. For TEM cells and the TEM CD27 -CD28 -subset no effect of age was observed in HH [R 2 = 0·001, not significant (n.s.) and R 2 = 0·01, n.s., respectively] contrasting with the increasing of these subpopulations with age in controls (R 2 = 0·09, P = 0·017 and R 2 = 0·22, P = 0·0005, respectively). Interestingly, patients homozygous for the A-A-T haplotype have lower numbers of CD8 + TEM cells due especially to lower numbers of TEM CD27 -CD28 -(0·206 Ϯ 0·119 and 0·066 Ϯ 0·067 ¥ 10 6 cells/ml, respectively) than patients carrying the G-G-G haplotype (0·358 Ϯ 0·195 and 0·246 Ϯ 0·202 ¥ 10 6 cells/ml, respectively). This may suggest an inability of HH patients to differentiate the CD8 + T cells into the most mature phenotype.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells

Macedo

Porto

Costa

et al. 2009

Clinical and Experimental Immunology

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“…Of note, there are other examples where independent haplotypes are associated with distinct forms of a disease (Cruz et al, 2008). In our study, the two independent haplotypes might be acting as modifiers of the clinical presentation or reflect two distinct patient sub-populations.…”

Section: Myo16 Finementioning

confidence: 65%

Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

Rodríguez-Murillo

Roos

et al. 2013

Neuropsychopharmacol

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We previously reported linkage of schizophrenia and schizoaffective disorder to 13q32-34 in the European descent Afrikaner population from South Africa. The nature of genetic variation underlying linkage peaks in psychiatric disorders remains largely unknown and both rare and common variants may be contributing. Here, we examine the contribution of common variants located under the 13q32-34 linkage region. We used densely spaced SNPs to fine map the linkage peak region using both a discovery sample of 415 families and a meta-analysis incorporating two additional replication family samples. In a second phase of the study, we use one family-based data set with 237 families and independent case-control data sets for fine mapping of the common variant association signal using HapMap SNPs. We report a significant association with a genetic variant (rs9583277) within the gene encoding for the myosin heavy-chain Myr 8 (MYO16), which has been implicated in neuronal phosphoinositide 3-kinase signaling. Follow-up analysis of HapMap variation within MYO16 in a second set of Afrikaner families and additional case-control data sets of European descent highlighted a region across introns 2-6 as the most likely region to harbor common MYO16 risk variants. Expression analysis revealed a significant increase in the level of MYO16 expression in the brains of schizophrenia patients. Our results suggest that common variation within MYO16 may contribute to the genetic liability to schizophrenia.

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“…One such factor could be a new 500 kb microhaplotype localized between HFE and the HLA-A locus as described by Cruz and coworkers [18]. This haplotype was associated with a more severe phenotype in its carriers and also with low CD8 + T lymphocyte numbers, which in previous studies from Portugal have predicted a more severe iron overload [19]–[22].…”

Section: Introductionmentioning

confidence: 95%

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

et al. 2013

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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-Trøndelag, 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-Trøndelag. 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-Trøndelag 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.

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A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis

Cited by 24 publications

References 25 publications

Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells

Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells

Fine Mapping on Chromosome 13q32–34 and Brain Expression Analysis Implicates MYO16 in Schizophrenia

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

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