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

Abstract

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.

Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

“…These SNPs are also in strong LD with multiple neighboring variants, including eQTLs associated with gene expression profiles in Afri- Genetic evidence from other studies. At least two studies have examined the genetic impact on CD8 T-cell counts in human populations (45,46). In study cohorts from Australia and the UK (45), a SNP (rs2524054) located in an intergenic region between HLA-B and HLA-C was associated with absolute CD8 T-cell counts in the general population.…”

Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo

“…All previous results in HH patients suggesting an impact of HFE on the expression profile of CD8 + T cells were still confounded not only by the known phenotypic heterogeneity among patients, possibly influenced by other MHC linked genetic determinants [ 16 , 18 ] but also by the strong correlation between the CD8 phenotypes and the severity of iron overload [ 8 ]. In order to address the relative impact of HFE and iron overload on the CD8 + T-lymphocyte gene expression profile in the absence of such confounding variables, we used the HFE deficient mouse model ( Hfe -/- ).…”

“…For the purpose of phenotypic grouping, HH patients were classified into one of these two types: “the low CD8 phenotype” defined as patients with absolute CD8 + T-lymphocyte numbers consistently lower than 300x10 3 /ml in at least 5 serial determinations, and the “normal/high CD8 phenotype” defined as patients with CD8 + T-lymphocyte numbers consistently higher or equal than 400x10 3 /ml. These limits were defined based on the normal distribution of values described in the Portuguese control population considering the limit for the low CD8 phenotype as the 25% lower percentile and the limit for a normal/high CD8 phenotype the average value in controls [ 8 , 18 ]. Clinical and laboratory data from the patients have been published previously [ 2 , 8 , 10 , 41 , 46 ].…”

“…It is known that modifications in gene expression concur to define the different properties of CD8 + T cells at different differentiation stages and therefore their homeostatic equilibrium [ 15 ]. We have shown that particular HLA-A alleles and haplotypes are significantly associated with CD8 + T-cell numbers in HH patients carrying the same HFE mutation [ 16 , 17 ] but they do not constitute a universal marker in all patients analyzed [ 18 ]. Studies are still pending trying to localize other relevant markers in the same chromosomal region.…”

Autoimmune Conditions in 235 Hemochromatosis Probands withHFEC282Y Homozygosity and Their First-Degree Relatives

“…In 1996, it was discovered that ~90% of whites with hemochromatosis were homozygous for a common mutation (exon 4, c.845G>A, p.C282Y; rs1800562) in a previously undescribed nonclassical class I major histocompatibility complex (MHC) gene on chromosome 6p [ 6 ]. The gene, now known as HFE , occurs in linkage disequilibrium with the HLA-A locus [ 3 , 7 , 8 ]. The most common hemochromatosis ancestral haplotypes in many northwestern European and derivative populations include HFE C282Y linked to HLA-A ∗ 03 [ 7 – 10 ], HLA-A ∗ 03, B ∗ 07 [ 7 – 9 ], or HLA-A ∗ 03, B ∗ 14 [ 7 – 9 , 11 ].…”