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.
Highlights
The major histocompatibility complex (MHC) region on chromosome 6p21.3 constitutes the most dense gene region of the human genome
Significant differences among the 3 populations of patients were observed in males for transferrin saturation (TfSat), serum ferritin (SF), and total body iron stores (TBIS), with P values,0.00001 in all cases
In the present study we showed that, in general, the presence in homozygosity of the A-A-T microhaplotype was associated to higher values of serum ferritin and total body iron stores in male patients, this association was not significantly sustained at the individual populations’ level and cannot be used as a reliable universal marker of the phenotypic expression in HH (Table 5)
Summary
The major histocompatibility complex (MHC) region on chromosome 6p21.3 constitutes the most dense gene region of the human genome. It has been estimated that 40% of classical MHC genes are expressed in the immune system [1] These genes are physically clustered, possibly reflecting functional relationships, and are characterized by high polymorphism levels and strong linkage disequilibrium. These characteristics make the MHC region a paradigm in many aspects of genomic research, in disease association studies. Fine mapping of those disease associations and the identification of specific functional variants remain difficult. Both structural and regulatory variants are important in disease associations and may operate in tandem [1]
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