Haemochromatosis gene mutations in Finns, Swedes and Swedish Saamis.

Frequencies of three different mutant haemochromatosis (HFE) alleles (282Tyr, 63Asp and 65Cys) were studied in three northern European populations, i.e. Finns, Swedes and Swedish Saamis. In Finns and Swedes the allele frequencies were within the range found in other populations from northern and western Europe. The Saamis differed from the Swedes with respect to all mutant alleles. Lower frequencies compared to Swedes were found for the 282Tyr (p = 0.0046) and 63Asp (p = 0.034) alleles, whereas the frequency of the 65Cys allele was higher (p = 0.046) in the Saamis. The total distribution of HFE alleles in Saamis showed a highly significant difference from that in Swedes (chi2 = 16.7, 3 d.f., p = 0.0008). These results further underline the genetic uniqueness of the Saamis.

Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma.

In hepatocellular carcinoma (HCC) iron has been implicated as a risk factor primarily in patients with hereditary haemochromatosis (HH) and cirrhosis. The wild-type HH (HFE) protein complexes with the transferrin receptor (TFR), and two HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of the TFR for transferrin resulting in an increased cellular uptake of iron. In previous studies we found an interaction between HFE and TFR genotypes in multiple myeloma and breast and colorectal carcinomas. In the present investigation we have studied HFE and TFR genotypes in 54 Swedish patients with HCC, using DNA from archival samples of paraffin wax blocks. The same HFE-TFR interaction as in the previously studied neoplastic disorders was found. Individuals carrying the HFE282Tyr allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser allele showed an increased risk for HCC (OR = 3.5; 95% confidence interval, CI = 1.3-9.3), which was further increased in HFE Tyr homozygotes and compound (Tyr/Asp) heterozygotes in combination with TFR 142Ser homozygosity (OR = 17.2; 95% CI = 1.8-168.9). The presence of liver cirrhosis could only be assessed in part of the patient material. In patients with verified liver cirrhosis the risk figures were substantially increased: for HFE 282 Tyr carriers in combination with TFR 142 Ser/Ser OR = 7.2; 95% CI = 2.0-25.5 and for HFE 282Tyr homozygotes and compound heterozygotes in combination with TFR 142Ser homozygosity, OR = 62.8; 95% CI = 6.1-642.5.

The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective.

A genetic perspective of human history in Europe was derived from 22 binary markers of the nonrecombining Y chromosome (NRY). Ten lineages account for >95% of the 1007 European Y chromosomes studied. Geographic distribution and age estimates of alleles are compatible with two Paleolithic and one Neolithic migratory episode that have contributed to the modern European gene pool. A significant correlation between the NRY haplotype data and principal components based on 95 protein markers was observed, indicating the effectiveness of NRY binary polymorphisms in the characterization of human population composition and history.

Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders.

A number of genes are involved in iron metabolism, including the transferrin receptor (TFR) and haemochromatosis (HFE) genes. In previous investigations an increased risk for neoplastic disease has been observed in individuals homo- and heterozygous for hereditary haemochromatosis. The HFE wild-type gene product complexes with the transferrin receptor (TF) and two different HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of TFR for TF and increase cellular iron uptake. In a recent study we found no associations for HFE and TFR separately, but an interaction between HFE and TFR genotypes in multiple myeloma. Individuals carrying the HFE Tyr282 allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser142 allele had an increased risk. In the present study the same association was found in breast and colorectal cancer. The odds ratio for all three neoplasms combined was 2.0 (95% CI 1.0-3.8). The risk for neoplastic disease was further increased (OR 7.7, 95% CI = 1.0-59.9) when the analysis was restricted to HFE Tyr homozygotes and compound heterozygotes in combination with TFR Ser homozygosity. Thus, an interaction between HFE and TFR alleles may increase the risk for different neoplastic disorders.

Protective effect of transferrin C3 in lung cancer?

In a previous study of lung cancer patients and controls from the Stockholm area in central Sweden, we found a significantly decreased frequency of the transferrin (TF) variant C3 in small cell and squamous epithelial lung cancer but not in adenocarcinoma, suggesting a protective effect of TF C3 in small cell and squamous lung cancer. In an attempt to replicate this association we studied TF types in lung cancer patients and controls from two additional Swedish subpopulations, viz. northern Sweden and southwestern Sweden. We were able to confirm the significantly decreased frequency of TF C3, especially in small cell lung cancer, in northern Sweden but not in southwestern Sweden. Thus the eventual protective effect of TF C3 in small cell lung cancer is an open question. We hypothesize that the association between TF C alleles and lung cancer may be secondary and dependent on linkage disequilibrium with allelic variants of newly discovered tumor-associated genes known to map to the same position (3q21) as TF, e.g. NCK and H-RYK.

New DNA polymorphisms define ethnically distinct haplotypes in the human transferrin receptor gene.

In a study of transferrin receptor (TFR) polymorphism in different ethnic groups using PCR and restriction cleavage we found a new Hin6I polymorphism in intron 7 and confirmed a tentative BanI polymorphism in exon 4 reported by Evans and Kemp [Gene 1997;199:123-131]. In all ethnic groups there was a complete and highly significant (p < 10(-10)) linkage disequilibrium where all BanI 1 alleles were linked to Hin6I 1 alleles. Furthermore in the European populations, but not in the Chinese, there was a close correlation between the three BanI-Hin6I haplotypes and the alleles of a previously described three-allelic RsaI polymorphism in the TFR gene studied by Southern blotting. There were distinct ethnic differences in TFR allele and haplotype frequencies. Thus the Saamis were significantly different from the other European ethnic groups, and the Lithuanians had a significantly increased frequency of the BanI 2-Hin6I 1 haplotype, suggesting that this marker may be informative in tracing prehistoric migrations and admixture by Baltic peoples. The new TFR polymorphisms and haplotypes may also be useful markers in studies of interactions with the transferrin and hemochromatosis genes, the genetic influence on body iron stores and disease associations.

DNA polymorphisms and haplotypes in the human transferrin gene.

Although a large number of human serum transferrin (TF) variants have been described, only one RFLP (AvaI) has so far been found. Here we report three new RFLPs (MvaI in intron 5 and exon 7, BbvI in exon 7) and correlations between RFLPs and between RFLPs and serum TF types. There were strong, but not always complete, disequilibria between RFLP and serum protein alleles. Thus, the most common serum TF variant, C1, was heterogeneous and could be subdivided into two common haplotypes, whereas the C2, C3, and DCHI variants were completely or almost completely (C2) homogeneous. There was a total genotypic agreement between the BbvI polymorphism and the presence/absence of the TF C3 variant, and the mutation that creates the BhvI site was found to lead to a G258S amino acid substitution.

Transferrin C2, metal binding and Alzheimer's disease.

Significant associations between the transferrin (TF) variant C2 and a number of disorders suspected to be caused by oxygen free radicals have been reported. Thus an increased frequency of the TFC2 variant has been found in patients with Alzheimer's disease (AD), and it has been hypothesized that AD is caused by free radical damage due to defective binding of iron and aluminium by TFC2. In a study of 64 patients with AD from northern Sweden we were able to confirm the association between TFC2 and AD, but there were no significant differences between TFC2 and other TF variants with respect to the binding of iron and aluminium.

[Hereditary hemochromatosis. Genetic findings result in new therapeutic possibilities]. / Hereditär hemokromatos. Genfynd ger nya behandlingsmöjligheter.

Hereditary haemochromatosis is a well-known disease characterised by abnormally high iron absorption and a variety of clinical manifestations. As it's expression is dependent on such factors as gender and diet, it has often been difficult to diagnose before the onset of damage to different organs. However, since the recent discovery of the gene for hereditary hemochromatosis, early detection and treatment of the disease has become possible.

Ethnic differences in the HFE codon 282 (Cys/Tyr) polymorphism.

Recent studies have shown that hereditary hemochromatosis (HH) is likely to be caused by homozygosity for a Cys282Tyr mutation in the HFE gene located 4.5 Mb telomeric to HLA-A. Population studies of this polymorphism are facilitated by the fact that the Cys282Tyr mutation creates a Rsal restriction site. We have studied the codon 282 (Cys/Tyr) polymorphism in different ethnic groups. In agreement with previous observations the Tyr allele appeared to be rare or absent in Asiatic (Indian, Chinese) populations. The highest allele frequency (7.5%) was found in Swedes. Saamis (2%) and Mordvinians (1.8%) had significantly lower frequencies of the Tyr allele. Comparisons with allele frequencies based on prevalence estimates of HH showed some disagreements with the RFLP data, particularly in Finns. The newly described HFE marker provides a new approach to the screening of HH as well as studies of the relationship between the HFE Tyr allele and different disorders including cancer.

Transferrin C3 offers protection against smoking-associated lung cancer?

In previous investigations increased body iron stores and transferrin (TF) variants have been found to be associated with adverse health effects, including cancer. In this investigation transferrin C (TF C) subtypes were studied in lung cancer patients and controls from the Stockholm area in central Sweden. There was a significant difference between patients and controls with respect to the distribution of TF C alleles and genotypes, which was mainly due to a low frequency of the TF C3 allele among the patients (P = 3 x 10(-6). However, in adenocarcinoma the frequency of TF C3 types was almost identical to that among the controls, whereas in the smoking-related (squamous and small cell) tumor types the TF C3 frequency was remarkably low (OR = 0.03, 95% CI = 0.00-0.22). Thus individuals with the TF C3 variant appear to enjoy an almost complete protection against smoking-related lung cancer. The frequency of individuals carrying the protective TF C3 variant is approximately 17% in central Sweden and 25% in Finland, which has the highest TF C3 frequency found so far. The mechanism behind the observed association, which appears to be independent of iron binding and body iron stores, remains to be elucidated.