The first Swedish case of familial amyloidotic polyneuropathy (FAP) was published in 1965. The same transthyretin (TTR met30) mutation as that seen in Japanese, Portuguese, and other populations was also found in Swedish FAP patients. More than 350 patients with clinical manifestations of FAP have been diagnosed in northern Sweden, most of them originating from the areas around SkellefteA and PiteA. The mean age of onset is 56 years, much later than in patients from Japan and Portugal. To estimate the frequency of the TTR met30 mutation in the counties of Vasterbotten and Norrbotten, sera from 1276 persons aged 24 to 65 years, randomly sampled from a health programme (MONICA), were screened with the monoclonal antibody FD6. In 19 persons, 13 females and six males, a positive reaction was seen in an Elisa test using this antibody. DNA analysis confirmed the TTR met30 mutation and showed that 18 were heterozygous and one homozygous for this mutation. Other mutations were not looked for in this study. The mean TTR met30 carrier frequency in the area was 1.5% ranging from 0 0 to 8-3% in 23 subpopulations. There was a notable discrepancy between the regional distribution of the TTR met30 allele and the morbidity rate for FAP. The estimated number of TTR met'0 gene carriers in a total population of 500 000 in the area is approximately 7500. The penetrance of the TTR met'4 mutation shows considerable variation between families, and the overall diagnostic (predictive) value in this population is as low as around 2%.

An association between the BstU I 1-1 (Pro-Pro) genotype of the p53 codon 72 polymorphism and lung cancer has previously been reported by Kawajiri et al. A reanalysis of the data by Kawajiri et al. revealed no significant difference between patients and controls with respect to allele frequencies, and the increased frequency of BstU I 1-1 homozygotes was mostly ascribable to a deviation from the Hardy-Weinberg equilibrium. In an attempt to replicate the results by Kawajiri et al. we have studied three p53 polymorphisms (BstU I and Msp I RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotypes in Swedish lung cancer patients and controls. The results concerning the codon 72 polymorphism were largely negative. Thus there was no significant association between lung cancer and the BstU I 1-1 type, and only a marginal difference (P = 0.044) with respect to the BstU I allele frequency when lung cancer patients were compared with patients with chronic obstructive pulmonary disease (COPD). However, when the analysis was based on haplotype frequencies larger differences appeared and it was found that only BstU I 1 (pro) alleles linked to 16 bp 1 alleles were associated with lung cancer. Pro alleles linked to the 16 bp duplication appeared instead to confer some protection against cancer. Thus the codon 72 alleles need not be functionally involved in lung cancer, but may rather be markers in linkage disequilibrium with other cancer susceptibility sites on p53.

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.

Three different p53 DNA polymorphisms (a 16-bp duplication in intron 3 and BstUland MsplRFLPs in exon 4 and intron 6, respectively) and haplotype combinations were studied in some major ethnic groups: Caucasians (Swedes), Chinese, Dravidian Indians and African Blacks. Significant ethnic differences in single polymorphisms were found between all groups except for African Blacks-Dravidian Indians, who differed only in their MspI7-16-bp duplication haplotype distribution. Since previous results have shown that p53 alleles are correlated with latitude (degree of insolation), the similarity between these two groups, who are genetically quite distinct, may be due to ecological adaptation to similar climatic conditions. All other major ethnic groups differed significantly from each other with respect to their haplotype distributions; thus, p53 alleles and haplotypes should be very useful as anthropological markers. Asiatic Mongoloid groups appear to be characterized by very low frequencies of the 16-bp duplication and the MspIA1 allele. These mutations have probably been introduced by migration to east Asia from either Europe or Africa, where the highest frequencies were found. The results of this study indicate that p53, besides its role as a tumor suppressor, shows distinct ethnic heterogeneity and may be involved in ecological (climatic) adaptation.

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 142Ser/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.

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.

The codon 31 polymorphism of the p53-inducible protein p21 was studied with respect to allele frequency variations between some major ethnic groups. The frequency of the A1 (Arg) allele showed highly significant variations ranging from 4% in Caucasians (Swedes) to 50% in Chinese. Compared to Caucasians, a relatively high frequency was found in African Blacks (29%) and Indians (16%). Furthermore, Finns and Mordvinians also had higher frequencies (9–10%) than west Europeans (French and Swedes), consistent with an Asiatic Mongoloid influence known to exist in Finno-Ugrian tribes. The geographic allele frequency patterns of p53 and its effector protein p21 were quite different. The p21 A1 mutations in African, Asiatic and European populations were identical at the DNA level. The geographical distribution of the A1 allele suggests an independent origin in Africa and Asia. The very pronounced ethnic differentiation of tumour suppressor genes and the fact that tumour suppressor genes may be teratogenes suggest that these polymorphisms are maintained by natural selection, probably operating in the intrauterine period.

The distribution of α₁-antitrypsin (PI) alleles was studied in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. The frequency of the PI Z allele, a typically Northwesteuropean marker gene, showed a highly significant regional variation in the Baltic Sea region. The highest frequency (4.5%) was found in the western part of Latvia (Courland). The PI S allele, another marker of Westeuropean influence, also showed an increased frequency in the Courland population. These results indicate that among the populations east of the Baltic Sea the Curonian population has the most pronounced Westeuropean influence. Archaeological data have shown that from the 7th century and for several hundreds of years Courland received immigrations from mainland Sweden and the island of Gotland. We speculate that the increased frequencies of the PI Z alleles and S alleles in Courland may have been caused by these migrations.