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.

GC serum groups and otosclerosis.

Five genetic serum protein marker systems (HP, TF, GC, BF and PI) were studied in patients with otosclerosis and in controls. The distributions of GC phenotypes and alleles showed significant differences between patients and controls with an excess of the IF-allele and the IF-variant among the patients.

Method for the typing of the C3 polymorphism in stored sera by means of isoelectric focusing.

A method is described by which the three common phenotypes of C3 can be typed by desialylation and isoelectric focusing in serum samples stored at -20 degrees C for several years.

DNA polymorphisms and haplotypes of human liver/bone/kidney alkaline phosphatase in Finns, Saamis and Swedes.

BclI and SstI restriction fragment length polymorphisms of human liver/bone/kidney or tissue-non-specific alkaline phosphatase were studied in population samples of Finns, Swedes and Swedish Saamis. No significant allele frequency differences were found between the three ethnic groups, but in comparison with a previously reported study of North American Caucasians, a highly significant difference was found with respect to BclI alleles. In contrast to previous findings, a significant linkage disequilibrium was found between BclI and SstI alleles.

Population studies in northern Sweden. XIX. The orosomucoid polymorphism.

Genetic polymorphism of orosomucoid (ORM1) was studied by isoelectric focusing in 3,817 conscripts and blood donors from the countries of Norrbotten and Västerbotten in northern Sweden. The individuals were distributed according to place of birth into 23 subpopulations. There was a significant heterogeneity between the 23 subpopulations with respect to the allele frequencies (p = 1 x 10(-8)). The ORM1*2 allele varied between 27 and 46%, and a clineal variation was observed with decreasing ORM1*2 allele frequencies in the northern direction. Significant correlations were found between the frequencies of the ORM1 alleles and previously studied Finnish and Saamish marker genes. The geographical variation of ORM1 alleles was in close agreement with the pattern expected from the known mixture of Finns, Saamis, and Swedes in northern Sweden and further underlines the impact of ethnic heterogeneity on the genetic differentiation of the north Swedish population.

RsaI and BclI polymorphism of the transferrin receptor gene.

Polymorphism of the transferrin receptor gene has previously not been observed. Here we report two new restriction fragment length polymorphisms (RFLPs) of the transferrin receptor gene. Digestion with RsaI revealed three variable fragments at 1.15, 1.05 and 0.85 kb. After cleavage with BclI, two polymorphic 2.8- and 2.3-kb fragments were found. There was strong linkage disequilibrium between the two RFLPs, and Saamis showed a highly significant difference from Finns and Swedes with respect to allele frequencies. The new polymorphisms of the transferrin receptor gene may be useful markers in population and linkage studies and in studies of associations with body iron stores and susceptibility to genotoxic damage and cancer.

Transferrin C subtypes and spontaneous abortion.

The transferrin C subtypes were studied in relation to spontaneous abortion and a number of different genetic markers and traits. Among mothers with a history of spontaneous abortion an increased frequency of the C2 gene and especially of the C2 type was found. A correlation was found between the maternal C2 type and the placental alkaline phosphatase variant F, which previously has been shown to be associated with spontaneous abortion. The mechanism behind the intrauterine selection implied is unlikely to be immunological incompatibility between mother and fetus. No association was found with ABO and Rh blood groups, Hp and Gc serum groups, the pregnancy zone protein (PZ), red cell acid phosphatase types and birth weight.

Serum complement (C3, BF, C4) types in Swedish Saamis.

Serum complement (C3, BF, C4) types were examined in Swedish Saamis (Lapps). In agreement with previous studies, a very low frequency of the C3*F allele (0.033) was found. Compared to Swedes and other Caucasian populations, Swedish Saamis showed a significantly increased frequency of the BFS, C4A4 and C4B2 variants, and a lower frequency of C4 deficiency. BFS, C4A4 and C4B2 show haplotype associations and thus the frequency of the S-A4-B2 complotype is significantly increased among the Saamis. Although the serum complement constitution of the Saamis shows some similarity with that of Asiatic Mongoloid populations it is unlikely to be due to Asiatic ethnic influence. The marked genetic deviations of the Saamis from all other populations has often been interpreted as a result of the founder effect and genetic drift. In this particular case, however, immunogenetic adaptation appears to be a plausible alternative explanation for the deviations in genetic complement factors.

Transferrin C subtypes and ethnic heterogeneity in Sweden.

Transferrin (TF) C subtypes were studied in Swedish Lapps (Saami) and in Swedes from northern, central and southern Sweden, and the allele frequencies were compared with those in other European populations. The Swedish Lapps were found to have the lowest frequency of the TF*C3 allele (1-2%) so far observed in Europe. Most European populations have TF*C3 allele frequencies between 5 and 7%. Finns differ by having high TF*C3 frequencies (13-14%). The relatively high TF*C3 frequencies found in northeastern Sweden (13%) and in central Sweden (9%) are most likely due to eastern influence. Unlike other genetic markers of eastern influence (e.g. TF*DCHI), which are of Asiatic Mongoloid origin, TF*C3 appears to originate from Finno-Ugric populations.

Population studies in northern Sweden. XV. Transferrin C subtypes.

The frequencies of transferrin C (TF C) subtypes were studied in 315 Finns, 222 Swedish Lapps and in 4,157 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The Swedish individuals were distributed according to place of birth into 23 subpopulations or regions. A significant heterogeneity between the 23 regions was observed for the TF C1, C2 and C3 genes and for rare genes. Clines were found for the TF C1 and C3 genes and for rare transferrin genes in northern Sweden. The frequencies of the C1 and C3 genes were increasing in the southwestern and northeastern direction, respectively, and the frequency of the rare transferrin genes was increasing in the northern direction. The geographical picture of the C3 gene and of rare transferrin genes could be interpreted in terms of Finnish influence. The frequency of the TF C3 gene in Finland and northern Sweden (14 and 15%) is the highest so far reported in the world. The overall picture of geographical variations of the C1 and C2 genes were not explainable in terms of ethnic influence and may be caused by random differentiation and/or selective forces.

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.

Orosomucoid polymorphism in Finns, Swedes and Swedish Saamis.

Genetic polymorphism of orosomucoid (ORM) was studied by isoelectric focusing and immunoblotting in Finns, Swedes and Swedish Saamis. The ORM2 locus was found to be monomorphic in all three ethnic groups. In the Swedish sample the frequency of the ORM1*2 allele (0.414) was within the range found in other European populations, whereas Finns (0.282) and Saamis (0.210) showed significantly lower ORM1*2 frequencies. The extremely low ORM1*2 frequency in the Saamis further underlines the genetic uniqueness of this population. The ORM1*2 frequency in Saamis resembles those in Asiatic Mongoloid populations, but this is unlikely to reflect an Asiatic influence, since the accumulated knowledge on genetic markers in the Saamis show no unequivocal evidence for an Asiatic influence in this population.

Transferrin types, iron-binding capacity and body iron stores.

Increased body iron stores and transferrin (TF) variants have been found to be associated with adverse health effects believed to be caused by oxygen free radicals. Previous attempts to establish a relationship between TF types, serum TF concentrations and iron-binding have been inconclusive. We have studied serum iron, total iron-binding capacity (TIBC), TF saturation and serum ferritin in relation to genetic TF types in a population sample (691 females and 639 males) from northern Sweden in an attempt to elucidate whether individuals with TF variants associated with adverse somatic and reproductive effects (TFC2 and C3) have increased body iron stores. As expected there was a highly significant sex difference, males manifesting increased body iron stores viz. increased levels of serum iron, TF saturation and serum ferritin, and a lower TIBC. There was no consistent and statistically significant association between the TFC2 variant and the parameters that indicate iron binding and storage. Thus the associations between TFC2 and somatic and reproductive damage appear to be independent of iron binding and body iron stores. TIBC (and TF levels) showed significant differences between TF types in females (p = 0.0015) but not in males. In females the TFC3 variant was associated with a significantly lower (p = 0.002) TIBC value. This decreased TIBC value was, however, not accompanied by an increased ferritin value, thus there was no unequivocal evidence for an association between TFC3 and increased body iron stores.

Transferrin C subtypes and myocardial infarction.

Transferrin C subtypes were studied in 124 patients who were survivors of myocardial infarction and population controls to test the hypothesis that the TFC2 type is associated with an increased risk for myocardial infarction. The TFC2 type showed, however, only a marginal increase among the patients (p = 0.038), whereas the TF*C3 allele (p = 0.0004) and the types carrying the TFC3 variant, TFC3-1 and C3-2, displayed a highly significant increase (p = 0.0002).

Orosomucoid and haptoglobin types in patients with sarcoidosis.

Association with HLA and complement factors has been reported in sarcoidosis, and the results of previous studies suggest a multifactorial and immunogenetic etiology of the disease. We have studied two genetic acute-phase reactant systems, orosomucoid (ORM) and haptoglobin (HP), in 226 patients with sarcoidosis and population controls from northern Sweden. Significant allele and phenotype differences between patients and controls were found in both systems. The ORM1 phenotype showed a significant increase in sarcoidosis (RR = 1.34, p = 0.036), which was more pronounced among patients with low (< 1,500 nkat/l) angiotensin-converting enzyme levels (RR = 1.83, p = 0.00065) and hypercalcemia (RR = 3.69, p = 0.0023). The HP1 type was significantly increased among the sarcoidosis patients (RR = 1.57, p = 0.013). The results suggest that the ORM1 1 and HP1 types may be contributory determinants in the multifactorial etiology of sarcoidosis.

DNA polymorphism of alkaline phosphatase isozyme genes: linkage disequilibria between placental and germ-cell alkaline phosphatase alleles.

The use of human placental alkaline phosphatase (PLAP) cDNA as a probe allows the detection and identification of restriction DNA fragments derived from three homologous genes, i.e., intestinal alkaline phosphatase (AP), germ-cell AP (GCAP), and PLAP. In previous RFLP studies we have reported linkage disequilibria between an RsaI and two PstI (a and b) polymorphic restriction sites and electrophoretic types of PLAP. In this report we present evidence that, in spite of the strong correlation with PLAP types, PstI(b) is an RFLP of GCAP. The data indicate close linkage between the PLAP and GCAP loci.

Correlation between RsaI restriction fragment length polymorphism and electrophoretic types of human placental alkaline phosphatase.

Restriction fragment length polymorphism (RFLP) of human alkaline phosphatases was studied in a population sample from northern Sweden using a placental alkaline phosphatase (PLAP) cDNA probe. After digestion of human genomic DNA with RsaI the Southern blots showed DNA fragments most probably derived from three genes: PLAP, germ cell alkaline phosphatase (PLAP-like) and intestinal alkaline phosphatase. In agreement with a previous study, a two-allele polymorphism was found in PLAP with bands at 1.6 kilobases (A1) and 1.8 kilobases (A2). The gene frequencies of A1 and A2 were 0.46 and 0.54, respectively. There was a significant correlation between the RsaI RFLPs and electrophoretic types of PLAP; RSAI A2 showed an association with the ALP2p allele of PLAP.

Genetic markers associated with high versus low performance on episodic memory tasks.

Associations were studied between six serum protein polymorphisms (C3, BF, HP, ORM, TF, and GC) and high versus low scoring on episodic memory tasks in an attempt to identify QTL (quantitative trait loci) contributing to the heritability of this quantitative trait. Since a highly significant sex difference (p = .00002) was found with respect to the distribution of high and low scoring, with men showing a poorer performance, associations were studied separately for males and females. In females significant differences (p < .05) between the high and the low groups were found in four of six marker systems (C3, HP, TF, and CG), whereas in males a significant difference was found only in the HP system. Significant differences from population frequencies were also found more frequently in females than in males. The strongest marker associations were found with complement C3 and the acute-phase reactant HP, which suggests that immune response factors may be of importance in preserving episodic memory function. The overall results appear to indicate that episodic memory is a multifactorial and heritable quantitative trait where sex is an important determinant.

Transferrin C subtypes and occupational photodermatosis of the face.

In a factory in northern Sweden where 120 workers were uniformly exposed to photoactive substances 73 developed occupational facial eczema while 47 showed no reaction. The workers were examined with respect to 16 genetic marker systems: HLA, blood groups (ABO, Rh, MNSs, P, K, Le and Fy) and serum groups (Hp, Tf, Gc, Pi, Bf, C3, C4 and C6). Between reactors and nonreactors the following differences were found: (1) a significant decrease (p less than 0.05) of HLA A11 among the reactors; (2) a significant increase (p less than 0.05) of the C3 FS type among the reactors; (3) a highly significant increase (p less than 0.001) of the transferrin C2 gene and of the C2 variant among the reactors. The association with Tf C2 remained significant also after correction for number of significance tests. Since transferrin (iron) is known to catalyze the formation of hydroxyl radicals we hypothesize that the Tf C2 variant is more efficient in promoting radical formation and thereby cell damage. Other results supporting the notion that transferrin C2 may be associated with an increased susceptibility to toxic damage are discussed.

A new PstI restriction fragment length polymorphism (RFLP) of placental alkaline phosphatase. RFLP haplotypes and correlation with electrophoretic types.

A new PstI restriction fragment length polymorphism (RFLP) of placental alkaline phosphatase (PLAP) was discovered in a study of a Finnish population sample and designated PstI(b)1 or Pst(b)2 depending on the presence or absence of the cleavage site. The frequency of the PstI(b)2 allele was 0.24. This allele showed a positive (p = 3 x 10(-6) association with the electrophoretic allele 2(F) and a negative association (2 x 10(-7) with the electrophoretic allele 1(S). The previously described PstI RFLP [PstI(a)] was also found to be associated with electrophoretic types; the PstI(a)1 allele (presence of site) was associated with the electrophoretic type 2 (p = 0.023). Haplotype frequencies and disequilibria were calculated between PstI(a), PstI(b) and RsaI RFLPs. A complete disequilibrium (p = 1 x 10(-6) was found between PstI(a) and RsaI, whereas there was no significant disequilibrium between PstI(b) and RsaI. There was no strict correlation between the distances between the RFLP loci and the degree of linkage disequilibrium. The allele controlling the electrophoretic variant PLAP 18 (D) was found in polymorphic frequency (0.024) in the Finnish population.