Biomedical subjects
Publications and source records attributed to L Beckman.
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.
A mutant variant of the serum protein transthyretin (TTR-met30) appears to be a necessary but not sufficient condition for the development of familial amyloidotic polyneuropathy (FAP). We have studied a number of serum protein markers (alpha 1-antitrypsin, properdin factor B, C3, C4A, C4B, haptoglobin, transferrin and group-specific component) in FAP patients and healthy controls in an attempt to identify additional pathogenic factors which may influence the risk for developing FAP in male and female patients as well as the age of onset of the disease. Statistically significant associations were found in the complement systems C3 and C4A. The C3F variant was significantly increased in all FAP patients with a relative risk (RR) of 2.0, more pronounced in female patients (RR = 2.6) and patients with an early onset of the disease (RR = 4.5). In the FAP patients only the variants A3 and A4 were found in the C4A system. C4A3 was found in all patients, which was significantly higher than in the controls. The remaining serum protein systems showed no statistically significant associations with FAP. The results suggest that genetic variants of complement factors C3 and C4A may interact with the mutant TTR-met30 by modifying the expression and onset of FAP.
Examples were discussed where heterozygosity was associated with increased or decreased disease risks and where the apparent mechanism is direct functional involvement of gene products and not linkage disequilibrium. Special attention was paid to the impact of Hp (haptoglobin) heterozygosity on a number of different multifactorial disorders. When phenotype distributions in patients show large deviations from the Hardy-Weinberg equilibrium significant differences between patients and controls may be found concerning phenotype distributions but not with respect to the frequencies of alleles and phenotypic factors. The common method of studying ratios of phenotypic factors by pooling homo- and heterozygotes is in principle a conservative approach which tends to underestimate the strength of associations and to obscure heterozygosity effects. A significant deviation from the Hardy-Weinberg equilibrium in a marker system examined in a group of patients is in itself a sensitive indicator of phenotypic association with the disease in question.
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Medical genetics as a discipline has contributed basic knowledge of great applicability in environmental medicine, e.g. 1) the demonstration that environmental agents may cause chromosomal damage, 2) that chromosome aberrations are correlated with increased risks for cancer and spontaneous abortion, and 3) that the susceptibility to cyto- and genotoxic damage may be influenced by genetic factors. This paper discusses examples of applications of genetic knowledge in environmental medicine and areas for future research.
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.
The frequencies of group-specific component (GC) subtypes were studied in a population of 4,053 conscripts and blood donors from the counties of Västerbotten and Norrbotten in northern Sweden. The individuals were distributed according to place of birth into 23 subpopulations. A significant heterogeneity between the 23 regions was observed for the GC*1F, GC*1S and GC*2 genes, and clines were found for all genes. The frequency of the GC*1F gene was increasing in the northern direction, and the frequencies of the GS*1S and GC*2 genes were increasing in the southern direction. The geographical pattern of the GC*1F gene frequency could be explained in terms of Lappish influence.
The group-specific component (Gc) subtypes were determined by isoelectric focusing and immunoblotting. The gene frequencies in the Swedish Lapps were Gc1F = 0.412, Gc1S = 0.367 and Gc2 = 0.221, which was significantly different from the frequencies found in Finns and in the populations of northern and central Sweden (p less than 0.001). The gene frequencies in the Swedish Lapps, although similar to those in Asiatic populations, are probably not reflecting an Asiatic influence, since the accumulated genetic information on the Swedish Lapps suggests that founder effect and genetic drift are to a large extent responsible for the peculiar gene pool of the original Lapp population.
Serum protein markers (alpha 1-AT, Bf, C3, C4A, C4B, Hp and Tf) were studied in a series of 36 patients with systemic lupus erythematosus (SLE) and compared to normal blood donors. In agreement with the results of previous investigations a significant increase of complement C4 deficiency was found among the SLE patients. The relative risks for AQ0 and BQ0 homozygosity were 7.2 and 4.1, respectively. Simultaneous occurrence of AQ0 and BQ0 was found in three patients with a calculated relative risk of about 65. A significant increase of the haptoglobin type 2-2 (p less than 0.05) was found among SLE patients. The remaining serum protein systems showed no statistically significant associations with SLE.
Radiation-induced chromosomal damage (after exposure to 1 Gy) in lymphocytes was studied in relation to transferrin C subtype (C1 vs. C2). In 72-hour lymphocyte cultures a significantly increased frequency of cells with radiation induced aberrations was observed in individuals with the transferrin type C2. Thus the results lend some support to the hypothesis that transferrin C2 may act as an enhancer of chromosomal damage.
Frequencies of the 6-phosphogluconate dehydrogenase (6-PGD) genes were studied in a series of 314 Finns from northern Finland and in a material of 4,348 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The Swedish individuals were distributed into 23 subpopulations according to place of birth. The frequency of the PGDC gene was comparatively high in Finns (5.3%) and showed significant variations between subpopulations (from 5.3 to 0.0%). The frequency of the PGDC gene showed a cline, with a decreasing gene frequency in the north-south direction. This geographical pattern could be explained in terms of Lappish and Finnish influence.
The possible explanations for heterosis and heterozygous advantage have included the hypothesis that the metabolic versatility of heterozygotes for functional alleles of structural genes would enhance resistance to environmental insult, i.e. would result in enhanced developmental homeostasis. Evidence on this hypothesis is conflicting. The paper presents additional evidence, based on four human polymorphisms and 9 quantitative traits in a sample of mother-offspring data from Sweden. These data do not support the hypothesis of interest. Reasons for the conflicting results are discussed.
Frequencies of the A1A2B0 blood group genes were studied in a material of 5,632 conscripts and blood donors from the counties of Norrbotten and Västerbotten in northern Sweden. The individuals were distributed according to place of birth into 23 subpopulations. In northern Sweden different clines were found for the A1, A2 and 0 genes. The frequencies of the A1 and A2 genes were increasing in the northeastern respectively northern direction, and the frequency of the 0 gene was increasing in the southwestern direction. These geographical patterns could be explained in terms of Finnish and Lappish influence.
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.
It has been hypothesized that the mechanisms behind the association between blood group A and gastric carcinoma is that the carcinoma cells produce an antigen immunologically related to blood group A, which particularly in O-individuals may have a protective effect by preventing the growth and spread of the tumour. The hypothesis predicts that O-individuals would have a longer survival time than A-individuals and that eventually the protective effect in blood group O would be somewhat stronger in women with multiple pregnancies. The results showed a significantly lower frequency of blood group O in females and a tendency towards a longer survival time in O-individuals among gastric cancer patients, but the relationship between blood group O and number of children was not in the expected direction. Thus the observations gave only partial support for the hypothesis that the association between ABO blood groups and gastric carcinoma is dependent on the antigenicity of the neoplasm. The data showed a significantly higher prevalence of gastric carcinoma and a lower average survival time in male patients.
Both regression and correlation estimates of genetical variance and heritability for a quantitative trait influenced by a major gene can be obtained from the error variance-covariance matrix of MANOVA using relative-relative phenotype pairs as factors. The method is illustrated with parent-offspring data on red cell acid phosphatase phenotypes and serum acid phosphatase activity.
HLA antigens, blood group systems (ABO, Rh, MNSs, P, Kell, Lewis and Duffy) and serum group systems (Hp, Tf, Gc, Pi, Bf, C3 and C4) were studied in a series of patients with intracranial aneurysms. A significantly increased frequency of HLA antigen A28, a significantly decreased frequency of HLA antigen B40, and a significantly decreased frequency of complement factor C4 B2 was found among the patients when compared with controls from the same geographic area.
In previous investigations transferrin C2 has been found to be associated with spontaneous abortion and premature birth. In a study of newborn infants from northern Sweden, no significant correlation was found between birth weight and transferrin C2 of the infants. Thus transferrin C2 appears to be associated with reproductive disturbances and with premature birth, but not with birth weight in mature infants.