Genetic predisposition to development of toxic liver cirrhosis caused by alcohol]

Comprehensive analysis of the contribution of genetic factors into predisposition to alcoholic toxic cirrhosis (TC) was performed. The ABO, RH, HP, TF, GC, PI, ACP1, PGM1, ESD, GLO1, and GST1 genetic polymorphisms were compared in 34- to 59-year-old male TC patients and control donors of the same sex and age. The phenotypic frequencies in the TC group deviated from the theoretically expected values; the main difference was the excess of rare homozygotes for the loci GC, ACP1, ESD, and GLO1. In the TC patients, the observed heterozygosity (Ho) was considerably lower than the theoretically expected value (H(e)). Wright's fixation index (F) in the TC patients was 30 times higher than in the control group (0.0888 and 0.0027, respectively). The frequencies of PI*Z and PI*S, the PI alleles that are responsible for lower concentrations of proteinase inhibitor, were 12 and 6 times higher in the TC than in the control group. The TC patients exhibited a significantly higher frequency of the liver glutathione-S-transferase GST1*0 allele, whereas the GST1*2 frequency was two times higher in the control subjects than in the TC patients (0.2522 and 0.0953, respectively). The TC and control groups showed statistically significant differences in the frequencies of the following alleles of six independent loci: ABO*0, TF*C1, TF*C2, PI*M1, PI*Z, ACP1*C, PGM1*1+, PGM1*1-, PGM1*2-, GST1*0, and GST1*2. The haptoglobin level was significantly higher and the serum transferrin level was drastically lower in all phenotypic groups of TC patients than in control subjects. The concentrations of IgM and IgG depended on the HP, GC, and PI phenotypes. The total and direct reacting bilirubin concentrations depended on the erythrocytic-enzyme phenotypes (ACP1, PGM1, and GLO1) in both TC and control groups.     

The Russian Gene Pool: Gene Geography of Erythrocytic Gene Markers (ACP1,PGM1,ESD,GLO1, and 6-PGD)

The study continues the series of works on the Russian gene pool. Gene geographic analysis of five erythrocytic gene markers best studied in the Russian population (ACP1, PGM1, ESD, GLO1, and6-PGD) has been performed. Gene-geographic electronic maps have been constructed for 13 alleles of these loci and their correlations with geographic latitude and longitude. For all maps, statistical characteristics are presented, including the variation range and mean gene frequencies, partial and multiple correlations with latitude and longitude, and parameters of heterozygosity and interpopulation diversity. The maps of eight alleles (ACP1*A, ACP1*C, PGM1*2+, PGM1*2–, PGM1*1–, ESD*1, GLO1*1, and PGD*C) are shown and analyzed in detail. The genetic relief and structural elements of the maps are compared with the ecumenical trends, main variation patterns of these genes in northern Eurasia, and genetic characteristics of the indigenous populations of the Urals and Europe.     

Genetic Polymorphism of Erythrocytic Enzymes in Yakut Populations

Polymorphism of the erythrocytic enzymes PGM1, ACP1, ESD, and GLO1 was found in Yakut populations. The allelic frequencies of the polymorphic systems studied varied within the following ranges: PGM1*1+, 0.5833–0.7791; PGM1*1–, 0.0345–0.1176; PGM1*2+, 0.1250–0.2813; ACP1*A, 0.1429–0.3382; ACP1*B, 0.6548–0.8571; ESD*2, 0.1250–0.4643; and GLO1*1, 0.0116–0.2845.     

The Russian Gene Pool: Gene Geography of Serum Gene Markers (HP,GC,PI,and TF)

The study continues the series of works on the Russian gene pool. Gene geographic analysis of four serum gene markers best studied in the Russian population (HP, GC, PI, and TF) has been performed. Gene-geographic electronic maps have been constructed for 14 alleles of these loci and their correlations with geographic latitude and longitude. For all maps, statistical characteristics are presented, including the variation range and mean gene frequencies, partial and multiple correlations with latitude and longitude, and parameters of heterozygosity and interpopulation diversity. The maps of five alleles (HP*1, GC*2, GC*1S, PI*M2, and TF*C2) are shown and analyzed in detail. The genetic relief and structural elements of the maps are compared with the ecumenical trends, main variation patterns of these genes in northern Eurasia, and genetic characteristics of the indigenous populations of the Urals and Europe.     

The Use of Discrete Characters in Discriminant Analysis for Diagnosis of Pulmonary Tuberculosis and for Classification of Patients Differing in Treatment Efficiency Based on Polymorphisms at Nine Codominant Loci: HP,GC, TF,PI, PGM1, GLO1, C3, ACP1, and ESD

Discriminant analysis was used to differentiate patients with pulmonary tuberculosis (N = 106) from healthy individuals (N = 328) and patients whose treatment was efficient (N = 71) from those whose treatment was inefficient (N = 35). The analysis involved the data on nine polymorphic codominant loci: HP, GC, TF, PI, PGM1, GLO1, C3, ACP1, and ESD. The loci were selected by significance of differences in genotype frequencies between tuberculosis patients and healthy controls (GC, TF, PI, C3, ACP1) or between the two groups of patients differing in treatment efficiency (HP, GC, PI, PGM1, C3, ESD). Discrimination was based on a graphic method of Bayes classification procedure with a single-variate nomograph allowing easy estimation of the a posteriori probabilities for an individual to be classified. The two groups of patients proved to be discriminated sufficiently well (probability of misclassification P _err = 0.24), whereas discrimination between tuberculosis patients and healthy individuals was less efficient (P _err = 0.33). The method was proposed as a means of predicting the efficiency of treatment in pulmonary tuberculosis. Along with clinical, roentgenological, and laboratory examination, discriminant analysis may be employed as an accessory test in diagnostics of pulmonary tuberculosis, especially when the diagnosis is questionable.     

Analysis of Heterozygosity at the PI, TF, PGM1, ACP1, HP, GC, GLO1, C3, and ESDLoci in Pulmonary Tuberculosis Patients Differing in Response to Treatment

Heterozygosity at nine genetic loci (PI, TF, PGM1, ACP1, HP, GC, GLO1, C3, and ESD) was analyzed in pulmonary tuberculosis patients with good (group 1, N= 71) and poor (group 2, N= 35) response to treatment. The observed heterozygosities were compared with the expected values, which were calculated from allele frequencies in a control sample of healthy individuals (N= 328 with all but one locus and 78 with ESD) according to Hardy–Weinberg expectations. The analysis showed that the observed heterozygosities g _l of patients significantly differed from the expected values h _lin the case of four loci (GC, PI, C3, and ACP1). The observed heterozygosity was higher than expected in three cases (PI, C3, and ACP1) and lower then expected (GC) in one case. When data on each individual locus were compared using Fisher's exact test, both groups of patients proved to significantly differ (P _F< 0.05) from the control group in the same four loci. No difference in observed heterozygosity was detected between the two groups of patients. The mean expected heterozygosity was h¯= 0.386 ± 0.00674; the mean observed heterozygosity was g¯ = 0.415 ± 0.02 in group 1, g¯ = 0.402 ± 0.026 in group 2, and g¯ = 0.371 ± 0.00955 in the control group. The ttest did not reveal a significant difference between the mean values of expected observed heterozygosities. Heterozygosity at individual loci, rather than mean heterozygosity, was proposed as an integral nonspecific indicator of the genetic control of a disease, because the former directly implicates individual marker loci in the development of a disorder, whereas effects of individual loci may eliminate each other when mean heterozygosity is computed. Based on the results obtained, a genetic control was assumed for the development of the tuberculosis process in the lungs.     

Genetic Polymorphism of the Blood Groups and Erythrocytic Enzymes in Three Ethnic Territorial Groups from the North of European Russia

Using the data on five red cell markers (AB0, PGM1, ACP1, GLO1, and ESD) polymorphisms, the population genetic structure of three ethnic territorial groups from the north of European Russia (Continental Nentsy, Kola Saami, and Russian Coast-dwellers) was described. In general, the groups studied a Caucasoid pattern of the frequency distribution of erythrocytic marker alleles. However, a substantial contribution of a Mongoloid component to the Nenets gene pool, expressed as a high frequency of the PGM1*1allele along with a low frequency of the GLO1*1allele, was observed. Three ethnic territorial groups examined were close to one another with respect to the distribution of classical biochemical markers. The interpopulation diversity was low (the mean F _ST= 0.015). The differences observed were for the most part caused by the genetic characteristics of Nentsy. The maximum interpopulation diversity was observed for the GLO1*locus (F _ST= 0.056).     

Red-cell enzyme polymorphisms in the Reggio Calabria province (Italy)

Acid phosphatase (ACP1), adenosine deaminase (ADA), esterase D (ESD), glyoxalase 1 (GLO1), phosphogluconate dehydrogenase (PGD) and phosphoglucomutase 1 and 2 (PGM1 and PGM2) polymorphisms have been studied in the Reggio Calabria province (Southern Italy). The ACP1*A allele and ADA, GLO1, PGD and PGM1 systems have frequencies similar to those reported for Sicily and Southern Italy.     

Familial benign hypercalcaemia (FBH; McK. No. 14598, 1983): Linkage studies in a large Dutch family

Summary By screening 27 hypercalcaemic and 21 normocalcaemic subjects in a large Dutch pedigree with familial benign hypercalcaemia (FBH; McK. No. 14598) (McKusick 1983) for more than 35 genetic markers, it was found that linkage of FBH can be excluded at about 25 centimorgans (cM) from GM, 20 cM from ABO, 15 cM from MNS and HLA, 10cM from JK and PI, and 5cM each from ACP1, AK1, ADA, GPT1, and PGP.     

The dagestan gene pool: Analysis of the frequencies of classical genetic markers in Avars

This study is part of long-term research in the gene pool of Dagestan ethnic groups. The phenotype (in percent), gene, and haplotype frequencies in three Avar populations are reported. A total of 37 alleles of 13 loci of immune and biochemical genetic marker systems (ABO, Rhesus, P, Lewis, HP, GC, C′3, TF, 6PGD, GLO1, ESD, ACP, and PGM1) have been studied. Rare haplotypes of the Rhesus system (CDE, Cde and cdE) have been found in the populations studied. In two out of three local populations (Khunzakh and Kharakhi), a typically “Caucasoid” rare gene ACP1 ^c of the AcP1 locus has proved to be relatively frequent (0.030 and 0.023, respectively). The frequencies of the allele variantsP ² , le, and Hp ¹ of loci of the P, Lewis, and HP systems, respectively, have been found to be lower than in other Caucasian ethnic groups and the total northern Eurasian population. The mean allele frequencies for the GC, C′3, TF, 6PGD, GLO1, and ESD systems in the populations studied are comparable wit those for both Caucasian ethnic groups and the total population of the European historical ethnographic province. Statistical analysis of the results has shown 11 cases of significant deviations of the observed phenotype frequencies from the Hardy-Weinberg equilibrium.     

Material for Studying the Gene Pools of Russia and Neighboring Countries: The Russian Population of the Pskov Oblast

The distributions of the genes and haplotypes for blood groups AB0, MN, Rhesus, P1, Lewis, and Kell–Cellano and biochemical markers of the genes of loci HP, GC, C"3, TF, 6PGD, GLO1, ESD, ACP1, and PGM1(including subtypes) were studied in 116 Russian subjects born in the Pskov oblast. Differences of this group from other Russian populations with respect to genetic structure were found.     

The Dagestan gene pool: Polymorphism of immunogenetic and biochemical markers in Kumyks

This study is a part of long-term investigations devoted to the analysis of the gene pool of Dagestan ethnic groups. The phenotype (in %), gene, and haplotype frequencies in Kumyk ethnic group are reported. A total of 39 alleles and six haplotypes of 14 loci (AB0, Rhesus, P, Levis, Kell, HP, GC, C’3, TF, 6PGD, GLO1, ESD, ACP, and PGM1) of immunobiochemical genetic marker systems were examined. Rare haplotypes of the Rhesus system were identified, including CDE in the Karabudakhkent population with the frequency of 0.030, and Cde and cdE in the Dorgeli population with the frequencies of 0.034 and 0.38, respectively. Similarly to the other ethnic populations of Dagestan examined, Kukyk populations carried rare, albeit typically “Caucasoid” gene ACP1 ^c of the AcP1 locus. The frequency of this allele in the two populations was similar, constituting 0.031 for Karabudakhkent and 0.032 for Dorgeli. In Kumyks, allele frequencies of the AB0, Rhesus, P, Lewis, Kell, HP, GC, C′3, TF, 6PGD, GLO1, ESD, ACP, but not PGM1, systems were similar to the mean allele frequencies at these loci observed in the other ethnic groups from the Dagestan, Caucasus, and the whole European historical ethnographic province. At the same time, the allele frequency values obtained were different from those for the populations of Kazakhstan, Central Asia, Siberia, and the Ruswsian Far East. Thus, the results obtained for classical genetic markers indicate that Kumyks are genetically closer to the indigenous populations of Dagestan than to Turkic-speaking populations. Analysis of the fit of the observed phenotype frequencies to the Hardy-Weinberg expectations showed that compared to other indigenous populations of Dagestan examined, in Kumyks the genetic state of the population upon random allele association was close to equilibrium. Probably, this state was determined by practical absence of the consanguineous marriages upon preservation of intra-aul endogamy.     

Genetic polymorphism of erythrocytic enzymes in Yakut populations

Polymorphism of the erythrocytic enzymes PGM1, ACP1, ESD, and GLO1 was found in Yakut populations. The allelic frequencies of the polymorphic systems studied varied within the following ranges: PGM1*1+, 0.5833-0.7791; PGM1*1-, 0.0345-0.1176; PGM1*2+, 0.1250-0.2813; ACP1*A, 0.1429-0.3382; ACP1*B, 0.6548-0.8571; ESD*2, 0.1250-0.4643; and GLO1*1, 0.0116-0.2845.     

Liver glutathione S-transferase polymorphism in Japanese and its pharmacogenetic importance

Summary A total of 168 autopsy liver extracts from Japanese individuals were examined for the glutathione S-transferase (GST) isozymes by means of starch gel electrophoresis. The gene frequencies of GST1^*1, GST1^*2, and GST1^*0 in Japanese were 0.252, 0.057, and 0.691, respectively. GST1^*3 was detected as a rare variant allele. The incidence of GST1 0 in 41 liver biopsy samples from patients suffering from various liver diseases was investigated using polyacrylamide gel isoelectric focusing. The GST1 0 phenotype was found more frequently in livers with hepatitis and carcinoma than in control livers. The isozymes coded by different GST loci were partially purified and characterized to study their biochemical properties. The apparent Km values with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate for the isozymes at the GST1, GST2, GST3, and GST4 loci were 604, 1345, 776 and 591 M, respectively.     

Alpha-1-antitrypsin: Evidence for a fifth PI M subtype and a new deficiency allele PI*ZAugsburg

Summary The phenotypes of the protease inhibitor (PI) alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels. With improved resolution by a modified procedure it was possible to demonstrate a fifth PI^*M suballele. The bands of PI M5 are located between PI M1 and PI M3. In addition, a further deficiency allele similar to PI^*Z was found in a female patient with obstructive pulmonary disease. This variant was provisionally named PI Zaugsburg (PI Zaug). Family data confirm a simple codominant mode of inheritance for PI Zaug.Dr. W. Jahn has met with a fatal accident on June 20th, 1985 while this paper was in press. This paper is dedicated to his memory     

Analysis of heterozygosity levels at P1,TF, PGM1, ACP1, HP, GC, GLO, C3, and ESD loci in pulmonary tuberculosis patients with different treatment outcomes]

Heterozygosity at nine genetic loci (PI, TF, PGM1, ACP1, HP, GC, GLO1, C3, and ESD) was analyzed in pulmonary tuberculosis patients with good (group 1, N = 71) and poor (group 2, N = 35) response to treatment. The observed heterozygosities were compared with the expected values, which were calculated from allele frequencies in a control sample of healthy individuals (N = 328 with all but one locus and 78 with ESD) according to Hardy-Weinberg expectations. The analysis showed that the observed heterozygosities gl of patients significantly differed from the expected values hl in the case of four loci (GC, PI, C3, and ACP1). The observed heterozygosity was higher than expected in three cases (PI, C3, and ACP1) and lower then expected (GC) in one case. When data on each individual locus were compared using Fisher's exact test, both groups of patients proved to significantly differ (PF < 0.05) from the control group in the same four loci. No difference in observed heterozygosity was detected between the two groups of patients. The mean expected heterozygosity was h = 0.386 +/- 0.00674; the mean observed heterozygosity was g = 0.415 +/- 0.02 in group 1, g = 0.402 +/- 0.026 in group 2, and g = 0.371 +/- 0.00955 in the control group. The t test did not reveal a significant difference between the mean values of expected observed heterozygosities. Heterozygosity at individual loci, rather than mean heterozygosity, was proposed as an integral nonspecific indicator of the genetic control of a disease, because the former directly implicates individual marker loci in the development of a disorder, whereas effects of individual loci may eliminate each other when mean heterozygosity is computed. Based on the results obtained, a genetic control was assumed for the development of the tuberculosis process in the lungs.     

Glyoxalase 1 (GLO) in the chicken: Genetic variation and lack of linkage to the MHC

Electrophoretic variation of glyoxalase 1 (GLO) has been detected in chicken red-cell lysates. Three phenotypes are shown to be inherited through a diallelic system, just as in humans and mice. The chicken GLO phenotypes differ from their mammalian counterparts in that one of the homozygotes is devoid of GLO activity. The heterozygote produces two bands, while the other homozygote yields a single band of GLO activity with mobility equal to the faster of these two bands. In noninbred White Leghorn birds, the GLO ^*2 allele occurred significantly more often in birds homozygous for the B ^*1 allele at the chicken MHC than in those homozygous for B ^*19, suggesting that the products of these loci may have population associations in the chicken. Absence of close linkage between the GLO and B loci was, however, demonstrated by appropriate test crosses.     

Gene pool of Daghestan ethnic groups: Polymorphism of classical gene markers in the Darghin ethnic group

The work is part of a study of the gene pool for Daghestan ethnic groups. In total, 38 alleles and eight genotypes were studied at 14 loci (AB0, Rhesus, P, Lewis, Kell, PH, GC, C′3, TF, 6-PGD, GLO1, ESD, ACP, and PBM1) of immunogenetic and biochemical polymorphic gene systems. A high frequency of allele d of the Rhesus system was observed in all populations examined (0.399–0.474). Among the rare haplotypes of the Rhesus system, we observed CDE in the Degva population, Cde in the Sergokala and Degva populations, and cdE in the Sergokala and Vanashimakhi populations. The typical Caucasian ACP1 ^c allele of the ACP1 locus, which is rather uncommon, was observed at a relatively high frequency in three (Segokala, Vanashimakhi, and Gubden) of the four local populations under study. In the Lewis system, a high frequency of the Le(a+b+) phenotype, which is characteristic of early childhood, was detected in the adult populations of Sergokala and Degva. The rare PGM ₁ ^V allele of the phosphoglucomutase 1 system (PGM1) was additionally observed in the Sergokala population. Statistical analysis identified 19 cases where the observed phenotype frequencies significantly differed from the frequencies expected from the Hardy-Weinberg equilibrium.     

The Russian Gene Pool: Frequencies of Genetic Markers

Frequency distribution of several genetic markers was studied in ethnic Russians from the Moscow, Bryansk, Ryazan', Kostroma, Novgorod, Arkhangel'sk, and Sverdlovsk oblasts and Udmurtiya. Systems AB0, RH, HP, TF, GC, PI, C"3, ACP1, PGM1, ESD, GLO1, 6PGD, and AK were analyzed in most samples. New data on informative polymorphic genetic loci showed that the Russian gene pool mostly displays Caucasoid features. Some data on polymorphism of nuclear genome loci are presented. In addition, Y-chromosomal short tandem repeats (STRs) DYS19, DYS390, and DYCAIIwere analyzed in the Russian samples. STRs of the chromosome are particularly valuable for elucidating ethnogenetic processes in Eastern Europe. Frequency distributions of the Y-chromosomal markers in Russians were intermediate between those of West European populations and eastern Finno-Ugric ethnoses of the Volga region. A marked longitudinal gradient was revealed for frequencies of several molecular markers.     

An association between α1-antitrypsin phenotype and chronic liver disease

Summary The phenotypes of alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels in 232 healthy Japanese blood donors and in 240 Japanese patients with chronic liver diseases: 69 with chronic active hepatitis, 122 with liver cirrhosis, 41 with hepatocellular carcinoma and 8 with primary biliary cirrhosis. The liver cirrhosis patients had a gene frequency of 0.07 forPI ^* M3, which was significantly higher (P<0.01) than that (0.03) in blood donors. The gene frequency of PI ^* M3 was significantly increased in cryptogenic liver cirrhosis (P<0.05), and there was a tendency toward an increased frequency of PI ^* M3 in post-transfusion groups, and in primary biliary cirrhosis. There were also tendenciestoward increased frequencies of PI ^* M3 in cryptogenic and post-transfusion groups of patients with chronic active hepatitis. The present study indicates that PI ^* M3 is a genetic or predisposing factor for chronic liver diseases, especially for cryptogenic and/or non A-non B viral chronic liver disease and also for primary biliary cirrhosis.