Search for associations between <Emphasis Type="Italic">G/A</Emphasis> polymorphism of the <Emphasis Type="Italic">EPAS1</Emphasis> gene and the maximal oxygen consumption in Russian athletes

This study investigates associations between G/A polymorphism of the epithelial PAS domain protein 1 (EPAS1) gene (rs1867785) and the maximum rate of oxygen consumption (VO_2max) in male Russian athletes. The study engaged 241 male athletes from different sports; the control group of nonathletes included 92 subjects. Increased frequencies of the AA and AG genotypes of the EPAS1 gene (χ² = 14.16, p = 0.03) were found in the cohort of male athletes. The frequencies of these alleles in the subgroups with moderate (EPAS1*A 38.1% and EPAS1*G 61.9%) and high (EPAS1*A 41.8% and EPAS1*G 58.2%) VO_2max values significantly differed from those in the control group (χ² = 7.53, p = 0.006 and χ² = 6.58, p = 0.01, respectively). The higher aerobic capacities are probably associated with the presence of at least one minor A allele of the EPAS1 gene in the genome.     

The study of a French family with two duplicated C4A haplotypes

Summary The finding of two duplicated C4A haplotypes in a normal French family led to a detailed study of their C4 polymorphism. The father had an extremely rare A^*6A^*11, B^* QO haplotype inherited by all of his children and the mother had the more common A^*3A^*2, B^*QO haplotype. Two HLA identical daughters only have four C4A alleles. The father's A11 allotype expresses Ch: 1 (Chido) rather than Rg:1 (Rodgers) and represents a new Ch phenotype Ch: 1,-2,-3,-4,-5,-6. In order to clarify the genetic background in this unusual family, DNA studies of restriction fragment length polymorphisms (RFLPs) were undertake. The father's rare haplotype, which expresses two C4A allotypes, results from a long and a short C4 gene normally associated with the A^*6, B^*1 that also exhibits the BglII RFLP. As it travels in an extended MHC haplotype HLA A2, B57 (17), C2^*C, BF^*S, DR7 that is most frequently associated with A^*6, B^*1, we postulate that the short C4B has been converted in the chain region to a C4A gene which produces a C4A protein. This report of a short C4A gene is the first example in the complex polymorphism of C4.     

Orosomucoid (ORM 1) subtyping and formal genetics

Summary Orosomucoid (ORM) phenotyping has been performed in 141 families with 407 children from southwest Germany. Eight families were observed in which duplicated ORM1 genes, F1F2, F1F3, segregated. The family data gave no information about the presence of tandemly duplicated ORM1 F1F4 and ORM1 F1F5 genes. To date, the segregation of the phenotypes of the children agrees with the extended formal model: two ORM1 loci with two common (^*F1, ^*S) and several rare (^*F1F2, ^*F1F3, ^*F4, ^*F5) alleles. The parental allele frequencies were calculated by gene counting as ORM1 ^*F1 = 0.5781, ^*S = 0.3901, ^*F1F2 = 0.0195, ^*F4 = 0.0053, ^*F1F3 = 00.0035, ^*F5 = 0.0035.     

Population and formal genetics of the human C81(α-γ) polymorphism

Summary One hundred and ninety-six unrelated healthy individuals and 30 families with 75 offspring have been studied for the C81(-) polymorphism. The following allele frequencies were calculated: C81^*A=0.5536; C81^*B=0.4286; C81^*A1=0.0178. Observed and expected phenotype frequencies were in a good agreement according to the Hardy Weinberg law. No exceptions from the mode of inheritance were found. In family W the segregation of the rare allele C81^*A1 could be followed. Comparing the results of this study with previous data from Boston and Oslo, a combined technology including C8-dependent lysis and C8 structural variation is suggested for future investigations.     

Characterization of mutants of the vitamin D-binding protein/group-specific component: molecular evolution of GC*1A2 and GC*1A3, common in some Asian populations

A well defined polymorphism of vitamin D-binding/ group-specific component (GC) resides in exon 11. To characterize the molecular basis of GC^*1A2 and GC^*1A3, common in some Asian populations, we analyzed all coding exons amplified by the polymerase chain reaction. GC^*1F was divided into GC^*1F^c and GC^*1F^T by a C-T transition in the third nucleotide of the codon (TGC/T) for cysteine²⁸³ in exon 8. The sequencing of exons 8 and 11 showed that GC^*1A2 and GC^*1A3 had occurred on a GC^*1F^c genetic background. They also shared a substitution of cysteine (TGC) for arginine (CGC) at position 429 in exon 11. GC^*1A2 was characterized by having glycine (GGC) instead of serine (AGC) at position 335 in exon 9. GC^*1A2 evolved from GC^*1F^T by three mutational events, i.e. GC^*1F^TGC^*1F^cGC^*1A3 GC^*1A2. No evidence was obtained for the existence of the duplicated gene GC^*1F · 1A2 suggested by isoelectric focusing (IEF) of serum samples. The idea that the characteristic banding pattern of GC^*1F · 1A2 after IEF results from partial formation of a disulfide bond in the additional cysteine at position 429 is discussed.Deceased     

Four variants of human plasma α2-glycoprotein (ZAG) in the Japanese population

Summary Zn-₂-glycoprotein (ZAG) of plasma from the general Japanese adult population (n=1224) was studied by polyacrylamide gel isoelectric focusing (IEF) followed by immunoblotting with specific antiserum to ZAG. Most of the plasmas showed a common band pattern, while 16 samples showed four other patterns. These ZAG band patterns were easily differentiated by desialyzing the samples prior to IEF. The asialo form of ZAG commonly showed a single band. The 16 plasma samples presenting double bands were classified into four types containing the common single band. The differences in ZAG phenotypes may be suggested to be due to amino acid substitutions of the ZAG molecule. The statistical frequencies of five alleles, which we proposed to designate ZAG^*1, ZAG^*2, ZAG^*3, ZAG^*4, and ZAG^*5, were 0.9935, 0.0025, 0.0016, 0.0004, and 0.0020, respectively. The genetic transmission of the rare alleles ZAG^*3 and ZAG^*4 was confirmed by two family studies.     

Molecular basis for subtypic differences of the “a” subunit of coagulation factor XIII with description of the genesis of the subtypes

The “a” subunit of human coagulation factor XIII (F13A) exhibits genetic polymorphism defined by four common alleles, F13A*1A, *1B, *2A, and *2B. We have previously suggested on the basis of the isoelectric focusing patterns of the four allele products that point mutations at two separate sites and one intragenic crossing over might be involved in the genes of F13A polymorphism. Here, we report nucleotide substitutions associated with F13A polymorphism. A C/T transition of the second nucelotide of codon 564 in exon 12 is responsible for the difference between F13A*1A and *1B and that between F13A*2A and *2B, and a set of two base changes in codons 650 and 651 in exon 14 leads to the differences between F13A*1A and *2A and those between F13A*1B and *2B. The four combinations of the point mutations at the two exons thus correspond to the four alleles, two of which were generated by the point mutations from ancestral monomorphic gene. The results suggest strongly that intragenic crossing over must be involved in the genesis of the fourth allele. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods discriminating these base changes in exons 12 and 14 are also presented.     

Genetics of human C4 polymorphism: Detection and segregation of rare and duplicated haplotypes

Applying a combined technology for the detection of allotypec variation of the fourth component of human complement (C4), including immunofixation with anti-C4 and C4-dependent lysis after agarose electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of C4 to separate the C4A and B -chains, and the determination of Rodgers (Rg) and Chido (Ch) determinants of C4 in serum and at the blotted C4 -chains, we detected rare human C4 allotypes and studied the genetic linkage. Partial inhibitors (p. i.) of anti-Rg and anti-Ch sera were found; the C4A51 allotype characterized as Rg p. i. and the C4A1 and C4B51 allotypes as Ch p. i. were genetically inherited. The C4A1 allotype has a unique Rg^- Ch⁺ C4A -chain. Duplicated C4A loci, A ^*3, A ^*2, and A ^*5, A ^*2 were both associated with a C4BQO and the HLA haplotype A3-Cw4-Bw35-DR1. These additions to the already known extensive C4 polymorphism may help to sort out their significance for the biological functions of human C4.Abbreviations used in this paper BF Factor B polymorphism of the alternative pathway of complement activation - C2 second component of complement - C4 fourth component of complement - C4D C4-deficient (C4^*QO/QO) - Ch Chido determinant on C4B^* products - EDTA ethylendiaminetetraacetic acid - GLO I glyoxalase I - HLA human leucocyte antigens, A, B, C and DR (D =related) loci - PAGE polyacrylamide gel electrophoresis - PGM3 phosphoglucomutase, third locus - p. i. partial inhibitor = serological inhibition of some, but not all anti-Ch and anti-Rg sera at selected dilutions - SDS sodium dodecyl sulphate; 94k/96k, 94 000 and 96 000 dalton molecular weight Presented in part at the 1V International Workshop on the Genetics of Complement, July 13–15, 1982, Boston, MA, and the Xth International Complement Workshop, May 25–27,1983 in Mainz, Federal Republic of Germany.     

The ITI system in South Koreans and iranians analysed by an improved classification procedure

Summary Phenotype and gene frequency distributions of the inter--trypsin inhibitor (ITI) system were analysed in populations from southern Korea and from Iran. The gene frequencies of the common alleles ITI^*I and ITI^*2 were 0.532 and 0.422, respectively, in southern Korea, and 0.612 and 0.354, respectively, in Iran. The postulated third allele, ITI^*3, was found in the homozygous form. Gene frequencies of this rare allele were calculated to be 0.042 and 0.029 in Korea and Iran, respectively. Two additional rare alleles, ITI^*4 and ITI^*5, determine further phenotypes found in the population from Taejon (Korea) and Iran, respectively, in combination with the common ITI^*2 allele. Gene frequencies of ITI^*4 and ITI^*5 were calculated to be 0.006 and 0.005, respectively. For phenotype classification, untreated sera were separated by isoelectric focusing (IEF) on polyacrylamide gels followed by immunoblotting.     

Association of polymorphic markers of chemokine genes,their receptors,and <Emphasis Type="Italic">CD14</Emphasis> gene with coronary atherosclerosis

Atherosclerosis represents an inflammatory response to the disturbance of the endothelial layer in the arterial bloodstream. In the present study, an analysis of associations of polymorphic markers for the genes controlling synthesis of proteins involved in atherosclerosis pathogenesis in coronary atherosclerosis (CA) patients (217 subjects) and in a control group (250 subjects) was conducted. The following genes were examined: rs991804 (CCL2 gene), rs1126579 (CXCR2 gene), rs4074 (CXCL1 gene), rs4073 (CXCL8 gene), rs333 (CCR5 gene), rs2471859 (CXCR4 gene), rs1801157 (CXCL12 gene), and rs2569190 (CD14 gene). Using the Monte Carlo and Markov chain (APSampler) method, allele/genotype combinations associated with both low and high CA risk were revealed. The most important findings included the following: CXCR4*T/T + CCL2*C + CCR5*I/I (P_perm = 1 × 10^–6, OR = 0.44, 95% CI 0.3–0.63), CXCR2*C + CD14*C + CXCL12*G + CCL2*C + CCR5*D (P_perm = 4 × 10^–6, OR = 5.78, 95% CI 2.34–14.28), CD14*C + CCL2*C/C + CCR5*D (P_perm = 6.3 × 10^–6, OR = 5.81, 95% CI 2.17–15.56), CXCL8*A + CXCR2*C + CD14*T + CXCR4*C (P_perm = 0.01, OR = 3.21, 95% CI 1.63–6.31).     

Association analysis of alcohol metabolizing enzymes <Emphasis Type="Italic">ADH1B,ADH7, CYP2E1</Emphasis> gene polymorphism with risk for coronary atherosclerosis

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5′-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B ^* G (+MslI) allele, CYP2E1 ^* C2 (+PstI) allele and CYP2E1 ^* C (-DraI) allele were 8.48 ± 1.86, 1.20 ± 0.69, and 10.00 ± 1.90%, respectively. The ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7 ^* C (-StyI) allele was 44.58 ± 3.21%. A significantly higher frequency of CYP2E1 PstI C2 allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03–20.01). The tendency to significant effect of A1A2 genotype in ADH1B MslI polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0.042) were also revealed. Association of A1A2 genotype in ADH1B MslI polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.     

Genetic polymorphism of inter-alpha-trypsin-inhibitor (ITI): Formal genetic and linkage analyses

Summary The polymorphism of inter-alpha-trypsin-inhibitor, ITI, was demonstrated by isoelectric focusing in agarose gels (pH 5–8) followed by protein blotting and immunoassay. Segregation in 239 families with 677 children is consistent with the formal hypothesis that there are two common codominant alleles, ITI^*1, ITI^*2, and one rare codominant allele, ITI^*3, at an autosomal locus ITI. Allele frequencies were calculated as ITI^*1=0.600, ITI^*2=0.393, ITI^*3=0.007. Linkage analysis with 36 markers is presented. Slightly positive lod scores were obtained for PGM3 (z=1,35, =0.10) and AK1 (z=1.34, =0.10).     

β-Globin gene linked DNA haplotypes and frameworks in three South-East Asian populations

Summary DNA haplotypes and frameworks (numbers in parenthesis) linked to the -globin gene were determined by restriction fragment analysis using eight restriction endonucleases on 86 (97) chromosomes bearing the normal -globin gene (HBB^*A) and 108 (118) chromosomes bearing HBB^*E in subjects homozygous for HBB^*A or HBB^*E from three South-East Asian populations with high HBB^*E frequencies (northern Thailand, north-eastern Thailand and Cambodia). A systematic nomenclature for -globin gene-linked haplotype characterized by six polymorphic sites is introduced. In all populations, HBB^*A occurred preferentially (>80%) in linkage with the haplotype 41 (+----+) and all three frameworks described by Antonarakis et al. (1982). In contrast, almost 80% of the HBB^*E genes occurred with the haplotype 27 (-+-+++). In northern and north-eastern Thailand, HBB^*E was present almost exclusively in framework 2; HBB^*E in framework 3 (Asian) was limited to the Khmer population of Cambodia, and the frequency of HBB^* E-linked framework 3 increased from the west to the east in this country.     

A “new” genetic polymorphism of a human serum protein: inter-alpha-trypsin-inhibitor

Summary A new genetic polymorphism of a human serum glycoprotein, the inter--trypsin-inhibitor (ITI), has been demonstrated by population and family studies. Sera were examined after neuraminidase treatment by isoelectric focusing on agarose gels followed by immunoblotting or by immunfixation with specific ITI-antiserum. Using this method, three common ITI phenotypes 1, 1–2 and 2, as well as two further rare ITI types 1–3 and 2–3 were disclosed. Genetically, these phenotypes are controlled by three allelic genes that determine a total of six phenotypes. These alleles are designated ITI^*1, ITI^*2 and ITI^*3. The homozygous form of the third allele ITI^*3 has not been found, as yet. The frequencies of ITI were examined in two population samples from Southern Germany (n=248) and from Tyrol, Austria (n=124). The gene frequencies of the common alleles ITI^*1 and ITI^*2 were 0.575 and 0.417, respectively, in Southern Germany, and 0.577 and 0.423, respectively, in Tyrol, Austria. The third allele ITI^*3 was found only in the sample from Southern Germany, thus far, and was calculated to be 0.008.     

Genetic polymorphism of complement component C8

Summary Extensive genetic polymorphism of complement component C8 was demonstrated by isoelectric focusing of serum or plasma samples followed by immunoblotting procedures. Using these methods, we could detect both - (C81) and (C82) chain polymorphisms in the same gel. Two-dimensional (2D) electrophoresis of C8 immunoprecipitates was used to obtain further information of the C8 patterns. Evidence was obtained that the C81 polymorphism resides in the structural gene of the C8 chain. Both C8 systems show autosomal, chiefly codominant inheritance, and the distribution of phenotypes agrees with the Hardy-Weinberg equilibrium. Our findings suggest at least five different alleles in the C81 system; the gene frequencies of the two most common ones, C81 ^*A and C81 ^*B being 0.59 and 0.39, respectively. In C82 we found evidence for at least three codominant alleles, the gene frequencies for the two most common ones, C82 ^*B and C82 ^*A being 0.94 and 0.05, respectively. In addition, family studies disclosed the existence of a null allele, C82 ^* Q0.     

Genetically polymorphic α-l-fucosidase (FUCA1) isozymes detected in blood plasma

The main isozyme patterns of desialylated blood plasma or serum -l-fucosidase (FUCA) were found to be almost identical to those of semen, urine, placental extracts, and leukocyte lysates, when detected by polyacrylamide gel isoelectric focusing, and activity staining using the fluorogenic substrate 4-methylumbelliferyl--l-fucopyranoside. Three phenotypes (1, 2-1, and 2) determined from plasma samples were identical to the phenotypes from urine and leukocyte lysates from the same individuals. A population study of plasma samples collected from 485 Japanese individuals indicated that the frequencies of the FUCA11 ^* and FUCA12 ^* alleles were 0.7505 and 0.2495, respectively. The mean plasma enzyme activities (+SD) of the three phenotypes were 318.8 ± 116.7 nmol/ml per h for type 1, 268.0 ± 108.3 nmol/ml per h for type 2-1, and 233.2 ± 84.4 nmol/ml per h for type 2. The mean activities of types 1 and 2 suggest that, on average, the FUCA11 ^* gene product in plasma has about 1.4 times the activity of FUCA12 ^*.     

Properties of a general model of DNA evolution under no-strand-bias conditions

Under the hypothesis of no-strand-bias conditions, the Watson and Crick base-pairing rule decreases the complexity of models of DNA evolution by reducing to six the maximum number of substitution rates. It was shown that intrastrand equimolarity between A and T (A ^* T ^*) and between G and C (G ^* C ^*) is a general asymptotic property of this class of models. This statistical prediction was observed on 60 long genomic fragments (>50 kbp) from various kingdoms, even when the effect of the two opposite orientations for coding sequences is removed. The practical consequence of the model for estimating the expected number of substitutions per site between two homologous DNA sequences is discussed.Abbreviations BPR Watson and Crick base pairing rule (A:T, G:C) - PRI Intrastrand type-1 parity rule (i j, m(i,j)m( )) - PRII Intra strand type-2 parity rule (A ^* T ^*, G ^* C ^*)     

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.     

Combinations of cytokine gene network polymorphic markers as potential predictors of myocardial infarction

With the intent to identify informative predictors of myocardial infarction (MI) development in an ethnically homogenous group of Russian men after MI (255 subjects) and in a corresponding control group (257 subjects), an analysis of genotype frequency distribution for polymorphic DNA markers (SNP) rs16944 (?511C>T, IL1B gene), rs1800796 (?572G>C, IL6 gene), rs1800872 (?592C>A, IL10 gene), rs3212227 (1159A>C, IL12B gene), rs1800629 (?308G>A, TNF), rs909253 (252A>G, LTA), rs767455 (36A>G, TNFRSF1A) was conducted. Using the Monte Carlo method and a Markov chain (APSampler), allele combinations associated both with decreased and increased MI risk were revealed. The most significant results were obtained for IL6*C/C (P = 3 × 10^?4, OR = 6.3 CI 2.37–16.75), LTA*A + IL6*G/G (FDR = 2.3 × 10^?4, OR = 0.25 CI 0.14–0.46), LTA*G/G + IL12B*A/A (FDR = 0.0053, OR = 4.92 CI 1.8–13.33), TNF*G + LTA*G/G + TNFRSF1A*A (FDR = 0.013, OR = 4.38, CI 1.6–12.01), TNFRSF1A*G + IL10*A/A + IL12B*C (FDR = 0.016, OR = 8.79, CI 2.17–35.63), TNF*G + LTA*G/G + IL10*C (FDR = 0.0105, OR = 3.54 CI 1.55–8.09).