Frequency Of Val Allele Research Articles

328 - Prevalence of mitochondrial superoxide dismutase gene Ala16Val polymorphism among Caucasian and Mongoloid adolescents

Background Mitochondrial superoxide dismutase (SOD2) catalyzes the superoxide dismutation into oxygen and hydrogen peroxide. The activity of SOD2 is determined by the SOD2 gene. The SOD2 gene is located on the chromosome 6q25.3. One of the most studied polymorphisms of this gene is polymorphism Ala16Val, which replaces the amino acid alanine with valine in the 16 position of the amino acid sequence. As a result, the alpha-helix of the SOD2 protein is disrupted. The altered protein has a 30-40% activity decrease, increasing the susceptibility of the cell to oxidative stress. The prevalence of Val allele of Ala16Val polymorphism varies in different races: 12.5% in Mongoloids, 46.6% in Caucasians. Methods We examined 119 adolescents aged 14-17 years: 65 Caucasian teenagers (Russians, average age 15.02 ± 0.98 years) and 54 Mongoloid teenagers (Buryats, mean age 15.31 ± 0.96 years). Genomic DNA was extracted from whole blood by commercial kits. Ala16Val polymorphism was genotyped using a polymerase chain reaction with electrophoresis detection. Results In the group of Caucasian adolescents, the frequencies of the genotypes Ala / Ala, Ala / Val and Val / Val are 27.7%; 43.1% and 29.2%. The frequency of Val allele is 50.8%. Among Buryats, the genotypes Ala / Ala, Ala / Val and Val / Val were detected in 7.4%; 53.7% and 38.9%, allele Val in 65.7%. This distribution of genotypes frequencies corresponds to the Hardy-Weinberg Law in both samples. Conclusion Allele Val of Ala16Val polymorphism of superoxide dismutase 2 gene in the group of Buryat adolescents occurs more often than in the group of Russian adolescents (χ² = 4.82, р = 0.0282). Similar tendency to more frequent occurrence of Val allele was found while comparing our research results with similar data in different populations of Mongoloids living around the world.

Prevalence of COMT Val158Met polymorphism in Eastern UP population.

Catechol-O-methyltransferase (COMT) is an abundant S-adenosylmethionine (SAM-)-dependent methyltransferase that methylates catechol compounds, including catecholamines and catecholestrogens.COMT gene located at chromosome 22q11.2 contains a functional polymorphism at codon 158(Val158Met), which has been related to psychiatric diseases and different types of cancer. COMT might affect tHcy levels because as a by-product it converts SAM to S-adenosylhomocysteine (SAH), which is reversibly converted to homocysteine. The aim of the present study was to determine the frequency of COMT Val158Met polymorphism in scheduled caste (SC) population of Jaunpur district. Total 100 healthy unrelated subjects belonging to SC, between the age group of 18 to70 years were randomly selected for the present study. 3 ml blood samples were collected from each subject. The inclusion criteria of subjects for present study are that they should be domicile of Uttar Pradesh, and healthy without any individual/ family history of genetic or metabolic disorders. COMT Val158Met polymorphism analysis was done by PCR-RFLP method. The Val/Val genotype was found in 48 subjects, Val/Met in 40 subjects and Met/Met genotype in 12 subjects. Genotype frequencies of Val/Val, Val/Met and Met/Met were 0.48, 0.40 and 0.12 respectively. The allele frequency of Val allele was found to be 0.68 and Met allele frequency was 0.32.

MnSOD and GPx1 polymorphism relationship with coronary heart disease risk and severity.

BackgroundDisturbance of the equilibrium between reactive oxygen species (ROS) and anti-oxidants (AOX) has been implicated in various diseases, including atherosclerosis, the most common pathologic process underlying coronary heart disease (CHD). Thus, the defense systems against ROS are critical protecting blood vessel walls against oxidative damage. In this study, we investigate whether Ala16Val MnSOD and Pro198Leu GPx polymorphisms are associated with CHD susceptibility and/or severity.MethodsBoth polymorphisms were genotyped in a sample of 203 controls and 164 patients. CHD risk and severity, antioxidant status (enzymatic and/or non enzymatic) and biochemical parameters were assessed and analysed by genotype.ResultsA significant association of MnSOD variant to CHD risk was revealed in males. Males harboring the Val/Val genotype were approximately at twofold increased risk of CHD compared to controls (Ala carriers vs Val/Val, adjusted OR 1.89; 95 % CI 1.18‒3.42, p = 0.03). Significant decreases in SOD activity and total antioxidant status (TAS) were observed in Val carriers and by CHD status. Whereas, no association of GPx variant genotype (Leu/Leu) and activity to cardiopathy events was discerned. CHD severity, as demonstrated by the number of vessel stenosis, was associated with significantly higher frequency of Val allele and LDL levels in CHD subjects.ConclusionsOur results showed a lack of association of Pro198Leu GPx polymorphism to CHD risk and severity. However, they suggest that Ala16Val MnSOD polymorphism and decreased antioxidant defences are likely contributed to CHD risk in Tunisian men. Furthermore, the Val encoding MnSOD allele and decreased SOD activity were significantly correlated with CHD stenosis progression.

Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility.

Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the -196 to -174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 -196 to -174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 -196 to -174 del, are likely to be associated with breast cancer development among females.

Evaluation of Superoxide Dismutase and Glutathione Peroxidase Enzyme Polymorphisms in Familial Mediterranean Fever Patients

Familial Mediterranean Fever (FMF) is a fairly common inflammatory disease in communities with mediterranean origin. It is characterized with autosomal recessive, recurrent short-term episodes of fever, peritoneal, pleural, synovial membrane involvement and skin lesions. The aim of the present study was to investigate possible associations between FMF and Ala-9Val polymorphism of MnSOD and Pro198Leu polymorphism of GPx1. The study included 129 FMF patients who has mutations (E148Q, P369S, F479L, M680I(G/C), M680I(G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H) in the heterozygous or homozygous form and 95 healthy subjects. To identify MnSOD Ala-9Val and GPx1 Pro198Leu SNPs, genotyping was performed using PCR amplification, and polymorphisms were detected with hybridization probes labeled with fluorescent dyes. Genotype and allele frequencies of Ala-9Val polymorphism of MnSOD and Pro198Leu polymorphism of GPx1 were detected. The MnSOD Val allele frequency is 132 (51.16%) in the FMF and 115 (60.52%) in the control group (p<0.05). The GPx1 Leu allele is 83 (32.17%) in the FMF and 61 (32.11%) in the control group (p=0.988). No significant differences were found between genotype frequencies of GPx1 and MnSOD polymorphisms.According to our findings MnSOD Val allele may be a genetic factor involved in the pathogenesis of FMF. The fact that there are only few studies in literature, we need more patients, other enzyme levels and works about polymorphism to support our study.

Polymorphisms in Mn-SOD and EC-SOD gene and risk of nephropathy in Western Indian Type 2 diabetic patients

Single-nucleotide polymorphisms in genes related to oxidative stress are a risk factor for the development of diabetes and its complications. The allele and genotype frequencies of missense polymorphism Ala-9Val and Val16Ala in Mn-SOD and Arg213Gly in EC-SOD genes were studied in (a) patients with Type 2 diabetes mellitus (T2DM) without any complication (T2DM), (b) diabetic nephropathy (DN), (c) non-diabetic nephropathy (NDN) and (d) control healthy subjects from Western region of India. The PCR products were digested with BshTI, BsaWI and Eco52I restriction enzymes to detect Ala-9Val, Val16Ala and Arg213Gly polymorphisms respectively. The frequency of Val allele of Ala-9Val (P = 0.568 and P = 0.571) and Ala allele of Val16Ala (P = 0.993 and P = 0.152) polymorphisms of Mn-SOD gene did not show a significant difference in patient with T2DM and NDN compared to control subjects respectively. Frequency of Val allele of Ala-9Val (42.8 % vs. 61.5 %, P < 0.001) and Ala allele of Val16Ala (39.0 % vs. 53.5 %, P = 0.005) polymorphisms of Mn-SOD gene was significantly higher in patients with DN than that of patient with T2DM. For Arg213Gly polymorphism of EC-SOD gene, the Gly allele frequency in T2DM and NDN group did not significantly (P = 0.993 and P = 0.152 respectively) differ from control subjects as well as non-significantly higher in DN compared to T2DM. These results suggests that Ala-9Val and Val16Ala polymorphism in Mn-SOD is not involved in development of diabetes but may play a crucial role in determining genetic susceptibility to diabetic nephropathy in Western Indian Type 2 diabetic patients. Our data found a lack of association of EC-SOD (Arg213Gly) polymorphism with development of diabetes and diabetic nephropathy.

Association of COMT gene polymorphisms with cerebral infarction in Han people of Tianjin

Background Catechol-O-methyltransferase (COMT) has a key function in the degradation of catecholamines and inactivating estrogen. A common polymorphism in the COMT gene is guanine-adenine (G-A) point mutation on rs4680, which causes a valine (Val) substitution to methionine (Met) in 108 and (or) 158 amino acid by this gene and is responsible for lowered activity of the enzyme. The Val/Met polymorphism has been recognized to be associated with psychiatric disorders, alcohol dependence and drug side effects, but few study has been done to examine the relationship with cerebral infarction (CI). The objective of this study is to investigate the relationship between the polymorphisms of COMT gene and CI. Methods The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect COMT Val158Met genotype in 181 CI patients and 148 cases of controls. Meanwhile the serum levels of glucose, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB) and ApoA in CI group were detected. Results The frequency of Val allele (78.45%) and Val/Val genotype (61.33%) in CI was significantly higher than that in the control group (68.24% and 45.95%, P 0.05) than that in the control group. The serum levels of glucose, TC, TG, LDL-C, HDL-C, ApoB, ApoA and the frequency of hypertension had no difference between Val/Val genotype and Val/Met + Met/Met genotypes ( P > 0.05, for all). Conclusion The frequencies of Val allele and Val/Val genotype can be considered as genetic risk factors of male CI patients. The effect of COMT on CI is not related to blood pressure, serum lipid and glucose.

Investigation of GSTP1 (Ile105Val) Gene Polymorphism in Chronic Myeloid Leukaemia Patients

The factors leading to the development of Chronic Myeloid Leukemia (CML) are not fully known. Associations between polymorphisms for genes encoding Glutathione S-transferase (GST) enzymes involved in Phase II detoxification reactions and susceptibility to some cancers have been shown in several studies. The aim of the present study was to investigate the influence of the GSTP1 (IIe105Val) gene polymorphism on human susceptibility to CML. Seventy-one CML patients and 67 control subjects with no cancer history were enrolled in our study . The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the GSTP1 (lle105Val) gene polymorphism. Genotypes were determined according to the bands that formed in agarose gels via gel electrophoresis. Leukocytes in the CML patient group were significantly different from those in the control group (p=0.0001). The frequency of the GSTP1 Val allele was found to be 22% in CML patients and 31% in controls. However, no statistical variation was found to exist between controls and patients in terms of the GSTP1 Val allele frequency (p=0.199). The relationship between the GSTP1 (IIe105Val) gene polymorphism and CML is not fully understood. Our results provide no evidence of a relationship between the GSTP1 (IIe105V al) gene polymorphism and susceptibility to CML in Turkish patients. However, these findings should be confirmed in studies with larger sample sizes.

Investigation of GSTP1 (Ile105Val) Gene Polymorphism in Chronic Myeloid Leukaemia Patients

The factors leading to the development of Chronic Myeloid Leukemia (CML) are not fully known. Associations between polymorphisms for genes encoding Glutathione S-transferase (GST) enzymes involved in Phase II detoxification reactions and susceptibility to some cancers have been shown in several studies. The aim of the present study was to investigate the influence of the GSTP1 (IIe105Val) gene polymorphism on human susceptibility to CML. Seventy-one CML patients and 67 control subjects with no cancer history were enrolled in our study . The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the GSTP1 (lle105Val) gene polymorphism. Genotypes were determined according to the bands that formed in agarose gels via gel electrophoresis. Leukocytes in the CML patient group were significantly different from those in the control group (p=0.0001). The frequency of the GSTP1 Val allele was found to be 22% in CML patients and 31% in controls. However, no statistical variation was found to exist between controls and patients in terms of the GSTP1 Val allele frequency (p=0.199). The relationship between the GSTP1 (IIe105Val) gene polymorphism and CML is not fully understood. Our results provide no evidence of a relationship between the GSTP1 (IIe105V al) gene polymorphism and susceptibility to CML in Turkish patients. However, these findings should be confirmed in studies with larger sample sizes.

An association study on Gilles de la Tourette's syndrome and catechol-O-methyl transferase gene polymorphism

Objective To investigate the association between catechol-O-methyl transferase (COMT) gene polymorphism and Gilles de la Tourette’s syndrome(GTS). Methods Using Amplification Refractory Mutation System(ARMS) PCR genotyping assay method, a polymorphism (val158met) of COMT gene was genotyped in 112 of all GTS patients (total GTS group) including 54 GTS-alone patients group, 48 GTS+ ADHD patients group among of them and 71 healthy controls. The correlation between positive association of polymorphism (val158met) of COMT gene in GTS and the age of onset in patients with GTS was also analyzed. Results Compared with healthy controls group, genotype of val158met did not differ in total GTS patients group or alone-GTS patients group (χ2=0.56, P=0.756; χ2=1.05, P=0.600 respectively). There was also no significant difference (P>0.05) in allele distribution of val158met in total GTS patients group or alone-GTS patients group compared with controls group respectively (χ2=0.18, P=0.669; χ2=0.29, P=0.593 respectively). However, genotype distribution of val158met was significantly different between GTS+ ADHD patients group and controls group(χ2=6.35, P=0.041). The frequency of the val allele of this locus was significantly higher in GTS+ ADHD patients group than those in controls group (χ2=5.49, P=0.019). The mean age of onset (6.80±1.54) in 36 children within GTS+ ADHD patients group with the val/val genotype of COMT gene val158met polymorphism was significantly earlier than the mean age of onset (8.04±1.54) in 12 children in val/val genotype(P=0.016). Conclusion Polymorphism (val158met) of COMT gene may be associated with GTS children with comorbid ADHD, which may play an important role to make the age of onset in children with GTS become earlier. Key words: Gilles de la Tourette's syndrome; Catechol-O-methyl transferase; Association analysis; Age of onset

Predominant genotypes and alleles of the Val-9Ala polymorphisms in the mitochondrial targeting sequence leading the manganese superoxide dismutase gene associated with their superoxide dismutase activity and total antioxidant status of healthy Thai subjec

Genotype distributions and allele frequencies of the Val-9Ala polymorphisms in the mitochondrial targeting sequence leading the manganese superoxide dismutase gene as well as associations with their superoxide dismutase activity and total antioxidant status of healthy Thai subjects were determined. The Val-9Ala polymorphisms in MTS-MnSOD gene of 221 healthy Thais including 135 females and 86 males were genotyped by a real-time PCR using protocol and all reagents of TaqMan Allelic Discrimination Demonstration Kit (PE Applied Biosystem, USA). The SOD activity of whole blood cells and plasma total antioxidant status (TAS) of each subject were assayed manually using protocol and all reagents of RANSOD and TAS kits (Randox Laboratories,UK) respectively. The Val/Val, Val/Ala genotypes and the Val allele frequency were found to be predominant rather than the Ala/Ala genotype and the Ala allele frequency in healthy Thai subjects both females and males similar to those previous reports of healthy Chinese, Japanese and Korean subjects. The average values of SOD activity and TAS level in healthy Thais were 2,129.±778 U/g Hb and 1.27±0.26 mmol/L respectively. The association of each genotype with SOD activity as well as TAS levels of Thai females and males showed that the average values of SOD activity and TAS in healthy Thais with the Val/Val and the Val/Ala genotypes were not statistically different (p>0.05) and not lower than those of the Ala/Ala genotypes. In conclusion, the predominant genotypes were the Val/Val and the Val/Ala and they were not associated with low levels of SOD and TAS.

Polymorphisms of cytochrome P450 1A1, glutathione s-transferases M1 and T1 genes in ouangolodougou (Northern Ivory Coast)

In this study, the frequencies of CYP1A1, GSTM1, and GSTT1 gene polymorphisms were determined in 133 healthy individuals from Ouangolodougou, a small rural town situated in the north of the Ivory Coast. As appeared in several published studies, ethnic differences in these frequencies have been found to play an important role in the metabolism of a relevant number of human carcinogens. In the studied sample, the frequencies of Ile/Ile (wild type), Ile/Val (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 genotypes were 0.271, 0.692, and 0.037, respectively. Frequencies of GSTM1 and GSTT1 null genotypes were 0.361 and 0.331, respectively. No significant differences were noted between men and women. In contrast to published data for Africans, CYP1A1 *Val Allele frequency (0.383) was significantly high (p < 0.001) in this specific population. For the GSTT1 null genotype, no differences were found between the studied and other African populations, the contrary to what occurred for the GSTM1 null genotype in relation to Gambia and Egypt.

Lack of an association between CYP1A1 gene Ile462Val polymorphism and polycystic ovary syndrome in Chinese

Polycystic ovary syndrome (PCOS) is a complex multi-factorial disorder involving a number of genetic and environmental factors. CYP1A1 (Cytochrome P450, family 1, subfamily A, polypeptide 1) gene, which belongs to Cytochrome P450 (CYP) super family, encodes a phase I cytochrome P450 enzyme, involved in the oxidative metabolism of estrogens. A recent study suggested that a common polymorphism Ile462Val of the CYP1A1 gene might be associated with PCOS development in Turkish women. To investigate a possible association between the CYP1A1 Ile462Val polymorphism and PCOS in Chinese women, we examined 205 PCOS patients and 177 healthy controls. All subjects were genotyped for CYP1A1. There was no statistical difference in CYP1A1 genotype and allele frequencies between PCOS cases and controls (chi(2) = 0.956, df = 2, P = 0.089 by genotype; chi(2) = 0.005, df = 1, P = 0.941 by allele). Compared with controls, there were no statistical difference in Val/Val genotype and Val allele frequency in the PCOS cases (4.9% vs. 5.1% by genotype; 51.7% vs. 52.0% by allele) (chi(2) = 0.009, df = 1, P = 0.926 by genotype; chi(2) = 0.005, df = 1, P = 0.941 by allele). Moreover, no association between CYP1A1 Ile462Val genotypes and metabolic parameters was observed in PCOS women. Our findings clearly indicated that this polymorphism does not represent an additional genetic risk factor for PCOS in Chinese women.

HER2 codon 655 polymorphism and breast cancer risk: a meta-analysis

To evaluate the association between HER2 codon 655 polymorphism and breast cancer risk in this meta-analysis. A comprehensive search was performed to identify all case-control studies investigating such association. Statistical analyses were conducted with software MIX 1.54. Twenty eligible reports, including 10,642 cases/11,259 controls, were identified. In overall analysis, the Val allele frequency in cases was significantly higher than that in controls (OR = 1.0921, 95% CI: 1.0013-1.191, P = 0.0466), while no associations were found in both recessive and dominant models. In subgroup analysis, HER2 codon 655 polymorphism was weakly associated with breast cancer risk in recessive (OR = 2.4624, 95% CI: 1.0619-5.7104, P = 0.0357), dominant (OR = 1.2781, 95% CI: 1.0353-1.5779, P = 0.0225), and co-dominant genetic models (OR = 1.2947, 95% CI: 1.0682-1.5693, P = 0.0085) in Asian population, respectively. Meanwhile, the susceptibility to breast cancer in people aged < or =45 was significantly increased in both recessive (OR = 2.2408; 95% CI: 1.2876-3.8998, P = 0.0043), and dominant models (OR = 1.2902, 95% CI: 1.1035-1.5085, P = 0.0014). No significant associations were observed in Caucasian, European, and Family history subgroups. So our analyses suggest HER2 codon 655 Val allele is weakly associated with an increased risk of breast cancer, and SNP at HER2 codon 655 could be considered as a susceptibility biomarker for breast cancer for Asian females or women age 45 years or younger.

Manganase superoxide dismutase polymorphism in chronic pelvic pain syndrome patients

Chronic pelvic pain syndrome (CPPS) is a common and serious health problem affecting the quality of life in men. In this study, we aim to investigate the manganese superoxide dismutase (MnSOD) polymorphism at nucleotide 47 as a result of the change of Ala to Val on the protein sequence in CPPS patients. The frequencies were 0.45 and 0.38 for the Ala and 0.55 and 0.62 for Val in National Institutes of Health category 3a and 3b groups. The differences between control and CPPS patients were statistically significant (P<0.05). However, frequencies recorded in 3a and 3b groups were not statistically different (P>0.05). Same results were obtained for enzyme analysis of MnSOD and glutathione peroxidase. Control group antioxidant enzyme levels were higher than patients' samples. The low antioxidant status of CPPS patients might be the clue for pathophysiological problems, and highly distributed Val allele frequency can be a mediator point of the illness. Our findings lead to the suggestion that oxidative disorder-linked medical health problems can be associated with genetic risk factors such as polymorphisms.

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent meta-analysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected P-value for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy-Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry.

Genetic polymorphisms of CYP2D6, CYP1A1, GSTM1 and p53 genes in a unique Siberian population of Tundra Nentsi.

The purpose of this study was to establish the frequencies of CYP2D6, CYP1A1, GSTM1 and p53 polymorphic genotypes in Tundra Nentsi, which comprises the small group of indigenous people belonging to Northern Mongoloids and Caucasians of Western Siberia. A total number of 102 Tundra Nentsi individuals and 96 Caucasians of Western Siberia were genotyped by means of polymerase chain reaction-based assays. Mutated alleles comprising CYP2D6*4, CYP1A1Val, GSTM1*0 and p53Pro were analysed along with the wild-type alleles. The results showed the intermedial position of CYP2D6*4 allele frequency in Tundra Nentsi, compared to Caucasians and Orientals (0.07 versus 0.2, P = 0.0003; 0.07 versus 0.003, P = 1 x 10(-6), respectively). Thus, our data indicate that the intermedial position of Tundra Nentsi between Orientals and Caucasians most likely shows the Caucasian ancestral origin of CYP2D6*4 allele. Comparative analysis of p53Pro allele frequency showed the pronounced ethnic differences with geographic gradient. Though the frequency of p53Pro allele ranged from 0.17 in Tundra Nentsi up to 0.3 in Caucasians of Western Siberia (P = 0.002), which is in agreement with the previously reported radial distribution of the known genetic markers. No differences were found in the CYP1A1Val allele distribution among Caucasians of Western Siberia and Caucasoid populations presented in other studies, whereas the frequency of Val allele in Nentsi was 1.5-fold higher (P = 0.076) compared to the Japanese group. It was found that the frequency of GSTM1 null genotype in Tundra Nentsi was only 39.8%. The frequency of GSTM1 null genotype in females was higher than in males (0.27 and 0.50, respectively) but that difference was not statistically significant. Comparative analyses of the distribution of putative markers towards cancer susceptibility, CYP1A1Val, GSTM1*0 and p53Pro alleles, have shown that the healthy Tundra Nentsi population (Northern Mongoloids) have a low number of p53Pro alleles and GSTM1*0/*0 genotypes and a high level of CYP1A1Val alleles. Further investigations of gene polymorphisms in isolated Northern native populations would be valuable in clarifying the origin of Northern natives. All this is important for comparative analyses of pharmacogenetic data in Mongoloid populations.

Confirmation of an excess of the high enzyme activity COMTval allele in heroin addicts in a family-based haplotype relative risk study

A previous case control study by Vandenbergh et al. [1997: Am J Med Genet 74:439-442] showed an association between the high activity catechol O-methyltransferase (COMT) polymorphism and polysubstance abuse in a group of North American subjects. In the current study we confirm these results by genotyping 38 Israeli heroin addicts and both parents using a robust family-based haplotype relative risk (HRR) strategy. There is an excess of the val COMT allele (likelihood ratio = 4.48, P = 0.03) and a trend for an excess of the val/val COMT genotype (likelihood ratio = 4.97, P = 0.08, 2 df) in the heroin addicts compared to the HRR control group. We also genotyped an additional 101 nonrelated heroin addicts and 126 control subjects using a case control design and found no significant difference in COMT val allele frequency (25.4% vs. 29.7%, likelihood ratio = 1.04, P = 0.31). A significant difference is observed in COMT allele frequency among the three principal Israeli ethnic groups (Ashkenazi Jewish, non-Ashkenazi Jewish, and Palestinian Arab) in a large group of control subjects we have so far examined (chi-square = 7.9, P = 0.019, df = 2, n = 1,422 alleles) suggesting that population stratification is responsible for our failure to observe an excess of the COMT val allele when using the case-control design.

The 677C > T mutation in 5,10-methylenetetrahydrofolate reductase and colorectal cancer risk.

This paper examines whether there is a relationship between a common mutation in the methylenetetrahydrofolate reductase gene, MTHFR*val, and the risk of colorectal cancer, with or without lymph node metastases. MTHFR genotypes were ascertained from peripheral leukocyte samples obtained from 200 colorectal patients, including TMN stages I-VI, and from 460 healthy, unrelated adults without colorectal cancer, who served as controls. The frequency of homozygosity for the MTHFR*val/*val genotype among the colorectal cancer patients was lower (14.0%) than among controls (16.1%). The latter finding results in an estimated MTHFR*val allele frequency of 0.41. The MTHFR*val allele (677C > T) reduces colorectal risk slightly [odds ratio (OR), 0.87]. However, there was a significantly higher incidence of metastatic lymph nodes per case in MTHFR*val/*val patients, when compared with MTHFR*ala/*ala controls (6.9 +/- 1.55 vs. 3.7 +/- 0.57, p = 0.003). These results suggest that the MTHFR genotype might be of prognostic significance in colorectal carcinoma.