Related Genetic Polymorphisms Research Articles

Genomic organization and localization of the NAD-dependent histone deacetylase gene sirtuin 3 (Sirt3) in the mouse

Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the Silent information regulator 2 (Sir2) family of histone deacetylases (sirtuin HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the murine Sirt3 genomic sequence, which spans a region of 18,646 bp and which has one single genomic locus. Determination of the exon-intron splice junctions identified murine SIRT3 to be encoded by 7 exons ranging in size from 101 (exon 4) to 420 bp (exon 7). Characterization of the 5' flanking genomic region, which precedes the murine Sirt3 open reading frame, revealed a number of STATx, GATA and SP1 transcription factor binding sites. A CpG island was not detected. The 1,473-bp murine Sirt3 transcript has an open reading frame of 774 bp and encodes a 257-aa protein (cytoplasmic SIRT3) with a predictive molecular weight of 28.8 kDa and an isoelectric point of 5.82. Recently, a 1,406-bp murine SIRT3 splice variant that encodes a 334-aa mitochondrial precursor protein with a molecular weight of 36.6 kDa and an isoelectric point of 7.19 has been described. Fluorescence in situ hybridization analysis identified a single genomic locus for murine Sirt3 gene on chromosome 7F4 and which is neighbored by the Ric8 and PSMD13 genes. Our study brings light and a number of corrections and additions to previous reports on the genomic organization and the genomic sequence of murine Sirt3, which may be of importance in view of studies on potential genetic polymorphisms in relation to cellular respiration, metabolism, aging-related disease and cancer.

Genetic risk factors for inflammatory bowel disease in a North‐eastern Mexican population

The purpose of this study was to assess the role of Helicobacter pylori and several genetic polymorphisms in relation to inflammatory bowel disease (IBD). We studied 44 unrelated patients with IBD and 75 subjects with no history of IBD as controls. Using pyrosequencing technology, we identified gene polymorphisms in IL-10, TNF-A, ILB-31, and TLR4. H. pylori status was determined by serology. Individuals homozygous for IL10-592 A or IL10-1082 A genotypes show significantly lower occurrence of IBD (P=0.03 and P<0.01, respectively). Individuals heterozygous at IL10-1082 have significantly increased occurrence of IBD, both ulcerative colitis and Crohn's disease (P<0.01). There was no difference in the prevalence of H. pylori infection between cases and controls. This study provides evidence that variation in IL10 is correlated with IBD occurrence in this Mexican population.

Cigarette smoking, genetic polymorphisms and colorectal cancer risk: the Fukuoka Colorectal Cancer Study

BackgroundIt is uncertain whether smoking is related to colorectal cancer risk. Cytochrome P-450 CYP1A1, glutathione-S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are important enzymes in the metabolism of tobacco carcinogens, and functional genetic polymorphisms are known for these enzymes. We investigated the relation of cigarette smoking and related genetic polymorphisms to colorectal cancer risk, with special reference to the interaction between smoking and genetic polymorphism.MethodsWe used data from the Fukuoka Colorectal Cancer Study, a population-based case-control study, including 685 cases and 778 controls who gave informed consent to genetic analysis. Interview was conducted to assess lifestyle factors, and DNA was extracted from buffy coat.ResultsIn comparison with lifelong nonsmokers, the odds ratios (OR) of colorectal cancer for <400, 400-799 and ≥800 cigarette-years were 0.65 (95% confidence interval [CI], 0.45-0.89), 1.16 (0.83-1.62) and 1.14 (0.73-1.77), respectively. A decreased risk associated with light smoking was observed only for colon cancer, and rectal cancer showed an increased risk among those with ≥400 cigarette-years (OR 1.60, 95% CI 1.04-2.45). None of the polymorphisms under study was singly associated with colorectal cancer risk. Of the gene-gene interactions studied, the composite genotype of CYP1A1*2A or CYP1A1*2C and GSTT1 polymorphisms was associated with a decreased risk of colorectal cancer, showing a nearly statistically significant (Pinteraction = 0.06) or significant interaction (Pinteraction = 0.02). The composite genotypes of these two polymorphisms, however, showed no measurable interaction with cigarette smoking in relation to colorectal cancer risk.ConclusionsCigarette smoking may be associated with increased risk of rectal cancer, but not of colon cancer. The observed interactions between CYP1A1 and GSTT1 polymorphisms warrant further confirmation.

Association of plasma homocysteine and gene polymorphisms of homocysteine with ulcerative colitis

Objective To evaluate association of plasma levels of homocysteine, folate and vitamin B12 as well as genetic polymorphisms of homocysteine with ulcerative colitis (UC). Methods Three hundred and ten consecutive patients with UC and 936 healthy controls were recruited.Polymorphisms of methylenetetrahyrdofolate reductase (MTHFR, C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G were genotyped using PCR-RELP methods. Eighty eight patients and one hundred healthy controls were randomly selected for determination of plasma levels of homocysteine by enzymatic cycling assay, and concentrations of folate and vitamin B12 were measured by corpuscle immune chemiluminescence assay. Results The variant allele and genotype frequencies of MTHFR 1298C, MTR 2756G and MTRR 66G were significantly higher in UC patients than in the healthy controls (P＜0. 01). Moreover, plasma homocysteine level was obviously higher in UC patients than in controls [(21.73±6.59) mmol/L vs(12.47±5.01)mmol/L,P<0.01).Whereas both folate F(11.25±6.19)nmol/L] and vitamin B12 [(322.81±128.47)pmol/L] concentrations were significantly lower in UC patients than in controls [(15.28±7.72)nmol/L and (422.59±129.36)pmol/L,respectively,P<0.01].Logistic analysis revealed that abnormal levels of homocysteine,folate and vitamin B12 were independent risk factors for UC(P<0.01).Conclusions Plasma levels of homocysteine,folate and vitamin B12 as well as the related genetic polymorphisms of homocystein are correlated with UC,which provides a theoretical basis for supplement of folate and vitamin B12 in treatment of UC patients. Key words: Colitis,ulcerative; Homocysteine; Folate acid; Vitamin B12

Polymorphisms in genes involved in DNA repair, cell growth, oxidative stress and inflammatory response, and melanoma risk

Polymorphisms in genes involved in DNA repair, cell growth, oxidative stress and inflammatory response, and melanoma risk

Can We Use Single Nucleotide Polymorphism and Runt Domain Transcription Factor 3 Methylation as Tumor Markers for Bladder Cancer?

Purpose: Although many tumor markers have been evaluated in relation to bladder cancer, none of these biomarkers reported to date has shown sufficient sensitivity and specificity for the detection of the whole spectrum of bladder cancer diseases in routine clinical practice. The limited value of the established prognostic markers requires analysis of new molecular parameters of interest for predicting the prognosis of bladder cancer patients. Materials and Methods: We conducted a review of the literature with a focus on recent advances in genetic polymorphism and hypermethylation events in relation to bladder transitional cell carcinoma. Results: Recently, there has been major progress in both genetic polymorphism in relation to bladder cancer and molecular genetic and epigenetic changes leading to the development of transitional cell carcinoma. However, studies on numerous single-nucleotide polymorphisms in relation to bladder cancer have provided only a few genetic polymorphisms with only marginal information on patients’ prognosis. For this reason, interest is increasing in epigenetic changes in bladder cancer. The epigenetic silencing of tumor suppressor genes is interesting from a clinical standpoint because of the possibility to reverse the epigenetic changes and thus restore gene function to a cell. Treatment with DNA methylation inhibitors can restore the activities of dormant genes and decrease the growth rate of cancer cells in a heritable fashion. Conclusions: Epigenetic modification may be possible to partially reverse the cancer phenotype, and this will eventually lead to targeted therapy tailored toward specific molecular therapy in the near future. (Korean J

Contemporary Epidemiology of Renal Cell Cancer

We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to trichloroethylene has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the von Hippel-Lindau gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers.

Genetic polymorphism and pathogenesis of benign prostatic hyperplasia

There is apparent uncertainty in etiology and pathogenesis of Benign Prostatic Hyperplasia. Though several hypothesis put forwarded, like other multifactorial complex diseases, BPH still lacks an integrated model of pathogenesis and progression. BPH is a common problem of aged men due uncontrollable non-cancerous prostatic growth. A wide variety of genetic factors have been associated with tissue hyperplasia in general. Androgen related genes and metabolism genes are closely associated with growth and function of prostate. Recent emergence of BPH as inflammation-mediated disease also opens new avenues in search for genetic factors of BPH. Knowledge of gene polymorphisms may be an important aid in genetic screening of risk of disease involved and the understanding of complex interactions involved in genesis and progression of BPH. Till to date there is no report of high penetrance genetic marker in BPH. There is immense possibility of evolving a model of low penetrance markers of BPH and with this prospect a more exhaustive search for all BPH associated polymorphism in larger population is needed. This strategy combined with high-throughput expression profiling and linkage studies of genes for establishing a clear picture of pathophysiology and risk factor of a complex disease like BPH. In this study, we have reviewed a variety of genetic polymorphisms in relation to their possible role in benign prostatic hyperplasia. We have included associations identified in molecular epidemiology studies and the consistency of findings reported to date. Suggestions for further research are also offered. Keyword: Polymorphism, Benign Prostatic Hyperplasia, Pathogenesis

Genetic Polymorphisms in Relation to Immunosuppressive Drug Pharmacokinetics in Organ Transplantation: Current Knowledge and Perspectives

Genetic Polymorphisms in Relation to Immunosuppressive Drug Pharmacokinetics in Organ Transplantation: Current Knowledge and Perspectives

Interleukin‐24, RANTES and CCR5 gene polymorphisms are not associated with chronic adult periodontitis

Cytokines, such as interleukin-10, and related genetic polymorphisms, have been implicated in the pathogenesis of chronic periodontitis. The aim of this study was to investigate a possible correlation between chronic periodontitis and genetic polymorphisms coding for two interleukin-10 related chemokines [interleukin-24 and regulated on activation, normal T cells expressed and secreted (RANTES)] as well as a RANTES receptor [CC chemokine receptor 5 (CCR5)]. A single-blind, two-centre, case-controlled study was carried out with test patients from the Clinic of Periodontics, Göteborg University, and from the Department of Periodontology, Glasgow University, and control subjects from the undergraduate clinics of both schools. Blood samples were collected from 106 patients (56 women and 50 men, mean age 51.7 yr) with generalized, severe chronic periodontitis and from 69 periodontally healthy subjects (37 women and 32 men, mean age 53.3 yr). The polymerase chain reaction (PCR) was used to identify the genetic coding for interleukin-24, RANTES and CCR5. Genotype and allele frequencies were compared between the test and control groups using Fischer's exact test at the 5% level of significance. There were no statistically significant differences between patients with chronic periodontitis and control subjects, regarding genotype distribution or allele frequency, irrespective of smoking status, in the combined Glasgow and Gothenburg cohort or in the specific location cohorts. The allele frequencies for healthy and control subjects for RANTES gave a p-value of 0.80 (allele G was 58.8% in healthy subjects and and 54.4% in subjects with periodontitis), for interleukin-24 the p-value was 0.90 (allele T was 56.2% in healthy subjects and and 54.9% in subjects with periodontitis) and for CCR5 the p-value was 0.90 (the wild-type allele was 85% in healthy subjects and and 82.7% in subjects with periodontitis). The interleukin-24, RANTES and CCR5 polymorphisms investigated are not associated with chronic periodontitis.

Influence of chemotherapy related genetic polymorphisms and FDG-PET on response and prognosis of locally advanced neoadjuvant treated adenocarcinomas of the esophagus (AEG I)

Influence of chemotherapy related genetic polymorphisms and FDG-PET on response and prognosis of locally advanced neoadjuvant treated adenocarcinomas of the esophagus (AEG I)

Folate, Vitamin B6, Vitamin B12, and Vitamin B2 Intake, Genetic Polymorphisms of Related Enzymes, and Risk of Colorectal Cancerin a Hospital-Based Case-Control Study in Japan

: We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms—MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys—were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.

Adaptation to past malarial endemia and susceptibility to common diseases in modern populations: A study of adenosine deaminase and MN blood group genetic polymorphisms

We carried out a study of adenosine deaminase (ADA) and MN blood group genetic polymorphisms in relation to past malarial morbidity in Sardinia and in relation to susceptibility to allergic asthma (a Th2 disorder) and Crohn's disease (a Th1 disorder) in the population of Rome. Eight hundred and eight schoolchildren, aged 7--14 years from 14 Sardinian villages located in the central area of the island, were considered. One hundred and twenty-two children with allergic asthma and 39 adult patients with Crohn's disease from the population of Rome were also studied. The data suggest an interaction between the two systems concerning resistance/susceptibility, both to malaria and to the diseases considered. In Sardinia, the frequency of the *L(M)/ADA*2 gametic type is negatively correlated with past malarial endemia, suggesting an increased susceptibility to malaria leading to its decrease in areas with high malarial endemia. In Rome, this gametic type is correlated negatively to allergic asthma and positively to Crohn's disease, suggesting a protective effect against allergic asthma and increased susceptibility to Crohn's disease.

Associations Between Drug Metabolism Genotype, Chemotherapy Pharmacokinetics, and Overall Survival in Patients With Breast Cancer

To evaluate associations between patient survival, pharmacokinetics, and drug metabolism-related genetic polymorphisms in patients receiving a combination chemotherapy regimen for breast cancer. A genotype association study was conducted on 85 chemotherapy-naïve patients with metastatic or inflammatory breast cancer that were evaluated for an extended period after receiving standard-dose chemotherapy followed by high-dose cyclophosphamide, cisplatin, and carmustine. Blood pharmacokinetics were evaluated, and DNA was genotyped for 29 polymorphisms in 17 drug metabolism genes. Patients with cyclophosphamide plasma exposures above the median (implying slower metabolic activation) had a shorter survival than those below the median (1.8 v 3.8 years, respectively; P = .042). Patients having a variant genotype of cytochrome P450 3A4 displayed higher blood concentrations of parent (inactive) cyclophosphamide with the second and third doses (P = .024 and .028, respectively) in addition to slower cyclophosphamide activation over the three doses (P = .031). Median survival for these patients was 1.3 years compared with 2.7 years for those without the variant (P = .043). Similar results were observed for patients carrying a genetic variant of P450 3A5. Median survival for patients with deletions of glutathione-S-transferase M1 gene was 3.5 v 1.5 years for patients with one or both copies (P = .041). Patients with a polymorphism in a gene regulating metallothionein had lower platinum concentrations and shorter survival (P = .033). These data suggest that pretreatment evaluation of drug metabolism genes may explain some interindividual differences in both anticancer drug pharmacokinetics and response. The correlations found here may have implications for other commonly used anticancer drugs.

Homocysteine and related genetic polymorphisms in Down’s syndrome IQ

Objective: Down’s syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to...

Performance of the Log-Linear Approach to Case-Parent Triad Data for Assessing Maternal Genetic Associations with Offspring Disease: Type I Error, Power, and Bias

Maternal genetic variation may serve as a biomarker in studies aimed at clarifying fetal determinants of infant or adult disease. The log-linear approach to case-parent triad data (LCPT) can be used to investigate maternal genetic polymorphisms in relation to offspring disease risk, but LCPT operating characteristics have been reported for only a limited range of situations. The authors performed a simulation study to investigate the performance of the LCPT for assessing maternal associations with offspring disease risk over a wide range of scenarios with varying sample sizes (n), high-risk allele frequencies (f ), and modes of inheritance, all of which greatly affect the expected number of triads in informative categories. For most f values less than 0.5, the LCPT approach with 200 triads allowed for approximately 80% power to detect valid, unbiased maternal relative risks of 2 when inheritance was log-additive or dominant. When inheritance was recessive, this was true for most f 's greater than 0.35. Outside of this range, however, power and bias depended greatly on the mode of inheritance, f, and n. On the basis of these findings, epidemiologists may consider the LCPT a useful approach for assessing maternal relative risks unless one expects a very rare or fairly common maternal allele to increase offspring disease risk.

Impact of Genetic Polymorphism in Relation to Other Factors on Expression and Function of Human Drug-Metabolizing P450s

A major cause for unpredictable drug response is the enormous variability of drug-metabolizing cytochrome P450s (CYPs) in human liver in which genetic polymorphisms, regulation of gene expression, and physiological factors, including sex, may play a role. To dissect these different factors, we established a large human liver bank with extensive clinical documentation. Recent work concentrated on CYPs 2D6, 2B6, and the 3A family. CYP2D6 expression is highly polymorphic with over 70 alleles. Using liver samples and DNA from phenotyped patients, we further elucidated the genetic basis of phenotypic differences and demonstrated a novel role of alternative splicing, leading to decreased enzyme activity. These studies further emphasize the intricacy of genetic regulation at the CYP2D6 locus. In contrast, CYP2B6, the human orthologue of the rodent phenobarbital-inducible P450 2B, is known to be inducible by a range of substances, but our recent studies also show a high degree of genetic polymorphism. However, the role of polymorphism in determining CYP2B6 expression and function is less decisive as compared with CYP2D6. Thus, with respect to the balance between genetic and nongenetic factors controlling expression, CYP2B6 appears to take an intermediate position. CYP3A4 is the major P450 of human liver and contributes critically to the metabolism of at least half of all drugs. CYP3A4 expression variability is not influenced much by genetic polymorphism. Studies in our liver bank confirm that both induction and down-regulation occur as a consequence of drug treatment. As a further major determinant of hepatic CYP3A4 expression, we found sexual dimorphism, with women expressing at least twice the amount of CYP3A4 protein than men. This surprising result explains the many pharmacokinetic findings of faster metabolism of CYP3A4 drug substrates in women. In conclusion, these data illustrate how various factors contribute to the individual CYP profile in human liver.

悪性腫ようの遺伝子解析的アプローチ 胃の前癌病変の遺伝子変化―Ｈ．ｐｙｌｏｒｉ感染との関連から―

Helicobacter pylori (H. pylori) is now known as one of major factors to evoke gastroduodenal diseases including gastric carcinoma. In Japan, although more than 60 million people are reported to be H. pylori-positive, only less than 0.5% people suffers from gastric cancer. To know the real high risk group for the extention of preneoplastic change among H. pylori-positive cohorts, the information about the host genetic characteristics is one of the important clues. The present review summarizes the results of differences in host factors using animal model for H. pylori infection as well as human approach in the field of genetic polymorphism in relation to H. pylori infection.

Functional analysis of six different polymorphic CYP1B1 enzyme variants found in an Ethiopian population.

Cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme of potential importance for the metabolism of estrogen and for metabolic activation of environmental carcinogens. We investigated an Ethiopian population for functional polymorphisms in the CYP1B1 gene using genomic DNA sequencing and detected three novel single nucleotide polymorphisms (SNPs). One of these (4360C-->G in exon 3) is present at a frequency of 7% and causes an Ala443Gly amino acid substitution. In addition, the four described previously missense mutations Arg48Gly, Ala119Ser, Leu432Val, and Asn453Ser were found with frequencies of 51, 50, 53, and 2%, respectively, yielding a total of 32 possible CYP1B1 haplotypes. Allele-specific PCR methods for haplotype analysis were developed and seven different CYP1B1 alleles were found: CYP1B1*1, *2, *3, *4, *5, *6, and *7 with frequencies of 8, 37, 39, 2, 0.7, 6, and 7%, respectively. The functional properties of different forms of CYP1B1, as well as of the Leu432Val + Asn453Ser and Leu432Val + Ala443Gly variants, were evaluated after heterologous expression of the corresponding cDNAs in Saccaromyces cerevisiae. The results revealed that CYP1B1.6 and CYP1B1.7, having the amino acid substitutions Arg48Gly, Ala119Ser, and Leu432Val in common, exhibited altered kinetics with significantly increased apparent K(m) and lowered V(max) values for both the 2- and 4-hydroxylation of 17 beta-estradiol, whereas the other constructs were indistinguishable from the CYP1B1.1 enzyme. The results emphasize the necessity of a complete haplotype analysis of enzyme variants for evaluation of functional consequences in vivo and for analyses of genetic polymorphisms in relation to, for example, cancer incidence.

Immune related genetic polymorphisms and schizophrenia among the Chinese

Genetic association studies were conducted among two independent cohorts of Chinese ethnicity. The samples consisted of cases and unrelated controls, ascertained from Guangzhou, China, and Singapore. The studies were prompted by our earlier report of an association between schizophrenia and HLA DQB1 alleles (HLA DQB1∗0602 and HLA DQB1∗0303) in the Singapore sample. Polymorphisms of HLA DQB1 and flanking markers on chromosome 6p21.3 were investigated in the first part of the study. A significant negative association with HLA DQB1∗0402 was detected in the Guangzhou sample (Odds ratio, OR 0.26, 95% confidence intervals, CI 0.1, 0.6; p < 0.02, corrected for multiple comparisons). Additional analysis of the Guangzhou and Singapore samples revealed associations at three other anonymous markers flanking HLA DQB1. In the second part of the study, three polymorphisms at the Interleukin-1 gene cluster (IL-1, chromosome 2q13-q21) were investigated in both cohorts, since associations with schizophrenia have been reported in another sample. Persuasive evidence for an association at IL-1 was not detected in either sample. Our results suggest a susceptibility locus for schizophrenia in the HLA region among the Chinese, but further clarification is necessary.