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PubMed2005

Genetic variants of DNA repair genes and prostate cancer: a population-based study.

As part of a population-based case-control study in Shanghai, China, we investigated whether variants in several DNA repair genes, either alone or in conjunction with other risk factors, are associated with prostate cancer risk. Genomic DNA from 162 patients newly diagnosed with prostate cancer and 251 healthy men randomly selected from the population were typed for five nonsynonymous DNA repair markers. We found that the XRCC1-Arg399Gln AA and the MGMT-Leu84Phe CT+TT genotypes were associated with an increased risk of prostate cancer [odds ratio (OR), 2.18; 95% confidence interval (CI), 0.99-4.81 and OR, 1.99; 95% CI, 1.19-3.34, respectively]. In contrast, XRCC3-Thr241Met, XPD-Lys751Gln, and MGMT-Ile143Val markers showed no significant associations with risk, although due to the much lower frequency of their variant alleles in this population we cannot rule out small to modest effects. There was a significant interaction between the MGMT-84 marker and insulin resistance (P(interaction) = 0.046). Relative to men with the MGMT-84 CC genotype and a low insulin resistance (<0.097), those having the CT-TT genotype and a greater insulin resistance had a 5.4-fold risk (OR, 5.39; 95% CI, 2.46-11.82). In addition, for the XRCC3-241 marker, relative to men with the CC genotype and a low intake of preserved foods (<12.7 g/d), those harboring the CT+TT genotype and having a higher intake of preserved foods (>12.7 g/d), which contain nitrosamines and nitrosamine precursors, had a significantly increased risk of prostate cancer risk (OR, 2.62; 95% CI, 1.13-6.06). In contrast, men with the CT+TT genotype and a low intake of preserved foods had a 69% reduction in risk (OR, 0.31; 95% CI, 0.10-0.96; P(interaction) = 0.005). These results suggest that genetic variants in the DNA repair pathways may be involved in prostate cancer etiology and that other risk factors, including preserved foods and insulin resistance, may modulate prostate cancer risk in combination with genetic susceptibility in these repair pathways. Replication in larger studies is necessary to preclude chance findings, particularly those among subgroups, and clarify the mechanisms involved.

Aged↗
PubMed2006

Association study between genetic variants at the PIP5K2A gene locus and schizophrenia and bipolar affective disorder.

Results from molecular and pharmacological studies point to involvement of the gene coding for the phosphatidylinositol-4-phosphate 5-kinase type II-alpha (PIP5K2A) in the development of schizophrenia and bipolar affective disorder (BPAD). The PIP5K2A gene locus, which is located on chromosomal region 10p12, has been implicated in the development of both disorders by independent linkage and association studies. On a cellular level, PIP5K2A is an enzyme component of the metabolism of inositol phosphate, which has been considered a potential target for the therapeutic action of lithium in BPAD patients. Given that the PIP5K2A gene is a promising candidate for the development of both disorders, we performed an association study between genetic variants at the PIP5K2A locus and 268 patients with schizophrenia, 260 patients with BPAD and 325 ethnically matched healthy controls. We failed to detect association to either disorder using PIP5K2A gene variants through single-marker and haplotype analysis. Therefore, our data does not support an involvement of the PIP5K2A locus in the etiology of either schizophrenia or BPAD in the German population.

Bipolar Disorder↗
PubMed2002

[Tuberculosis in children less than 11 years old: primary resistance and dominant genetic variants of Mycobacterium tuberculosis in Antananarivo].

Tuberculosis during childhood is often due to Mycobacterium tuberculosis primo-infection. Tuberculosis is highly prevalent in Madagascar and most people are infected during childhood. Our objectives were to evaluate the primary resistance of M. tuberculosis and to determine the genotypes responsible for recent infection in the population. Thus we studied 142 isolated strains from 97 children (66 with pulmonary tuberculosis and 31 with extra-pulmonary tuberculosis) recruited in different health centers in Antananarivo from 1997 to 2000. Excepting one strain resistant to isoniazide, all strains were susceptible to the four antibiotics (streptomycin, isoniazid, ryfampicin and ethambutol). This result confirms the low rate of primary resistance reported during the two surveys in 1994-1995 and 1999-2000. 67 strains of 1997-2000 were typed with the genetic marker IS6110, 44 has been assigned to 13 clusters containing each 2 to 8 similar strains. Some IS6110 clusters have already been reported in 1994-1995. Some genotypes observed in 1994-1995 seemed to have disappeared in 1997-2000. (As the rate of the frequency of some genetic variants according to the period are more likely due to a difference in strain virulence). Since there is minimal antibiotic resistance versus M. tuberculosis in Madagascar, one can not explain the appearance or disappearance of certain variants because of drug resistance. Rather, this is due to the virulence of the various M. tuberculosis strains.

Age Distribution↗
PubMed2000

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Adult↗
PubMed2001

Genetic variants of the tumour necrosis factor-alpha promoter gene do not influence the development of necrotizing enterocolitis.

UNLABELLED: Previous studies indicated that elevated tumour necrosis factor-alpha (TNF-alpha) levels may play a role in the development of necrotizing enterocolitis (NEC). The A(-308) and A(-238) variants of the promoter region of the TNF-alpha gene are reportedly associated with altered TNF-alpha production. The aim of our study was to determine the impact of these gene polymorphisms on the development and course of NEC in very-low-birthweight (VLBW) infants. Dried blood samples from 46 VLBW neonates with NEC were analysed using the method of restriction fragment length polymorphism. Samples from 90 VLBW neonates without NEC were used as controls. The prevalence of alleles with guanine-adenine transition in the -308 and -238 positions was the same in NEC and control subjects (12% vs 10% and 3% vs 4%, respectively). CONCLUSION: The investigated genetic variants of the TNF-alpha gene promoter region have no influence on the risk and course of NEC in VLBW infants.

Adenine↗
PubMed1984

Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence.

We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV -specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV -specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence.

Acute Disease↗
PubMed1999

A naturally occurring genetic variant in the human chorionic gonadotropin-beta gene 5 is assembly inefficient.

The hCGbeta gene family is composed of six homologous genes linked in tandem repeat on chromosome 19; the order of the genes is 7, 8, 5, 1, 2, and 3. Previous studies have shown that hCGbeta gene 5 is highly expressed during the first trimester of pregnancy. The purpose of our study was to identify naturally occurring polymorphisms in hCGbeta gene 5 and determine whether these alterations affected hCG function. The data presented here show that hCGbeta gene 5 was highly conserved in the 334 asymptomatic individuals and 41 infertile patients examined for polymorphisms using PCR followed by single stranded conformational polymorphism analysis. Most of the polymorphisms detected were either silent or located in intron regions. However, one genetic variant identified in beta gene 5 exon 3 was a G to A transition that changed the naturally occurring valine residue to methionine in codon 79 (V79M) in 4.2% of the random population studied. The V79M polymorphism was always linked to a silent C to T transition in codon 82 (tyrosine). To determine whether betaV79M hCG had biological properties that differed from those of wild-type hCG, a beta-subunit containing the V79M substitution was created by site-directed mutagenesis and was coexpressed with the glycoprotein hormone alpha-subunit in Chinese hamster ovary cells and 293T cells. When we examined betaV79M hCG biosynthesis, we detected atypical betaV79M hCG folding intermediates, including a betaV79M conformational variant that resulted in a beta-subunit with impaired ability to assemble with the alpha-subunit. The inefficient assembly of betaV79M hCG appeared to be independent of beta-subunit glycosylation or of the cell type studied, but, rather, was due to the inability of the betaV79M subunit to fold correctly. The majority of the V79M beta-subunit synthesized was secreted as unassembled free beta. Although the amount of alphabeta hCG heterodimer formed and secreted by betaV79M-producing cells was less than that by wild-type beta-producing cells, the hCG that was secreted as alphabeta V79M heterodimer exhibited biological activity indistinguishable from that of wild-type hCG.

Abortion, Spontaneous↗
PubMed2005

Genetic variants of hepatitis B virus and their clinical relevance.

Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma (HCC). Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. Evidence has been accumulating that HBV mutants are associated with certain clinical disease manifestations, may affect the natural course of the infection and confer resistance to antivirals. Naturally occurring mutations have been identified in the structural and non-structural genes as well as regulatory elements of the virus. The best characterized mutants comprise the pre-core (pre-C) stop codon mutation resulting in a loss of hepatitis B e antigen (HBeAg), defined clusters of mutations in the core promotor resulting in enhanced viral replication and mutations in the hepatitis B core and surface antigens (HBcAg and HBsAg) altering the antigenicity of the virus. More recently, several mutations in the reverse transcriptase/polymerase gene have been identified conferring resistance to antivirals used for the treatment of chronic hepatitis B. In this review, we will focus on the biological phenotype of HBV genetic variants and discuss their clinical relevance for the pathogenesis of HBV-induced liver disease.

Antiviral Agents↗
PubMed1995

Primary structure of ovine alpha s1-caseins: localization of phosphorylation sites and characterization of genetic variants A, C and D.

The primary structures of ovine alpha s1-casein variants A, C and D (formerly called Welsh variant) were determined. Separation of variants from whole casein was achieved using a fast and reliable reversed-phase HPLC method. Extended structural characterization of the purified proteins using electrospray mass spectrometry, automated Edman degradation and peptide mapping by means of HPLC-fast atom bombardment-mass spectrometry demonstrated that the mature protein was a mixture of two molecular species that differed in the deletion of residues 141-148 and were therefore 199 and 191 residues long respectively. The 199 residue peptide chain, which accounted for approximately 80% of the entire translated alpha s1-casein, was as long as its caprine and bovine counterparts, and had a 98 and 89% degree of identity with those two proteins respectively. Nine serine residues (positions 12, 44, 46, 64 to 68 and 75) were fully phosphorylated in alpha s1-casein A, whereas Ser115 and Ser41 were phosphorylated by approximately 50 and approximately 20% respectively. The differences between the three genetic variants A, C and D were simple silent substitutions, which however involved the degree to which the protein was phosphorylated. Variant C differed from variant A in the substitution Ser13-->Pro13 which determined the loss of the phosphate group on site 12 of the protein chain, SerP12-->Ser12. A further substitution, SerP68-->Asn68 caused the disappearance of both phosphate groups in the phosphorylated residues Ser64 and Ser66 in variant D; in this last casein variant there was no evidence of phosphorylation at Ser41.

Amino Acid Sequence↗
PubMed1997

Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group.

BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser447-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n = 820) with normal to mildly elevated total and LDL cholesterol levels. METHODS AND RESULTS: Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (P = .034), normal postheparin HL activity (P = .453), higher HDL cholesterol levels (P = .013), and lower triglyceride levels (P = .044) than noncarriers. The influence of the Ser447-Stop allele on LPL activity was pronounced in patients using beta-blockers (P = .042) and not significant in those not using them (P = .881), suggesting a gene-environment interaction between the Ser447-Stop mutation and beta-blockers. CONCLUSIONS: We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on beta-blockers. The LPL Ser447-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.

Adrenergic beta-Antagonists↗
PubMed2005

Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer.

BACKGROUND & AIMS: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Single nucleotide polymorphisms (SNPs) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. This study sought to identify functional SNPs in the COX-2 promoter and evaluated their effects on the risk of developing esophageal squamous cell carcinoma (ESCC). METHODS: Thirty individual DNA samples were sequenced to search for SNPs, and the function of the SNPs was examined by a set of biochemical assays. Genotypes and haplotypes were analyzed in 1026 patients and 1270 controls, and odds ratios and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: Three SNPs, -1290A-->G, -1195G-->A, and -765G-->C, were identified; the frequencies of variant alleles were 0.04, 0.51, and 0.02, respectively. The -1195G-->A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 messenger RNA levels in esophageal tissues compared with the -1195G-containing counterparts. A case-control analysis showed a 1.72-fold (95% CI, 1.35-2.20) and 2.24-fold (95% CI, 1.59-3.16) excess risk of developing ESCC for the -1195AA or -765CC genotype carriers compared with noncarriers. A greater risk of developing ESCC was observed for A(-1195)-C(-765)-containing haplotypes compared with G(-1195)-G(-765)-containing haplotypes, suggesting an interaction between the -1195G-->A and -765G-->C polymorphisms in the context of haplotype. CONCLUSIONS: These findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.

Adult↗
PubMed2003

The DNA-binding capacity of genetic variants of the bovine STAT5A transcription factor.

The STATs are a family of transcription factors. STAT5A, previously known as MGF, transduces prolactin signals to the milk protein genes. Here, we describe the detection of nucleotide sequence polymorphism in exon 16 of the bovine STAT5A gene, coding for the SH2 domain. SSCP was found in a 281-bp PCR amplified gene fragment, lying between positions 12,525 and 12,806, and encompassing parts of intron 15 and exon 16 of the bovine STAT5A gene (GenBank AJ 237937). Three SSCP patterns (genotypes) were identified in a group of 108 animals of different cattle breeds. The DNA sequencing showed that they differed by a CCT deletion at position from 12,549 in intron 15, and a T-->C substitution at position 12,743 in exon 16. The latter mutation changes an amino acid sequence in the STAT5A protein - a Val/Ala substitution at position 686. Since T-->C substitution creates a new MslI site, genetic variants in the bovine STAT5A gene can be distinguished with RFLP analysis. The frequency of alleles T and C varied between the different cattle breeds studied; the CC genotype was the least frequent and the frequency of alleles T and C was 0.842 and 0.158, respectively. Proteins were extracted from the cell nuclei of liver tissues derived from bulls of different STAT5A genotypes and subjected to EMSA in order to study if the amino acid substitution might change the DNA-binding capacity of STAT5A transcription factor. Statistically significant (p<0.05) differences in nuclear protein binding to DNA were observed between genotypes TT and CC; nuclear proteins derived from CC animals always showed less DNA protein complexing than those of TT animals. EMSA competition experiments confirmed that STAT5 transcription factors take part in the formation of the DNA-protein complexes.

Alleles↗
PubMed2005

Genetic variants of Anaplasma phagocytophilum infecting dogs in Western Washington State.

Eight dogs from western Washington State suspected of being infected with Anaplasma phagocytophilum because of the finding of morulae in peripheral blood neutrophils were studied for determination of the etiologic agent of disease. All cases were diagnosed between April 2003 and April 2004. Six of the eight dogs had no travel history during the 6 months prior to presentation. Two dogs had traveled within the Northwest United States and Canada. Fever, lethargy, and anorexia were the most common clinical signs in the dogs. Lymphopenia, thrombocytopenia, and an elevated activity of alkaline phosphatase in the serum were the most common laboratory findings. All dogs tested during the acute phase of clinical signs were seropositive for A. phagocytophilum antibodies but negative for Ehrlichia canis antibodies. PCR amplification and direct sequencing of portions of the 16S rRNA gene from the whole blood of all seven dogs that were tested yielded A. phagocytophilum after a comparison to bacterial sequences available in the GenBank database. Five genetic variants were identified based on one or two nucleotide differences in the 16S rRNA gene sequences at nucleotide positions 54, 84, 86, and 120. Individual dogs were infected with more than one variant. Treatment with doxycycline or tetracycline resulted in a rapid resolution of clinical signs. The occurrence of canine granulocytic anaplasmosis in western Washington State suggests that A. phagocytophilum infection should be considered in differential diagnoses of dogs presenting with lethargy, anorexia, fever, and lameness, particularly in the context of lymphopenia, thrombocytopenia, and increased serum alkaline phosphatase. The zoonotic importance of A. phagocytophilum should support an increase in surveillance for horses and people residing in this area.

Anaplasma phagocytophilum↗
PubMed1987

Behavioral and cytogenetic analysis of the cacophony courtship song mutant and interacting genetic variants in Drosophila melanogaster.

The courtship song of a Drosophila melanogaster male consists of tone pulses interspersed with humming sounds. An X chromosomal mutation, cacophony (cac), causes the production of polycyclic pulses readily distinguishable from those in wild type, which are mono- or bicyclic. Yet, courtship hums and flight wing beats are normal in this mutant, suggesting a specific role of the cac gene in the neural program underlying one particular feature of the fly's wing vibrations. A precise cytogenetic localization of cac is presented; this was obtained by uncovering the song abnormality with deletions that are missing all or the distal part of region 11A; the flies tested were diplo-X adults that had been turned into males by the transformer mutation. Duplications including distal 11A covered cac. The possibility of behavioral specificity for cac's effects was examined by screening a variety of sexual and nonsexual behaviors; these experiments included tests of flies in which the mutation was uncovered by a small deletion. We conclude that cac causes only a limited array of well-defined defects: longer and louder tone pulses in the song and depressed locomotor activity. Further complementation tests involving cac and other closely linked genetic variants--the night-blind-A (nbA) visual mutation, l(1)L13 lethal mutations, and a series of X chromosomal breakpoints--suggested complex interactions among these factors: the breakpoints uncover all three types of mutations; cac and nbA appear to be alleles of l(1)L13, whereas the two behavioral mutations complement each other.

Animals↗
PubMed1997

Puumala virus and two genetic variants of Tula virus are present in Austrian rodents.

Puumala and Tula viruses are hantaviruses found in Europe and are associated with the rodents Clethrionomys glareolus and Microtus arvalis, respectively. Puumala virus is associated with the human disease nephropathia epidemica. In Austria, ten clinically diagnosed cases of nephropathia epidemica, presumably caused by Puumala virus infection, have been reported but not virologically confirmed [Leschinskaya et al., 1991; Aberle et al., 1996]. To identify the hantaviruses that are present in Austria, five species of rodents were trapped and screened for virus antibodies, antigen, and RNA. Hantaviruses were detected in two species, Cl. glareolus and M. arvalis, by reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR products from Cl. glareolus tissues yielded a unique Puumala virus sequence distinct from Puumala virus sequences reported from other parts of Europe. RT-PCR products from M. arvalis tissues yielded two genetically distinct Tula virus sequences, one similar to sequences reported from Slovakia and the Czech Republic and another that appears to be a novel genetic variant of Tula virus. This is the first confirmed report of hantaviruses in Austria.

Animals↗
PubMed1988

The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins.

Covalent binding of the fourth complement protein, C4, to immune complexes is an important first step in the complement mediated processing of the complexes. Many of the initial encounters between the proteins of the complement system and antigen and antibody occur in solution, and prior to this report, studies of the interactions between them have focused on complement binding to preformed immune precipitates that most likely are not found in vivo. We have characterized the covalent binding of C4b to immunoglobulin molecules in a fluid-phase system consisting only of antibody in solution and purified C4 and C1s. We demonstrate that human C4b binds to IgG in the fluid phase, that its covalent binding is predominantly to the heavy chain of IgG, and that the covalent linkage is by either amide or acyl ester bonds. In addition, we compare the covalent binding efficiencies of two genetic variants of C4, C4A3 and C4B1, to IgG. C4A3 binds 3-4 times more IgG than C4B1 over a range of C4 concentrations, and C4A3 has a higher binding efficiency than C4B1 for IgM, IgA, IgG2a and F(ab')2 as well as for a protein antigen, BSA. Furthermore, we found that whereas C4A3 is bound to immunoglobulins in the fluid-phase predominantly by amide linkage, C4B1 is bound by either amide or acyl ester bonds. The results presented here suggest that the covalent binding efficiency of C4A3 and C4B1 to IgG is similar to that reported for their covalent binding to small molecules.

Chemical Phenomena↗
PubMed1986

Monoclonal antibodies specific for different regions of human apolipoprotein A-I. Characterization of an antibody that does not bind to a genetic variant of apoA-I (Glu----136 Lys).

Three monoclonal mouse hybridoma antibodies, designated 2AI, 4AI, and 5AI, specific for human plasma apolipoprotein A-I (apoA-I) were characterized. In an enzyme-linked immunosorbent assay (ELISA) each of the antibodies reacted with purified apoA-I and with A-I in normal human serum. Immunoblotting of apoA-I subjected to isoelectric focusing revealed that the three antibodies reacted with all the charge isomorphs of apoA-I and with proapoA-I. Using a solid phase competitive displacement assay, the antigenic determinant for antibody 5AI could be localized to cyanogen bromide fragment 3 of apoA-I (residues 113-148), while the epitope for antibody 4AI resided in cyanogen bromide fragment 4. Dot blot experiments and data obtained by the competitive displacement assay revealed that antibody 2AI reacts with high affinity with CNBr fragment 2 but that it also reacts with lower affinity with fragments 1 and 4. The antibody 5AI did not bind to a genetic variant of apoA-I (Glu----136 Lys), demonstrating that the substitution of a single amino acid in human apoA-I can cause the loss of an antigenic determinant.

Animals↗
PubMed2006

Genetic variants in epigenetic genes and breast cancer risk.

Epigenetic events, resulting changes in gene expression capacity, are important in tumour progression, and variation in genes involved in epigenetic mechanisms might therefore be important in cancer susceptibility. To evaluate this hypothesis, we examined common variants in 12 genes coding for DNA methyltransferases (DNMT), histone acetyltransferases, histone deacetyltransferases, histone methyltrasferases and methyl-CpG binding domain proteins, for association with breast cancer in a large case-control study (N cases = 4474 and N controls = 4580). We identified 63 single nucleotide polymorphisms (SNPs) that efficiently tag all the known common variants in these genes, and are also expected to tag any unknown SNP in each gene. We found some evidence for association for six SNPs: DNMT3b-c31721t [P (2 df) = 0.007], PRDM2-c99243 t [P (2 df) = 0.03] and t105413c [P-recessive = 0.05], EHMT1-g-9441a [P (2df) = 0.05] and g41451t (P-trend = 0.04), and EHMT2-S237S [P (2df) = 0.04]. The most significant result was for DNMT3b-c31721t (P-trend = 0.124 after adjusting for multiple testing). However, there were three other results with P < 0.05. The permutation-based probability of this occurring by chance was 0.335. These significant SNPs were genotyped in 75 human cancer cell lines from different tumour types to assess if there was an association between them and six epigenetic measures. No statistically significant association was found. However, a trend was observed: homozygotes for the rare alleles of the EHMT1, EHMT2 and PRDM2 had a mean value for both trimethylation of K9 and K27 of histone H3 remarkably different to the homozygotes for the common alleles. Thus, these preliminary observations suggest the possible existence of a functional consequence of harbouring these genetic variants in histone methyltransferases, and warrant the design of larger epidemiological and biochemical studies to establish the true meaning of these findings.

Adult↗