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At least 235 records · Page 13Linked to original sources
PubMed2007

TSP1 and MMP9 genetic variants in sporadic prostate cancer.

Angiogenesis plays an important role in the initiation and progression of many malignancies including prostate cancer (PCa). Therefore, genes implicated in angiogenic pathways could be susceptibility candidate genes for this malignancy. In this respect, we investigated the impact of functional genetic variants of TSP1 (N700S) and MMP9 (-1562 C/T) genes on the development and progression of PCa. This case-control study included 101 PCa patients and 106 healthy controls analyzed by polymerase chain reaction -restriction fragment length polymorphism assay. No association was observed between any of the TSP1 genotypes and PCa risk or severity; however, subjects carrying one copy of the MMP9 T allele exhibited threefold higher risk of developing PCa (OR = 2.86; P = 0.004). Regarding prognostic value, a significant association was found between the occurrence of the MMP9 T allele and the high-grade tumor (OR = 3.21; P = 0.004) and the advanced disease (OR = 2.47; P = 0.026). We also analyzed the effect of the combined genotypes on PCa risk. The patients with two high-risk genotypes exhibited 2.8-fold higher risk of developing PCa than those with only low-risk genotypes, but the association was not statistically significant. These findings suggest that MMP9 polymorphism is an independent risk factor of PCa development and aggressiveness.

Adenocarcinoma↗
PubMed1990

Binding of warfarin, salicylate, and diazepam to genetic variants of human serum albumin with known mutations.

Possible effects of single point mutations on the ligand-binding capabilities of human serum albumin (Alb) were investigated by studying the interactions between the strongly bound drugs warfarin, salicylate, and diazepam and five structurally characterized genetic variants of the protein. Equilibrium dialysis data, obtained with the variants and normal serum Alb, revealed pronounced reductions in high affinity binding of all three ligands to Alb Canterbury (313 Lys----Asn) and to Alb Parklands (365 Asp----His). By contrast, unchanged binding of the drugs was found in the case of Alb Verona (570 Glu----Lys). Different effects on binding were observed for the other two variants. Salicylate was the only drug bound with a lower affinity to Alb Niigata (269 Asp----Gly), whereas binding of both salicylate and diazepam to Alb Roma (321 Glu----Lys) were moderately reduced. In about half of the cases of diminished binding, the primary association constant was reduced by 1 order of magnitude, giving rise to an increase in the unbound fraction of the drugs of 500% or more at therapeutically relevant molar ratios of drug and protein. Changes in protein charge seem to be of only minor importance for reduced binding. More likely, conformational changes in the 313-365 region of the proteins are the main cause for diminished binding of these diverse ligands, which probably have different high affinity binding sites. The specific reduction in salicylate binding after modification of residue 269 may be due to conformational changes at or close to the salicylate binding site.

Binding Sites↗
PubMed2024

Genetic variants reduced POPs-related colorectal cancer risk via altering miRNA binding affinity and m6A modification.

Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC-MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m6A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.

Humans↗
PubMed2007

Effect of genetic variants of CCR2 and CCL2 on the natural history of HIV-1 infection: CCL2-2518GG is overrepresented in a cohort of Spanish HIV-1-infected subjects.

BACKGROUND AND OBJECTIVES: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection, although data are inconsistent. Our aim was to determine whether functionally active CCR2 and CCL2 genetic variants influence the risk of infection and disease progression in a cohort of white Spaniards. PATIENTS AND METHODS: This was a multicenter genetic association case-control study. Two single nucleotide polymorphisms (SNPs), V64I (G > A) of the CCR2 gene and -2518 (A > G) of the CCL2 gene, were assessed in 318 individuals: 73 HIV-1-infected long-term nonprogressors (LTNPs) of >16 years duration, 109 HIV-1-infected usual progressors (UPs), 36 heavily exposed to HIV-1 but uninfected individuals (EUs), and 100 control subjects. The distribution of the CCR5Delta32 allele was also assessed. Genotyping was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) or PCR and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared by the chi2 test and the Fisher exact test. RESULTS: CCR2 genotype distribution and allele frequencies showed nonsignificant differences between groups. The distribution of CCL2 alleles showed no significant differences between groups. HIV-1-infected individuals had, however, a significantly higher prevalence of the variant homozygous CCL2 GG genotype compared with EUs (P = 0.02). This result persisted when we studied only individuals with wild-type CCR5. Genotype and allele distribution of CCL2 was similar in HIV-1-infected UPs and LTNPs. CONCLUSIONS: In our cohort of white Spaniards, homozygosity for the variant CCL2-2518GG genotype is overrepresented in HIV-1-infected subjects.

Adult↗
PubMed1992

Genetic variants of alpha 1-antitrypsin and hemoglobin typed by isoelectric focusing in preselected narrow pH gradients with PhastSystem.

In this method for automatically running and staining isoelectric focusing (IEF) gels, pre-made dehydrated polyacrylamide gels were rehydrated before assays run with the PhastSystem (Pharmacia LKB Biotechnology). The typing of genetic variants of hemoglobin and alpha 1-antitrypsin in narrow pH gradients (pH 6.7-7.7 and 4.2-4.9, respectively) was simple, convenient, and reproducible. The clinically important variants of alpha 1-antitrypsin (ZZ and SZ) were identified from serum or dried blood on filter paper. The fast screening of abnormal hemoglobin samples (HbS) for cases in clinical medicine was easily performed. The total analysis time for the phenotyping with conventional protein staining was approximately 60 min.

Genetic Variation↗
PubMed2004

Genetic variants for chick biology research: from breeds to mutants.

The availability of the draft sequence of the chicken genome will undoubtedly propel an already important vertebrate research model, the domestic chicken, to a new level. This review describes aspects of chicken natural history and cross-disciplinary biological value. The diversity of extant genetic variants available to researchers is reviewed along with institutional stock locations for North America. An overview of the problem of lack of long-term stability for these resources is presented.

Animals↗
PubMed2003

Genetic variants of WNK4 in whites and African Americans with hypertension.

Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P=0.027) or without (P=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Africa↗
PubMed1995

Genetic variants of human serum albumin: molecular defects and biological stability.

Because of recent studies, more heritable structural variants of serum albumin are known than for any other human protein except haemoglobin. However, alloalbumins are benign and thus they are detected only by screening of blood proteins in studies of population genetics or during routine clinical electrophoresis. We report the results of a collaborative study undertaken on genetic variants to define the structural changes and correlate these with the molecular properties of albumin. Our strategy consists in CNBr cleavage of the alkylated purified variants followed by isoelectric focusing (IEF) analysis to identify the fragment in which the substitution occurs. The abnormal peptide is then purified and digested with trypsin or V8 protease. A map of the digests is obtained by Rp-HPLC, the variant peptide is purified, and its amino-acid composition and sequence are determined. This procedure has so far allowed the identification of the molecular defects in 20 among the 26 alloalbumins detected in Italy. In the present study the mutations of the characterized variants are correlated with their frequency, geographic distribution, and biological stability. Point mutations, with only a few exceptions which are discussed, do not affect the stability of the protein. Alterations at the N-terminal, as in the case of proalbumins or Arg-Albumin, and extensive modifications at the C-terminal of the molecule, as well as changes involving the disulfide bridges, reduce the amount of the circulating protein.

Drug Stability↗
PubMed2002

Genetic variants of the receptors for thromboxane A2 and IL-4 in atopic dermatitis.

Thromboxane A2 (TXA2) is an arachidonate metabolite which is considered to relate to chronic inflammation in atopic diseases characterized by elevated immunoglobulin E productivity. The elevation of immunoglobulin E levels involves many molecules including interleukin-4 (IL-4) and interleukin-4 receptor alpha chain (IL-4R alpha). To assess whether genetic variants of TXA2 receptor, IL-4 and IL-4R alpha genes relate to the elevation of serum immunoglobulin E levels in patients with atopic dermatitis (AD), we conducted an association study of genetic polymorphisms of TXA2 receptor (795C/T), IL-4 (-589C/T), and IL-4R alpha (Ile50Val) in a Japanese population (n = 789). The TXA2 receptor 795TT genotype strongly related to AD with high serum immunoglobulin E concentrations. AD patients with both TXA2 receptor 795TT genotype and the IL-4R alpha Ile50/Ile50 genotype showed the greatest immunoglobulin E concentrations. These results suggest TXA2 receptor polymorphism strongly interacts with IL-4R alpha polymorphism as a major determinant of high serum immunoglobulin E levels in AD.

Adolescent↗
PubMed2004

Microstructure and rheology of an acid-coagulated cheese (Karish) made with an exopolysaccharide-producing Streptococcus thermophilus strain and its exopolysaccharide non-producing genetic variant.

The objective of this research was to determine the effect of exopolysaccharide (EPS) production by lactic acid bacteria on the microstructure and rheology of Karish cheese, a soft acid coagulated cheese made using skim milk. An EPS-producing strain of Streptococcus thermophilus, and its EPS non-producing genetic variant were used to make comparable batches of the cheese. EPS in cheese was visualized by cryo-SEM as a large, dense, filamentous mass. Cheese made with the EPS non-producing culture was characterized by a dense protein network with smaller pores compared to that prepared with the EPS-producing culture. High elastic and viscous moduli measured by dynamic rheology were observed for EPS negative cheese and was attributed to its dense protein network. Creep test experiments demonstrated that cheese prepared with the EPS non-producing strain was more rigid and recovered its deformation, while cheese made using the EPS producing culture was more deformable. These results indicate that EPS-producing cultures can improve the physical properties of Karish cheese by reducing undesirable rigidity.

Cheese↗
PubMed2000

DNA technology for the detection of common genetic variants that predispose to thrombophilia.

With the identification of common single locus point mutations as risk factors for thrombophilia, many DNA testing methodologies have been described for detecting these variations. Traditionally, functional or immunological testing methods have been used to investigate quantitative anticoagulant deficiencies. However, with the emergence of the genetic variations, factor V Leiden, prothrombin 20210 and, to a lesser extent, the methylene tetrahydrofolate reductase (MTHFR677) and factor V HR2 haplotype, traditional testing methodologies have proved to be less useful and instead DNA technology is more commonly employed in diagnostics. This review considers many of the DNA techniques that have proved to be useful in the detection of common genetic variants that predispose to thrombophilia. Techniques involving gel analysis are used to detect the presence or absence of restriction sites, electrophoretic mobility shifts, as in single strand conformation polymorphism or denaturing gradient gel electrophoresis, and product formation in allele-specific amplification. Such techniques may be sensitive, but are unwielding and often need to be validated objectively. In order to overcome some of the limitations of gel analysis, especially when dealing with larger sample numbers, many alternative detection formats, such as closed tube systems, microplates and microarrays (minisequencing, real-time polymerase chain reaction, and oligonucleotide ligation assays) have been developed. In addition, many of the emerging technologies take advantage of colourimetric or fluorescence detection (including energy transfer) that allows qualitative and quantitative interpretation of results. With the large variety of DNA technologies available, the choice of methodology will depend on several factors including cost and the need for speed, simplicity and robustness.

DNA↗
PubMed2006

Genetic variants of the vitamin D receptor gene alter risk of cutaneous melanoma.

Sunlight causes DNA damage but also induces production of vitamin D whose metabolite 1,25-(OH)2D3 has antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma (CM) cells mediated through the vitamin D receptor (VDR). We hypothesized that genetic polymorphisms of VDR are associated with risk of CM. In a hospital-based case-control study of 602 non-Hispanic white CM patients and 603 cancer-free control subjects frequency matched by age and sex, we genotyped two VDR polymorphisms (TaqI and FokI) and assessed their association with CM risk. We found that a significantly decreased risk was associated with VDR-TaqI Tt (adjusted odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90) and Tt+tt (OR=0.70; 95% CI, 0.55-0.89) genotypes, compared with the VDR-TaqI TT genotype, whereas an increased risk was associated with VDR-FokI Ff genotype (OR=1.32; 95% CI, 1.03-1.68), and a borderline significantly increased risk was associated with Ff+ff (OR=1.26; 95% CI, 1.00-1.59) genotypes, compared with the VDR-FokI FF genotype. In conclusion, genetic variants (i.e., TaqI t protective allele and FokI f risk allele) in VDR may alter risk of CM.

Alleles↗
PubMed2006

Genetic variants of the NOTCH3 gene in migraine--a mutation analysis and association study.

Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Exons 3 and 4 are mutation hotspots. Migraine is a clinical hallmark of CADASIL. The objective of this study was to investigate whether genetic variants in exons 3 and 4 of the NOTCH3 gene are associated with migraine. Exons 3 and 4 of the NOTCH3 were analysed for mutations and polymorphisms by direct DNA sequencing in 97 migraineurs and the same number of control individuals. No mutations in exons 3 and 4 of the NOTCH3 gene were found in 97 patients with migraine. However, association analysis revealed significant association of the single nucleotide polymorphism (SNP) rs1043994 with migraine.

Adolescent↗
PubMed1998

Role of genetic variants of the renin-angiotensin system in chronic renal allograft injury.

In the the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time, often termed as "chronic rejection" or "chronic allograft injury." Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may play an important role in this complex syndrome. There is currently little hope that the responsible genes can be identified through sib-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears the only feasible approach. Thus far, studies have focused mainly on the role of functional genetic variants of the renin-angiotensin system on renal allograft funding. These studies, however, have not identified these variants as important determinants of renal allograft survival. Clearly, future studies will have to address the role of other variants of this system as well as genes encoding for other systems deemed to be of pathophysiological significance for the development and progression of chronic transplant injury.

Angiotensinogen↗
PubMed1998

Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.

BACKGROUND: Pathways involved in androgen metabolism have been implicated in the etiology of prostate cancer. The goal of this study was to evaluate the effect of CYP3A4, a gene associated with the oxidative deactivation of testosterone, on the clinical presentation of prostate cancers. METHODS: A polymerase chain reaction-based approach was used to identify sequence variants of the human CYP3A4 gene. To ascertain whether allelic variants of the CYP3A4 gene were associated with tumor stage and grade and age of the patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men with incident prostate cancer. RESULTS: We identified a novel genetic variant (CYP3A4-V) that has an altered 5' regulatory element, containing an A to G mutation, upstream of the CYP3A4 gene. We then compared clinical characteristics of prostate cancers in men who did and did not carry this variant. The presence of the CYP3A4-V allele was associated with a higher tumor-lymph node-metastasis (TNM) stage and Gleason grade. The association between CYP3A4 genotype and tumor stage was most pronounced in men diagnosed at a relatively old age who reported no family history of prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17; chi2(1) = 12.28; two-sided P<.001). CONCLUSIONS: We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.

Adult↗
PubMed2004

APOBEC3G genetic variants and their influence on the progression to AIDS.

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.

APOBEC-3G Deaminase↗
PubMed2001

Immunological characterization of human luteinizing hormone with special regard to a common genetic variant.

Immunoassays are widely used for measuring gonadotropins, including luteinizing hormone (LH), as these are both specific and sensitive. Because LH is microheterogeneous it has been claimed that the specificity of monoclonal antibodies used in two-site immunoassays can limit their clinical utility. Furthermore, we reported earlier a common genetic variant form of LH due to amino acid alterations in the LHbeta gene that is poorly or not recognized by antibodies directed against epitopes present in the intact molecule. We here report the result of an LH epitope mapping using 30 different monoclonal antibodies. The antigenic area affected by the amino acid alterations is fairly large, as antibodies to the two intact domains are able to sandwich each other. Combinations of alpha-beta or beta-beta antibodies generally provide alternatives for unbiased detection of circulating LH and some have reasonably good discrimination of human chorionic gonadotropin. The beta-beta combinations exhibit a peculiarity in urine determinations as they detect the urinary beta-core fragment. Our aims were to study the altered immunoreactivity caused by the amino acid changes and to design two-site LH assays fully capable of recognizing the biologically active LH variant. We also conclude that the variability in recognizing the universally occurring LH variant is the most important factor contributing to the widely documented LH immunoassay discrepancies.

Antibodies, Monoclonal↗