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PubMed1998

Genetic polymorphisms of the renin-angiotensin system and the outcome of focal segmental glomerulosclerosis in children.

BACKGROUND: The clinical course of primary focal segmental glomerulosclerosis (FSGS) in children is variable, with some patients having a much more rapidly progressing course than others. The purpose of our study was to compare the frequency of three polymorphisms of the renin-angiotensin system (RAS) in children with FSGS with that in healthy controls of matching ethnic groups, and to determine whether the clinical outcome of FSGS was associated with different RAS genotypes. METHODS: Three RAS genotypes were examined in 47 Jewish and Arab children with biopsy-proven primary FSGS and in a large control group: the ACE insertion/deletion polymorphism in intron 16, the M235T mutation in the angiotensinogen gene, and the A1166C in the angiotensin II type 1 receptor gene (AT1R). RESULTS: Arab patients showed a greater tendency towards progressive renal disease than their Jewish counterparts (12 of 21 vs. 9 of 26, P = 0.05) and were less likely to achieve remission (3 of 21 vs. 11 of 26, P < 0.04), despite similar clinical presentation, medical management and follow-up. The RAS allele prevalence was similar among patients and controls of matching ethnic backgrounds, and no difference in allele frequency was found between Arabs and Jews. Homozygotes for the ACE insertion genotype (II) were significantly less likely to have progressive renal disease than patients with the other genotypes (ID and DD; 0 of 6 vs. 21 of 41; P < 0.022). The other RAS polymorphisms were not associated with variations in the clinical course of childhood FSGS. CONCLUSIONS: Homozygosity for the ACE insertion allele may have a protective effect in children with FSGS and can serve as a positive prognostic indicator at diagnosis. The D allele may exert a detrimental dominant effect on outcome. Neither the ACE gene polymorphism nor the other RAS polymorphisms studied are associated with disease prevalence. The AT1R and angiotensinogen gene polymorphisms are not associated with progression of renal disease in FSGS. Ethnic differences in the clinical course of the disease are not linked to these polymorphisms.

Adolescent↗
PubMedDate not supplied

The impact of genetic polymorphisms on the protein composition of ruminant milks.

The purpose of this review is to give an overview of our current knowledge on the polymorphisms occurring in genes coding for milk proteins and responsible for quantitative variability in their expression, thus influencing the protein composition of livestock ruminant milk. The overall genomic organisation of the 6 main ruminant milk protein genes: alpha-lactalbumin, beta-lactoglobulin and the four caseins (alpha(s1), alpha(s2), beta and kappa), their chromosomal location and their expression pattern are first summarised before presenting general mechanisms controlling gene expression both at the transcriptional and the post-transcriptional levels. Polymorphisms found in cis-regulatory elements, mainly within the 5'-flanking region of the genes encoding beta-lactoglobulin and alpha(s1)- and alpha(s2)-caseins, have been found, in cattle, to influence their transcription rate. In addition, polymorphisms found in the transcription unit, within intron as well as exon sequences, have been shown to be responsible for defects in the processing of primary transcripts and/or the export of messenger RNA to the cytoplasm. Mutations responsible for the occurrence of premature stop codons in alpha(s1)- and beta-casein mRNAs have been shown to be associated both with a decrease in the level of the relevant transcripts and the existence of multiple forms of messengers due to alternative splicing (exon skipping, usage of cryptic splice sites). Such a situation, well-exemplified by the gene encoding alpha(s1)-casein in the goat, may have dramatic biological consequences (secretion pathway, casein micelle structure, fat content, etc.) by modifying the message and accordingly the primary structure of the protein as well as its expression. Since some of these polymorphisms dramatically affect technological properties of milk, including cheese yields and organoleptic characteristics, methods mainly based on the PCR technique have been designed and applied in selection and breeding programmes to improve milk protein quality.

Animals↗
PubMed2002

Plasminogen activator inhibitor-1 4G/5G genetic polymorphism does not affect peritoneal transport characteristic.

There is evidence that type 1 plasminogen activator inhibitor (PAI-1) may have an important role in peritoneal function. We studied the effect of physiologically relevant PAI-1 promotor polymorphisms on peritoneal permeability. We performed a standard peritoneal equilibration test (PET) in 100 new continuous ambulatory peritoneal dialysis (CAPD) patients. We studied another 48 prevalent CAPD patients who had a baseline PET performed 2 years before; a standard PET was repeated on enrollment. The PAI-1 promotor polymorphism was examined. All patients then were followed up for 16.7 +/- 15.0 months. Prevalences of 4G/4G, 4G/5G, and 5G/5G genotypes were 31.8%, 46.6%, and 21.6%, respectively. Of the 100 new CAPD patients, there was no difference in net ultrafiltration (UF), dialysate-plasma (D/P) creatinine ratio at 4 hours, or mass transfer area coefficient (MTAC) of creatinine among the three genotype groups. D/P creatinine ratios at 4 hours were 0.595 +/- 0.133, 0.607 +/- 0.137, and 0.627 +/- 0.142 for the 4G/4G, 4G/5G, and 5G/5G groups, respectively (one way analysis of variance, P = 0.715). Of the 48 prevalent patients, PAI-1 genotype did not affect the longitudinal change in net UF, D/P creatinine ratio at 4 hours, or MTAC of creatinine. During follow-up, 16 patients developed peritonitis episodes that required Tenckhoff catheter removal. One patient died, 8 patients returned to long-term CAPD therapy after peritonitis resolved, and the other 7 patients developed peritoneal failure and were switched to long-term hemodialysis therapy. PAI-1 promotor genotype did not predict peritoneal failure after an episode of severe peritonitis (chi-square test, P = 0.328). We conclude that PAI-1 promotor polymorphism is not associated with peritoneal transport characteristics in stable peritoneal dialysis patients, longitudinal change in peritoneal transport, or development of peritoneal failure after an episode of severe peritonitis.

Biological Transport↗
PubMed2002

Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study.

Interferon alfa (IFN-alpha) therapy remains a mainstay of treatment in active hepatitis B. However, sustained remission rates remain relatively low, and the search for factors important for response to therapy continues. Our study aimed to identify the host single nucleotide polymorphisms (SNPs) that predict IFN response in hepatitis B patients. We selected genes in the IFN pathway involved in antiviral and signaling activities and sequenced 22 SNPs for each of our 82 patients. Our results identified 2 SNPs in the antiviral pathway that may influence IFN response. One SNP in the regulatory region of the eIF-2alpha gene revealed A/G alleles. The rate of A/G heterozygotes is 22% in nonresponders (NR) and 2% in sustained responders (R), with an odds ratio (OR) of 12.82 (95% CI: 1.52-107.85, P =.009). After adjustment for age, sex, and HBV DNA level, the OR reaches 14.94 (95% CI: 1.45-153.71, P =.023). This marker revealed greater significance than HBV DNA levels (OR: 5, 95% CI: 1.01-2.43, P =.033) as a marker for IFN response, suggesting its potential advantage over conventional predictors. In addition, borderline significance for the SNP in MxA gene promoter at nt -88 revealed G/T alleles, with the G/T heterozygote rate being 19% in nonresponders and 43% in sustained R (P =.061), concurring with a previous study involving hepatitis C patients. In conclusion, this pilot identified SNPs as potential markers that could predict hepatitis B patient response. These observations may help guide future large-scale studies in examining host SNPs for their clinical utility in predicting IFN response.

Adult↗
PubMed2000

Serum arylesterase/diazoxonase activity and genetic polymorphisms in patients with type 2 diabetes.

Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidation of low-density lipoprotein (LDL) in vitro, suggesting that PON1 protects against atherosclerosis. We detected 3 polymorphisms of the PON1 gene and investigated PON1 enzyme activities as paraoxonase (PON), arylesterase (ARYL) and diazoxonase (DIAZ), and serum PON1 concentration in 106 patients with type 2 diabetes and 161 control subjects. All 3 enzyme activities and specific activities of PON1 in diabetic patients were significantly lower than those in controls, while there was no difference in serum PON1 concentration between the patient and control groups. The specific activities of PON, ARYL, and DIAZ in patients were 6.82 +/- 3.14 nmol x min(-1) x U(-1) (mean +/- SD, U; unit for serum PON1 concentration), 4.77 +/- 0.17 micromol x min(-1) x U(-1), and 193 +/- 92 nmol x min(-1) x U(-1), respectively, whereas those in controls were 9.33 +/- 3.92 nmol x min(-1) x U(-1), 5.36 +/- 0.14 micromol x min(-1) x U(-1), and 242 +/- 103 nmol x min(-1) x U(-1), respectively. There was no significant difference in the allelic frequencies of -108C/T, 55L/M, or 192Q/R between the patient and control groups. When each enzyme activity was compared between the patient and control groups in each genotype subgroup, all activities were lower in the patient group. The PON and ARYL activities were lower in patients with retinopathy or nephropathy than in those without such complications, and the ARYL activity was also lower in patients with neuropathy. In conclusion, all specific enzyme activities of PON1 were lower in patients with type 2 diabetes independent of the -108C/T, 55L/M, or 192Q/R polymorphism, and this impaired PON1 function may be involved in development of diabetic microangiopathy.

Aged↗
PubMed2001

Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population.

To investigate APOE gene--environment interaction effects on plasma lipid concentrations, we conducted a cross-sectional study in a Mediterranean Spanish population consisting of 396 men and 513 women aged 18 to 66 years. The frequency of the epsilon 4 variant was 0.071 (95% confidence interval 0.059, 0.082), confirming the lower frequency of this allele in Southern Europe. In general, the carriers of the epsilon 2 variant had lower concentrations (P <.05) of total and low-density lipoprotein cholesterol (LDL-C), carriers of the epsilon 3 variant had intermediate concentrations, and carriers of the epsilon 4 variant had higher concentrations (P <.05) in both sexes, even after multivariate adjustment for age, body mass index, alcohol consumption, tobacco smoking, physical activity, marital status, and education. However, when the homogeneity of allelic effects according to environmental factors was tested, significant interaction terms were found. In women, an important interaction between alcohol consumption and the APOE polymorphism in determining LDL-C concentrations was found (P <.003). LDL-C concentrations in female drinkers with the epsilon 2 variant were significantly lower (P <.014) than in nondrinkers with the epsilon 2 variant. Likewise, in female drinkers with the epsilon 4 variant, LDL-C concentrations were also significantly (P <.010) lower than in nondrinkers with the epsilon 4 variant. Moreover, in female drinkers, LDL-C concentrations did not differ between carriers of the epsilon 4 and the epsilon 3 variants, and in nondrinkers, LDL-C concentrations did not differ between carriers of the epsilon 2 and the epsilon 3 variants. We also found a statistically significant interaction effect (P <.001) between the APOE polymorphism and physical activity in determining high-density lipoprotein cholesterol concentrations in men. Our results indicate that environmental factors are important modulators of the effect of the APOE polymorphism on plasma lipid concentrations.

Adolescent↗
PubMed1998

Genetic polymorphisms and risk of coronary artery disease.

The fact that certain ethnic groups and specific populations residing in certain geographic areas carry an increased risk for thrombosis and that thrombosis occurs in young patients without established risk factors indicates the presence of new, previously unrecognized inherited conditions predisposing to thrombosis. We are now aware that interindividual variations within the loci coding for proteins relevant to lipid and vascular metabolisms as well as blood coagulation are universally found. Platelets play central roles in cerebrovascular diseases and acute coronary syndromes, as demonstrated by histopathological findings and clinical observations showing the efficacy of antiplatelet therapies for these disorders. In this article, we show our recent findings on the association between coronary artery disease (CAD) and polymorphisms in platelet membrane glycoproteins. The glycoprotein (GP) Ib/IX complex is a receptor for von Willebrand factor, which mediates shear stress-dependent platelet activation. It has recently been implicated in the pathogenesis of acute coronary syndromes. We have determined genotypes of the "size-polymorphism" of GPIb alpha--i.e., the variable number (1-4) of a 13 amino acid sequence (399-411)--in angiographically proven Japanese CAD patients with myocardial infarction or angina pectoris as well as in individuals from the general population with no history of angina or other heart diseases and normal resting electrocardiograms (ECG). We have found that the genotypes having at least one 4-repeat allele (4R) are more frequently found in patients than in controls. Logistic regression analyses for the adjustment of age, sex, and other acquired coronary risk factors provided an odds ratio of 7.94 (p=0.0043) for those with 4R vs. those without 4R, suggesting that the presence of 4R is an independent risk factor for CAD. The molecular mechanisms underlying this association are currently under investigation. Relationships between arterial thrombosis and polymorphisms in other platelet GPs (collagen receptor and fibrinogen receptor), blood coagulation factors, fibrinolytic factors, vasoactive substances, and factors relevant for lipid metabolisms are also discussed.

Adult↗
PubMed2001

Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19.

BACKGROUND: Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. METHODS: The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. RESULTS: The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. CONCLUSION: Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers.

Adult↗
PubMed2001

Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19.

OBJECTIVE: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylation. METHODS: A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction-based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron-capture detection. RESULTS: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC(0-infinity)) values (983.6 +/- 199.3 microg x h/L versus 697.6 +/- 133.0 microg x h/L; P <.05) and terminal elimination half-life values of sertraline (35.5 +/- 5.6 hours versus 23.5 +/- 4.4 hours; P <.01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3 +/- 19.4 L/h) was significantly lower than that of extensive metabolizers (148.4 +/- 28.6 L/h). The area under the concentration-time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6 +/- 203.8 microg x h/L versus 972.1 +/- 270.3 microg x h/L; P <.05; and 23.6 +/- 6.5 nmol/L versus 32.4 +/- 8.2 nmol/L; P <.01; respectively). CONCLUSIONS: The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.

Administration, Oral↗
PubMed2006

Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: two ways to promote multifunctionality.

Calcium signaling pathways control a variety of cellular events such as gene transcription, protein phosphorylation, nucleotide metabolism, and ion transport. These pathways often involve a large number of calcium-binding proteins collectively known as the calmodulin or EF-hand protein superfamily. Many EF-hand proteins undergo a large conformational change upon binding to Ca(2+) and target proteins. All members of the superfamily share marked sequence homology and similar structural features required to sense Ca(2+). Despite such structural similarities, the functional diversity of EF-hand calcium-binding proteins is extraordinary. Calmodulin itself can bind >300 different proteins, and the many members of the neuronal calcium sensor and S100 protein families collectively recognize a largely different set of target proteins. Recent biochemical and structural studies of many different EF-hand proteins highlight remarkable similarities and variations in conformational responses to the common ligand Ca(2+) and their respective cellular targets. In this review, we examine the essence of molecular recognition activities and the mechanisms by which calmodulin superfamily proteins control a wide variety of Ca(2+) signaling processes.

Animals↗
PubMed2002

Mismatch-targeted transposition of Mu: a new strategy to map genetic polymorphism.

Phage Mu DNA transposes to duplex target DNA sites with limited sequence specificity. Here we demonstrate that Mu transposition exhibits a strong target site preference for all single-nucleotide mismatches. This finding has implications for the mechanism of transposition and provides a powerful tool for genomic research. A single mismatch could be detected as a preferred target of Mu transposition in the presence of 300,000-fold excess of nonmismatched sites. We demonstrate the detection of both heterozygous and homozygous mutations in the cystic fibrosis transmembrane conductance regulator gene and single nucleotide polymorphism in HLA region by Mu transposition mismatch analysis procedure.

Bacteriophages↗
PubMed1969

Genetic polymorphism of rhesus thyroxine-binding prealbumin: evidence for tetrameric structure in primates.

Polymorphism in primate thyroxine-binding prealbumin was investigated with agarose gel electrophoresis at pH 8.6. In the rhesus monkey (Macaca mulatta), three forms of this protein were found in random sera: a single rapidly migrating band similar to that in human and other primate sera, a single slowly migrating band cathodal to rhesus albumin, and a five-banded form, the most rapid and slowest bands of which corresponded to the other two forms. The frequencies of occurrence of these three forms were consistent with the hypotheses that rhesus prealbumin is under the control of two codominant autosomal alleles, PA(F) and PA(S), and that the protein occurs naturally in serum as a tetramer composed of similar subunits.It was possible, by simple mixing in vitro, to produce five-banded prealbumin patterns from rhesus PA SS serum and rhesus PA FF serum, M. arctoides serum, P. hamadryas serum, and human serum. Thyroxine was bound by all the hybrid molecules produced in this fashion.

Alleles↗
PubMed1976

Genetic polymorphism of IgD-like cell surface immunoglobulin in the mouse.

Lymphocyte surface antigens from spleen cells of several mouse strains were studied by cell surface radioiodination, extraction with detergent incubation with various antisera, and separation of complexes using protein A-containing staphylococci as a solid phase adsorbent. Complexes were then dissociated and analyzed by polyacrylamide gel electrophoresis in the presence of sodium diodecyl sulfate. Using this technique and an alloantiserum prepared in C57BL mice against CBA spleen cells, four distinct specific peaks of radioactivity were found with CBA spleen cells. These corresponded to H-2 and Ia antigens, immunoglobulin light chain, and a heavy chain previously proposed to be the murine homolog of the human delta chain. With the same serum, B10.BR spleen cells revealed only H-2 and Ia antigens, whereas C57BL.Ige (allotype congenic) spleen cells showed only the light chain and "delta" chain peaks. Depletion of immunoglobulin from the surface-iodinated preparations resulted in removal of the light chain and "delta" chain peaks. The tissue distribution and membrane expression of this "delta" chain antigen was then studied by indirect immunofluorescence with various C57BL derived alloantisera and lymphoid cells from C57.Ige allotype congenic mice. Significant numbers of positive cells were found in spleen, lymph nodes, and Peyer's patches, whereas few if any positive were found in bone marrow or thymus. No reaction was found between this molecule and alloantisera to any of the previously described immunoglobulin allotypes. It is proposed that these alloantisera to spleen cells recognise one allelic form of the murine "delta" chain coded for by a gene locus closely linked to the known structural genes for mouse immunoglobulin heavy chains. The designation Ig-5 is proposed for this new immunoglobulin heavy chain locus.

Animals↗
PubMed1996

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Two isoforms of the human growth hormone receptor (hGHR), which differ in the presence (hGHRwt) or absence (hGHRd3) of exon 3, are expressed in the placenta. Specifically, three expression patterns are observed: only hGHRwt, only hGHRd3, or an approximately 1:1 combination of both isoforms. We investigated several potential regulatory mechanisms which might account for the expression of the hGHR isoforms. The frequency of hGHRd3 expression did not change when placentas from differing stages of gestation were examined, suggesting splicing was not developmentally regulated. However, when hGHR isoform expression patterns were examined in each component of a given placenta, it was evident that alternative splicing of exon 3 is individual-specific. Surprisingly, the individual-specific regulation of hGHR isoforms appears to be the result of a polymorphism in the hGHR gene. We analyzed hGHRwt and hGHRd3 expression in Hutterite pedigrees, and our results are consistent with a simple Mendelian inheritance of two differing alleles in which exon 3 is spliced in an "all-or-none" fashion. We conclude the alternative splicing of exon 3 in hGHR transcripts is the result of an unusual polymorphism which significantly alters splicing of the hGHR transcript and that the relatively high frequency (approximately 10%) of homozygous hGHRd3 expression suggests the possibility it may play a role in polygenic determined events.

Alleles↗
PubMed2000

Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms.

Human soluble epoxide hydrolase (sEH), an enzyme directing the functional disposition of a variety of endogenous and xenobiotic-derived chemical epoxides, was characterized at the genomic level for interindividual variation capable of impacting function. RNA was isolated from 25 human liver samples and used to generate full-length copies of soluble epoxide hydrolase cDNA. The resulting cDNAs were polymerase chain reaction amplified, sequenced, and eight variant loci were identified. The coding region contained five silent single nucleotide polymorphisms (SNPs) and two variant loci resulting in altered protein sequence. An amino acid substitution was identified at residue 287 in exon 8, where the more common arginine was replaced by glutamine. A second variant locus was identified in exon 13 where an arginine residue was inserted following serine 402 resulting in the sequence, arginine 403-404, instead of the more common, arginine 403. This amino acid insertion was confirmed by analyzing genomic DNA from individuals harboring the polymorphic allele. Slot blot hybridization analyses of the liver samples indicated that sEH mRNA steady-state expression varied approximately 10-fold. Transient transfection experiments with CHO and COS-7 cells were used to demonstrate that the two new alleles possess catalytic activity using trans-stilbene oxide as a model substrate. Although the activity of the glutamine 287 variant was similar to the sEH wild type allele, proteins containing the arginine insertion exhibited strikingly lower activity. Allelic forms of human sEH, with markedly different enzymatic profiles, may have important physiological implications with respect to the disposition of epoxides formed from the oxidation of fatty acids, such as arachidonic acid-derived intermediates, as well in the regulation of toxicity due to xenobiotic epoxide exposures.

Alleles↗