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PubMed1996

Downregulation of nitrovasodilator-induced cyclic GMP accumulation in cells exposed to endotoxin or interleukin-1 beta.

1. Induction of nitric oxide synthase (iNOS) results in overproduction of nitric oxide (NO), which may be a principal cause of the massive vasodilatation and hypotension observed in septic shock. Since NO-induced vasorelaxation is mediated via the soluble isoform of guanylate cyclase (sGC), the regulation of sGC activity during shock is of obvious importance, but yet poorly understood. The aim of the present study was to investigate the activation of sGC by sodium nitroprusside (SNP) before and after exposure of rat aortic smooth muscle cells to endotoxin (LPS) or interleukin-1 beta (IL-1 beta). 2. Exposure of rat aortic smooth muscle cells to SNP (10 microM) elicited up to 200 fold increases in cyclic GMP. This effect was attenuated by 30-70% in IL-1 beta- or LPS-pretreated cells, in a pretreatment time-and IL-1 beta- or LPS-concentration-dependent manner. When, however, cells were exposed to IL-1 beta or LPS and then stimulated with the particulate guanylate cyclase activator, atriopeptin II, no reduction in cyclic GMP accumulation was observed. 3. Pretreatment of rats with LPS (5 mg kg-1, i.v.) for 6 h led to a decrease in aortic ring SNP-induced cyclic GMP accumulation. 4. The IL-1 beta-induced reduction in SNP-stimulated cyclic GMP accumulation in cultured cells was dependent on NO production, as arginine depletion abolished the downregulation of cyclic GMP accumulation in response to SNP. 5. Reverse-transcriptase-polymerase chain reaction analysis revealed that the ratio of steady state mRNA for the alpha, subunit of sGC to glyceraldehyde phosphate dehydrogenase was decreased in LPS- or IL-1 beta-treated cells, as compared to vehicle-treated cells. 6. Protein levels of the alpha 1 sGC subunit remained unaltered upon exposure to LPS or IL-1 beta, suggesting that the early decreased cyclic GMP accumulation in IL-1 beta- or LPS-pretreated cells was probably due to reduced sGC activation. Thus, the observed decreased responsiveness of sGC to NO stimulation following cytokine or LPS challenge may represent an important homeostatic mechanism to offset the extensive vasodilatation seen in sepsis.

Animals↗

PubMed2005

Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency.

UNLABELLED: Protein S deficiency is an autosomal dominant disorder that results from mutations in the PROS1 gene. Conventional mutation detection techniques fail to detect a pathogenic PROS1 mutation in approximately 50% of cases. The present study investigates whether large deletions of PROS1 are found in families where mutations in the PROS1 gene have not been found despite sequencing. For this purpose,a dense set of SNP and microsatellite markers were used in segregation analysis to identify deletions. Large deletions were identified by this technique in three out of eight investigated families (38%). The deletions encompassed at least 35 kb, 437 kb and 449 kb respectively. The deletions were confirmed by quantitative PCR. Haplotype analysis showed that the three large deletions and the five other disease haplotypes were all different. All of the eight disease haplotypes co-segregated with protein S deficiency, but each of the five non-deletion haplotypes were present also in normal individuals. IN CONCLUSION: Large deletions of PROS1 are relatively common in protein S deficiency patients and screening for large deletions in PROS1 mutation-negative individuals are therefore warranted.

DNA Mutational Analysis↗

PubMed2006

Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene.

Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or approximately 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

Amino Acid Substitution↗

PubMed2003

Haplotypic analysis of the TNF locus by association efficiency and entropy.

BACKGROUND: To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and population-based reconstruction methods. RESULTS: We found 32 different haplotypes, of which 13 were shared between the two populations. Both populations were haplotypically diverse (gene diversity = 0.80, Gambia; 0.85, Malawi) and significantly differentiated (p < 10-5 by exact test). More than a quarter of marker pairs showed evidence of intragenic recombination (29% Gambia; 27% Malawi). We applied two new methods of analyzing haplotypic data: association efficiency analysis (AEA), which describes the ability of each SNP to detect every other SNP in a case-control scenario; and the entropy maximization method (EMM), which selects the subset of SNPs that most effectively dissects the underlying haplotypic structure. AEA revealed that many SNPs in TNF are poor markers of each other. The EMM showed that 8 of 12 SNPs (Gambia) and 7 of 12 SNPs (Malawi) are required to describe 95% of the haplotypic diversity. CONCLUSIONS: The TNF locus in the Gambian and Malawi sample is haplotypically diverse and has a rich history of intragenic recombination. As a consequence, a large proportion of TNF SNPs must be typed to detect a disease-modifying SNP at this locus. The most informative subset of SNPs to genotype differs between the two populations.

Adult↗

PubMed2002

[Research approaches in the behavioral genetics of psychiatric disorders].

Multi-factorial inheritance combines genetic and environmental effects. Each factor contributes a relatively small part to the overall phenotype. Multi-factorial multi-genetic illnesses are usually divided into two categories: 1. Continuous variation of the normal distribution--phenotypes that can be measured within the normal scale (i.e. blood pressure). A normal distribution is obtained and the mean is in the middle. 2. Multi-factorial threshold trait--a threshold separates between the existence or absence of the phenotype. The curve of distribution obtained only predicts sensitivity for the illness rather than it's existence, since the illness appears only beyond a specific threshold, which represents a specific combination of defected genes. Mental illnesses (psychoses, affective disorders and neuroses) are multi-factorial illnesses, affected at a level of approximately 50% by inheritance. These diseases are not inherited in a simple Mendelian way, and, most probably, many genes are involved. Today, there is still no biochemical or molecular marker for any of the mental illnesses, and diagnosis of patients is obtained according to behavioral accepted scales. The aim of behavioral genetics is to understand the interaction between genes and behavioral variability among individuals. Most behaviors are complex, and when a genetic influence is observed, we can not point at a single responsible gene. Behavioral genetics targets to identify multiple genes and to understand the contribution of each of them to a specific behavioral trait. Methods to study multi-gene diseases include linkage analysis, family studies, twin and adoption studies, search for candidate genes affected by drug therapy of the patients, analysis of candidate genes using knockout mice and SNP's, methods that identify the effect of specific genes on behavior by QTL, and gene expression using DNA differential display and DNA microarray chips. The present review summarizes and exemplifies these issues.

Genetics, Behavioral↗

PubMed2005

Whole genome SNP arrays using DNA derived from formalin-fixed, paraffin-embedded ovarian tumor tissue.

Array-based genotyping platforms, such as the Affymetrix mapping array, have been validated as reliable methods for obtaining high-resolution copy number and allele status information when using DNA derived from fresh tissue sources. However, the suitability of such systems for the examination of DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissues has not been tested. Therefore, we analyzed DNA derived from five matching fresh frozen and FFPE ovarian tumors for gene copy number changes and loss of heterozygosity using the Affymetrix GeneChip Human Mapping 10 K Array Xba 131. The data was analyzed using Affymetrix proprietary software, GeneChip DNA Analysis Software, and Chromosome Copy Number Tool. The average SNP call rate (rate of successful genotype identification) of the fresh samples was 89.44% (range 78.72-96.22%, median 92.72%) and was only slightly lower for the matching FFPE samples at 83.48% (range 76.93-93.17%, median 82.60%). The average concordance (rate of agreement between successful genotype calls) between the fresh and matching FFPE samples was 97.06% (range 92.70-99.41%, median 97.52%). Loss of heterozygosity (LOH) profiles of the fresh and FFPE samples were essentially identical across all chromosomes. Copy number data was also comparable, although the quantification of copy number changes appears overstated in the FFPE samples. In conclusion, we have shown that it is possible to achieve high-performance outcomes using FFPE-derived DNA in the Affymetrix 10 K mapping array. This advance will open up vast archival tissue resources to high-resolution genetic analysis and unlock a wealth of biological information.

DNA↗

PubMed2001

3rd International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis: SNPs: 'some notable progress'.

Fervent activities for the collection and exploitation of single nucleotide polymorphism (SNP) data continue, amid concerns about their real utility. The desire to understand complex disease aetiology remains a key driving force for this activity. Recent developments provided a level of cautious optimism not seen in previous International Meetings on Single Nucleotide Polymorphism and Complex Genome Analysis. The 3rd such meeting, held 8-11 September 2000 in Taos, New Mexico, covered research on technologies for SNP scoring, analytical tools for using SNPs to map disease genes, examples from researchers using SNPs for specific disease studies, and databases and tools for facilitating these activities. Studies of human history, and a range of studies upon model organisms were also represented. Whilst the transition from technology oriented work (methods, discovery, etc.) to successful biological application is occurring relatively slowly, a clear trend in this direction is now apparent, and it will surely gain momentum in future months and years. Many fundamental properties of SNPs remain unknown, and many other basic questions are still unanswered, but the field is moving forward on all necessary fronts, promising exciting advances just around the corner.

Genetic Techniques↗

PubMed2005

Evaluation of linkage disequilibrium and its effect on non-parametric multipoint linkage analysis using two high density single-nucleotide polymorphism mapping panels.

Genotype data from the Illumina Linkage III SNP panel (n = 4,720 SNPs) and the Affymetrix 10 k mapping array (n = 11,120 SNPs) were used to test the effects of linkage disequilibrium (LD) between SNPs in a linkage analysis in the Collaborative Study on the Genetics of Alcoholism pedigree collection (143 pedigrees; 1,614 individuals). The average r2 between adjacent markers across the genetic map was 0.099 +/- 0.003 in the Illumina III panel and 0.17 +/- 0.003 in the Affymetrix 10 k array. In order to determine the effect of LD between marker loci in a nonparametric multipoint linkage analysis, markers in strong LD with another marker (r2 > 0.40) were removed (n = 471 loci in the Illumina panel; n = 1,804 loci in the Affymetrix panel) and the linkage analysis results were compared to the results using the entire marker sets. In all analyses using the ALDX1 phenotype, 8 linkage regions on 5 chromosomes (2, 7, 10, 11, X) were detected (peak markers p < 0.01), and the Illumina panel detected an additional region on chromosome 6. Analysis of the same pedigree set and ALDX1 phenotype using short tandem repeat markers (STRs) resulted in 3 linkage regions on 3 chromosomes (peak markers p < 0.01). These results suggest that in this pedigree set, LD between loci with spacing similar to the SNP panels tested may not significantly affect the overall detection of linkage regions in a genome scan. Moreover, since the data quality and information content are greatly improved in the SNP panels over STR genotyping methods, new linkage regions may be identified due to higher information content and data quality in a dense SNP linkage panel.

Alcoholism↗

PubMed2003

Haplotype sharing analysis with SNPs in candidate genes: the Genetic Analysis Workshop 12 example.

Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct influence on affection and harbors more than 70 SNPs. Haplotype sharing analysis depends heavily on previous haplotype estimation. Using GENEHUNTER haplotypes, strong evidence was found for most SNPs in the isolated population sample, thus providing evidence for an involvement of this gene, but the maximum -log(10)(p) values for the haplotype sharing statistics (HSS) test statistic did not correspond to the location of the true variant in either population. In comparison, transmission disequilibrium test (TDT) analysis showed the strongest results at the disease-causing variant in both populations, and these were outstanding in the general population. In this example, TDT analysis appears to perform better than HSS in identifying the disease-causing variant, using SNPs within a candidate gene in an outbred population. Simulations showed that the performance of HSS is hampered by closely spaced SNPs in strong linkage disequilibrium with the functional variant and by ambiguous haplotypes.

Chromosome Mapping↗

PubMed2006

[Correlations between serine hydroxymethyltransferase1 C1420T polymorphisms and susceptibilities to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma].

BACKGROUND & OBJECTIVE: Serine hydroxymethyltransferase (SHMT), a key enzyme in the folate metabolism, affects gene methylation and DNA synthesis through providing one-carbon units for purine, thymidylate, and methionine. It is closely related to the development and progression of tumors. This study was to investigate the correlations between SHMT1 C1420T single nucleotide polymorphisms (SNP) and susceptibilities to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). METHODS: SHMT1 C1420T SNP was genotyped by polymerase chain reaction-confronting two-pair primers (PCR-CTPP) analysis in 584 ESCC patients, 467 GCA patients, and 540 healthy controls. The correlations between SHMT1 C1420T SNP polymorphisms and susceptibilities to ESCC and GCA were analyzed with Logistic regression model. RESULTS: Family history of upper gastrointestinal cancer (UGIC) significantly enhanced the risk of developing ESCC and GCA [the age, gender, smoking status, and family history of UGIC adjusted odds ratio (OR)=2.89, 95% confident interval (CI)=2.23-3.73; OR =1.68, 95% CI=1.28-2.23]. The frequency of 1420C/T genotype was significantly lower in ESCC and GCA patients than in healthy controls (12.0% vs. 16.5%, P<0.05; 10.9% vs. 16.5%, P<0.01). Compared with C/C genotype, C/T genotype significantly reduced susceptibilities to ESCC and GCA, with adjusted OR of 0.70 (95% CI=0.50-0.98) for ESCC and 0.55 (95% CI=0.38-0.81) for GCA. Stratification analysis showed that C/T genotype significantly reduced susceptibilities to ESCC and GCA among non-smokers, with adjusted OR of 0.54 (95% CI=0.33-0.90) for ESCC and 0.56 (95% CI=0.33-0.95) for GCA. In addition, C/T genotype significantly reduced susceptibility to GCA among individuals with or without UGIC history, with adjusted OR of 0.46 (95%CI=0.24-0.90) and 0.62 (95% CI=0.38-0.99) respectively, and reduced susceptibility to ESCC only among individuals with UGIC history, with adjusted OR of 0.51 (95% CI=0.29-0.89). CONCLUSION: SHMT1 1420C/T genotype could significantly reduce susceptibilities to ESCC and GCA among individuals from high risk areas in Hebei Province of China.

Adenocarcinoma↗

PubMed2006

Family-based association tests suggest linkage between surfactant protein B (SP-B) (and flanking region) and respiratory distress syndrome (RDS): SP-B haplotypes and alleles from SP-B-linked loci are risk factors for RDS.

Genetic variants of surfactant protein B (SP-B) have been associated with respiratory distress syndrome (RDS) in the prematurely born infant. We wished to determine linkage between RDS and SP-B single nucleotide polymorphisms (SNPs) [-18 (A/C), 1013 (A/C), 1580 (C/T), and 9306 (A/G)] or SP-B-linked microsatellite [(D2S388, D2S2232, (AAGG)n, and GATA41E01 (or D2S1331)] loci and identify susceptibility or protective alleles and haplotypes. We genotyped 132 families consisting of one or two parents and at least one child affected with RDS and performed biallelic and multiallelic family-based association test (FBAT) analysis, and extended transmission disequilibrium test (ETDT). ETDT analysis identified the microsatellite SP-B-linked loci (except D2S2232) to be linked to RDS. One allele from each of these three marker loci contributes to the risk of RDS. Multiallelic FBAT analysis detected a signal of linkage for the region of the four SNP loci. Three haplotypes within this region contribute to RDS risk. Although no other region showed significant linkage as judged by multiallelic FBAT, biallelic FBAT analysis revealed three potential susceptibility haplotypes formed by two to four loci within the SP-B and SP-B-linked microsatellite region. Each haplotype included GATA41E01, which was identified by ETDT analysis to be linked to RDS. We conclude that SP-B or SP-B-linked loci are linked to RDS and certain alleles or haplotypes are susceptibility or protective factors for the development of RDS in infants born prematurely.

Adult↗

PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗

PubMed2006

Endothelial nitric oxide gene T-786C polymorphism and subarachnoid hemorrhage in Korean population.

We aimed to elucidate whether the eNOS T-786C mutant allele is implicated in subarachnoid hemorrhage (SAH) susceptibility or vasospasm after SAH, and whether the mutant allele is differentially expressed in those with small and large ruptured aneurysms in Korean population. 136 consecutive patients diagnosed with aneurismal SAH and 113 controls were recruited. Polymerase chain reaction and direct sequencing of both strands were performed to determine genotypes with respect to the eNOS T-786C mutation. No significant difference was found between cases and controls with respect to the distributions of the two eNOS T-786C single nucleotide polymorphism (SNP) genotypes. No significant differences in the distributions of the eNOS T-786C SNP genotypes were found with regard to the sizes of ruptured aneurysms or the occurrence of vasospasm after SAH. Multiple logistic regression analysis after controlling for age and sex showed the eNOS T-786C SNP T/C geno-type was independently associated with an unfavorable outcome (GOS grade 3-5) of SAH (Exp (beta)=4.27, 95% CI 1.131-16.108, p=0.032). In conclusion, the eNOS T-786C mutation was not found to be associated with either a susceptibility to SAH or vasospasm after SAH, or with aneurysm size in Korean population. The eNOS T-786C SNP T/C genotype could be used as a prognostic marker in individuals with SAH.

Adult↗

PubMed2005

Genetic variation in the proto-oncogene SKI and risk for orofacial clefting.

BACKGROUND: SKI is a proto-oncogene that is required for development of the central nervous system and skeletal muscle, and is involved in specifying selected cranial neural-crest-derived craniofacial structures. To identify genetic variants within the SKI gene and investigate the potential association between SKI polymorphisms and risk for orofacial defects, we initially re-sequenced the gene. METHODS: DNA re-sequencing of all seven exons of the SKI gene was performed on 100 control samples. Subsequently, we genotyped 394 samples (148 CLP cases, 99 CP cases, and 147 control infants) for a novel SNP identified in the DNA re-sequencing effort using restriction fragment length polymorphism (RFLP) analysis. RESULTS: We identified one polymorphism in exon 1 of the SKI gene (257C>G) from controls. This SNP resulted in an amino acid change from alanine to glycine (A62G, GenBank Accession No. NM_003036). Among all samples genotyped by the RFLP method, variants (CG, GG) were found in 10.5% of the cases, compared to a prevalence of 17.7% in the controls. The odds ratio was calculated to be 0.6, with a 95% confidence interval (CI) of 0.3-1.0. CONCLUSION: In a population of California infants with craniofacial defects, a novel polymorphism of the SKI gene was found to be associated with a decreased risk for orofacial defects. The function of this polymorphism and how it might confer protection to the embryo against craniofacial malformations is currently under investigation in our laboratory.

Case-Control Studies↗

PubMed2026

Genetic Evidence That Stroke Causally Increases Circulating PDGFB Levels: a Two-Sample Mendelian Randomization Study.

Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood-brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance-weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95% CI 0.088 to 0.331, p = 7.3 × 10-4). A similar association was observed for ischemic stroke (β = 0.155, SE = 0.059, 95% CI 0.039 to 0.270, p = 0.009), with directionally consistent results across sensitivity analyses. MR-Egger regression for ischemic stroke initially suggested pleiotropy.After removal of a radial-MR outlier (rs2289252), the intercept was attenuated and no longer statistically significant (- 0.0190, p = 0.282). In contrast, no evidence of a causal association was found between cardioembolic stroke liability and plasma PDGFB levels across all MR methods (β = - 0.078, SE = 0.087, 95% CI - 0.248 to 0.092, p = 0.368). These findings provide genetic evidence that liability to stroke, particularly ischemic stroke, is causally associated with increased circulating PDGFB levels, whereas cardioembolic stroke does not show such an effect. This suggests that elevated PDGFB reflects vascular responses specific to ischemic stroke rather than a general consequence of all stroke subtypes.

Humans↗

PubMed2005

Linkage between I172N mutation, a marker of 21-hydroxylase deficiency, and a single nucleotide polymorphism in Int6 of CYP21B gene: a genetic study of Sardinian family.

Congenital adrenal hyperplasia (CAH) is a genetic disorder due to 21-hydroxylase deficiency. More than 90% of CAH cases are caused by mutations of CYP21B gene, most of which are the result of microconversion events between the functional gene and its pseudogene. Using a combination of RFLP and direct sequencing analysis, in this paper we describe the genetic study of a Sardinian family carrying I172N mutation in linkage with a SNP namely 1636 Int6. The characterization of new polymorphisms in CYP21B can improve the analysis of segregation of CYP21B mutated alleles especially in genetic familial studies. The analysis of linkage between specific mutations and this SNPs, especially if focused on genetic familial studies, may improve the quality of genetic analysis of 21-hydroxylase deficiency.

17-alpha-Hydroxyprogesterone↗

PubMed2003

Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs.

The multi-drug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette (ABC) superfamily of membrane transporters. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multi-drug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of various types of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and indicated that a single nucleotide polymorphism (SNP), C3435T in exon 26, which caused no amino acid change, was associated with the duodenal expression of MDR1 and thereby the plasma concentrations of digoxin after oral administration. Interethnic differences in genotype frequencies of C3435T have been clarified, and, at present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on the effects of C3435T on MDR1 expression and function in the tissues, and also on the pharmacokinetics and pharmacodynamics have been performed around the world; however, there are still discrepancies in the results, suggesting that the haplotype analysis of the gene should be included instead of SNP detection, and the design of clinical trials must be carefully planned to avoid misinterpretations. A polymorphism of C3435T is also reported to be a risk factor for a certain class of diseases such as the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this might also be explained by the effects on MDR1 expression and function. In this review, the latest reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Variable SNP density in aspartyl-protease genes of the malaria parasite Plasmodium falciparum.

An analysis of the diversity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5' flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite diversity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional diversity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the diversity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under diversifying selection, may contribute to the observed diversity. We discuss the importance of diversity and local selection effects when choosing drug targets for intervention strategies.

Animals↗