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PubMed1999

Ototoxicity of sodium nitroprusside is not due to nitric oxide.

Sodium nitroprusside (SNP) has been used as a donor for nitric oxide (NO) to study the effects of NO on the mammalian cochlea. In the present study, we set out to determine whether NO was the chemical responsible for the ototoxic effects seen after the application of SNP at the round window membrane of the adult guinea pig cochlea. In the first instance, NO released from S-nitrosocysteine, a compound not related to cyanide, has no toxic effect on the hair cells of the cochlea. Light-exposed SNP that could no longer produce NO, light-exposed SNP to which acetylcysteine (ATC) or hydroxycobalamin (HCL) was added to eliminate cyanide, and freshly prepared SNP to which ATC or HCL was added were also tested. Six groups of animals consisting of three animals in each group were used. The single chemical or combination of chemicals stated above was soaked in a piece of gelfoam that was then applied to the round window membrane of the animal under ketamine-xylasine anesthesia. The animals were reanesthetized 3 days later and perfused for scanning electron microscopy and hair cell quantitative analysis. The results showed that, in animals given S-nitrosocysteine, no hair cell loss was noted, while light-exposed SNP led to severe hair cell damage similar to that seen after the administration of fresh SNP. In animals treated with the mixture of light-exposed SNP and ATC or HCL, or fresh SNP with ATC or HCL, ototoxicity was significantly attenuated. These results have convincingly demonstrated that NO at a certain level is not destructive to auditory hair cells and the hair cell loss observed after SNP application is most likely due to the cyanide released from the SNP instead of NO.

Acetylcysteine↗
PubMed2002

Mapping quantitative effects of oligogenes by allelic association.

Regression analysis of a quantitative trait as a function of a single diallelic polymorphism has been extended to allelic association by composite likelihood under the Malecot model for multiple markers. We applied the method to 10 single nucleotide polymorphisms (SNPs) spanning 27 kb of the angiotensin-I converting enzyme (ACE) gene in British families, localising a causal SNP between G2530A and 4656(CT)3/2 in the 3' region, at a distance of 21.6+/-0.9 kb from the most proximal SNP T-5491C. Neither they nor the I/D polymorphism is causal. To clarify genetic parameters we applied combined segregation, linkage and association analysis. Stronger evidence for the 3' region was obtained, with significant evidence of a lesser 5' effect as reported in French and Nigerian families. However, rigorous confirmation requires that the causal SNPs be identified. Both Malecot and parametric analysis appear to have high power by comparison with alternative methods for localizing oligogenes and their causal polymorphisms.

Chromosome Mapping↗
PubMed2001

Rapid single nucleotide polymorphism analysis by primer extension and capillary electrophoresis using polyvinyl pyrrolidone matrix.

Rapid molecular diagnosis of 21-hydroxylase deficiency by detecting the most common mutation in the 21-hydroxylase gene is presented using primer extension and capillary electrophoresis with a polyvinyl pyrrolidone matrix. DNA samples were subjected to polymerase chain reaction (PCR) in order to amplify a 422 bp fragment of the CYP21 gene containing the single nucleotide polymorphism (SNP) site. This product served as a template in the primer extension reaction using a fluorescently labeled primer in close proximity to the SNP. ddGTP was used to block the extension if the mutation was present and the other three dNTPs to enable elongation of the primer. Fast analysis of the resulting fragments was performed by capillary electrophoresis using 10% polyvinylpyrrolidone as sieving and wall coating matrix. The Cy5-labeled primer and the two possible primer extension products (mutant and wild type) were completely separated in 90 s.

Adrenal Hyperplasia, Congenital↗
PubMed2005

Allelic variation in the erythropoietin receptor gene is associated with uterine capacity and litter size in swine.

A single nucleotide polymorphism (SNP; C vs. T) that creates an extra GATA-1 site (T allele) in intron 4 of the swine erythropoietin receptor (EPOR) gene was discovered and a genotyping assay for this SNP was developed. A total of 402 gilts from lines selected either at random (control), for ovulation rate (OR) or for uterine capacity (UC) for 11 generations were unilaterally hysterectomized-ovariectomized (UHO) at 160 days of age, mated at approximately 250 days of age and slaughtered at 105 days of pregnancy. Blood samples and spleens were collected from each foetus and the numbers of corpora lutea (CL) and live foetuses, the weights of each foetus and placenta, and each foetal haematocrit were recorded. In addition, intact gilts from the OR line or from a Yorkshire, Landrace, Duroc, crossbred line (BX) were mated and farrowed. At farrowing, the numbers of fully formed and live piglets were recorded for each litter. Genomic DNA was isolated for both the UHO and intact gilts, from foetuses from the UHO gilts that were heterozygous for the EPOR SNP, and from the boars from the BX line and were then used to determine EPOR SNP genotypes. Only CC and CT gilts were observed in the control, OR and UC selected lines. Presence of the EPOR T allele was associated (P < 0.05) with increased UC in these gilts. The number of heterozygous and homozygous foetuses did not differ within UHO litters, or did EPOR genotype influence foetal haematocrit. In intact gilts from the OR line, litter size was significantly associated (P < 0.05) with EPOR SNP genotype. Finally, results from intact gilts of the BX line, in which both the gilt and the boar genotypes were known, allowed an analysis to determine the effect of the gilt and/or the foetal genotype on litter size. This analysis indicated that the predicted foetal genotype (with gilt genotype as covariate) was associated with litter size (an increase of 2.6 +/- 1.0 piglets born alive predicted for homozygous T litters compared with homozygous C litters, P < 0.01) whereas the effect of the gilt genotype (adjusted for foetal genotype) on litter size was not significant. These results indicate that the EPOR SNP is associated with UC and litter size in two distinct populations and could be useful in increasing litter size in swine that are not limited in OR.

Animals↗
PubMed2001

Tyrosine kinase receptor activation inhibits NPR-C in lung arterial smooth muscle cells.

We have previously demonstrated that expression of the atrial natriuretic peptide (ANP) clearance receptor (NPR-C) is reduced selectively in the lung of rats and mice exposed to hypoxia but not in pulmonary arterial smooth muscle cells (PASMCs) cultured under hypoxic conditions. The current study tested the hypothesis that hypoxia-responsive growth factors, fibroblast growth factors (FGF-1 and FGF-2) and platelet-derived growth factor-BB (PDGF-BB), that activate tyrosine kinase receptors can reduce expression of NPR-C in PASMCs independent of environmental oxygen tension. Growth-arrested rat PASMCs were incubated under hypoxic conditions (1% O2) for 24 h; with FGF-1, FGF-2, or PDGF-BB (0.1-20 ng/ml for 1-24 h); or with ANG II (1-100 nM), endothelin-1 (ET-1, 0.1 microM), ANP (0.1 microM), sodium nitroprusside (SNP, 0.1 microM), or 8-bromo-cGMP (0.1 mM) for 24 h under normoxic conditions. Steady-state NPR-C mRNA levels were assessed by Northern blot analysis. FGF-1, FGF-2, and PDGF-BB induced dose- and time-dependent reduction of NPR-C mRNA expression within 1 h at a threshold concentration of 1 ng/ml; hypoxia, ANG II, ET-1, ANP, SNP, or cGMP did not decrease NPR-C mRNA levels in PASMCs under the above conditions. Downregulation of NPR-C expression by FGF-1, FGF-2, and PDGF-BB was inhibited by the selective FGF-1 receptor tyrosine kinase inhibitor PD-166866 and mitogen-activated protein/extracellular signal-regulated kinase inhibitors U-0126 and PD-98059. These results indicate that activation of tyrosine kinase receptors by hypoxia-responsive growth factors, but neither hypoxia per se nor activation of G protein-coupled receptors, inhibits NPR-C gene expression in PASMCs. These results suggest that FGF-1, FGF-2, and PDGF-BB play a role in the signal transduction pathway linking hypoxia to altered NPR-C expression in lung.

Animals↗
PubMed2004

Pharmacogenetics of acenocoumarol pharmacodynamics.

OBJECTIVE: The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response. METHODS: A total of 263 healthy volunteers were genotyped for CYP2C9*2, CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, as well as for the nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase 1 genetic polymorphism (NQO1*2). Moreover, the 5'-flanking region of the CYP2C9 gene was investigated for new polymorphisms, and haplotype analysis was then performed. Finally, CYP2C9 phenotype was evaluated after a single oral dose of 4 mg of acenocoumarol. Factor VII coagulant activity was measured before and 24 hours after acenocoumarol intake. RESULTS: The CYP2C9*3 allele was the only nonsynonymous single nucleotide polymorphism (SNP) influencing acenocoumarol pharmacodynamics; the percentages of remaining factor VII were 60% +/- 19%, 39% +/- 17%, and 17% for CYP2C9*1/CYP2C9*1, CYP2C9*1/CYP2C9*3, and CYP2C9*3/CYP2C9*3 subjects, respectively (P =.001). Among the white subjects, the CYP2C9 promoter showed the existence of 6 SNPs at positions G-1538A, T-1189C, G-1097A, G-982A, T-640 del, and G-620T with allelic frequencies of 0.085, 0.0398, 0.136, 0.086, 0.005, and 0.0138, respectively. Four major haplotypes could be inferred among white subjects. The haplotype that contains the CYP2C9*3 allele was the only one influencing acenocoumarol pharmacodynamics, explaining 14.3% of its interindividual variability. Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect. CONCLUSION: Overall, CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. The information found by haplotype analysis is mainly related to the CYP2C9*3 SNP.

Acenocoumarol↗
PubMed2005

Human adenosine 2B receptor: SNP discovery and evaluation of expression in patients with cystic fibrosis.

OBJECTIVES AND METHODS: We analyzed the adenosine 2B (A2B) receptor gene, which consists of two exons, for single nucleotide polymorphisms (SNPs) and tested the hypothesis that coding sequence polymorphisms in the gene contribute to disease state in patients with cystic fibrosis (CF). Using PCR and restriction fragment length polymorphism (RFLP) analysis, we assessed 53 American subjects of mixed ethnicity, 64 European Caucasian control subjects and 148 Caucasian patients with CF for A2B SNPs. RESULTS: We identified one SNP in the 5' untranslated region (UTR) and seven SNPs in the open reading frame. One SNP was identified in the coding region of a German patient with CF but in none of the American subjects. No other SNPs were found in CF patients. A nonsynonymous SNP was identified in exon 2 of the German controls with an allelic frequency of 11%. The US subjects were of mixed ethnicity and most frequently (10.4%) had a SNP in the 5'UTR; 7 coding SNPs occurred in <3%. All SNPs other than the Leu96Phe and Gly136Arg variants were found only in African-Americans. Of the 26 African-Americans who were genotyped, 42% were hypertensive but the study group was too small to show an association between blood pressure status and SNP expression. CONCLUSIONS: The data show that SNPs in the A2B receptor gene are much more frequent in African-Americans than in Caucasians and that German Caucasians, but not African-Americans, express Gly136Arg. None of the SNPs identified in A2B receptors are likely to be modifiers in CF.

Adult↗
PubMed2004

Reduced arterial elasticity is associated with endothelial dysfunction in persons of advancing age: comparative study of noninvasive pulse wave analysis and laser Doppler blood flow measurement.

BACKGROUND: Endothelial dysfunction is the earliest marker for age-related abnormalities in vascular function, and examination of endothelial function has important clinical relevance. The present study was performed to evaluate effects of aging on arterial elasticity by using pulse waveform analysis and to investigate whether the changes in arterial elasticity might be used as a noninvasive measure for endothelial dysfunction. METHODS: A total of 24 healthy male volunteers were divided into young (n = 12) and elderly (n = 12) groups. Endothelial function was evaluated by delivering acetylcholine (Ach) and sodium nitroprusside (SNP) to the forearm vessels using iontophoresis, respectively, and measured blood flow using laser Doppler fluximetry. Large and small artery elasticity indices were noninvasively assessed using pulse wave analysis. RESULTS: Basal blood flow was similar between the young and elderly groups (14.58 +/- 3.4 v 13.52 +/- 3.41 PU, P = NS). Peak blood flow induced by Ach was significantly reduced in the elderly group compared with the young group (83.4 +/- 11.9 v 93.75 +/- 10.87 PU, P < .05). However, peak blood flow induced by SNP was similar in the two groups (119.17 +/- 16.76 v 128.33 +/- 21.29 PU, P = NS). In parallel, C1 large artery elasticity and C2 small artery elasticity indices were significantly reduced in the elderly group compared with the young group (11.42 +/- 1.67 v 16.75 +/- 2.09 mL/mm Hg x 10, P < .001; and 7.67 +/- 1.56 v 10.75 +/- 1.86 mL/mm Hg x 100, P < .001, respectively). The Ach-induced peak blood flow correlated with C1 large and C2 small artery elasticity indices. CONCLUSIONS: Advancing age is associated with endothelial dysfunction and reduced arterial elasticity. Reduced arterial elasticity parallels changes in impaired endothelium dependent vasodilation. It appears that reduced arterial elasticity may be used as a noninvasive measure for the determination of endothelial function.

Acetylcholine↗
PubMed2006

Analysis of synapsin III-196 promoter mutation in schizophrenia and bipolar disorder.

BACKGROUND: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), -196G/A, has been identified in the promoter region. The -196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. OBJECTIVE: To determine whether or not the -196 SNP is associated with either SZ or bipolar disorder (BD). METHODS: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the -196 SNP affected protein binding. RESULTS: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the -196 SNP binds to a brain protein in an allele-specific manner. CONCLUSIONS: These data, while inconclusive, suggest that -196 SNP should be further investigated as a candidate for 22q13-linked SZ.

Black or African American↗
PubMed2006

[Analysis of polymorphisms in Y-DNA haplotypes and mtDNA haplogroups in Yao ethnic group from Guizho].

The frequencies of Y-chromosome haplotypes consisting of 12 single nucleotide polymorphisms (SNP) and mitochondrial DNA (mtDNA) haplotypes consisting of 9 SNPs were investigated using PCR-RFLP in 97 Yaos from Guizhou to study the patrilineal and matrilineal genetic structure and the origin of Yao Ethnic Group from Guizhou. Results showed that all 97 samples were classified into 4 Y-DNA haplotypes (H7, H8, H9 and H11). The major haplotype H7 of Hmong-Mien Population was highly prevalent (92.4%) in Yaos from Guizhou. Eight mtDNA haplotypes were identified through mtDNA analysis and all the haplotypes could be classified into 5 haplogroups (B4, B5, D4, D5 and N*) that were defined previously. The frequency of a 9-bp deletion in the human mtDNA Co II/tRNALys intergenic region was 58.2% in the 97 samples. These data suggest that the patrilineal genetic structure of Yao ethnic group from Guizhou was simple and Yaos from Guizhou had the typical genetic character of the Hmong-Mien Population and some admixture with other populations. The matrilineal genetic structure of Yaos from Guizhou was relatively complex and the 9-bp deletion was a characteristic genetic marker of the matrilineal genetic structure of Yaos from Guizhou.

Asian People↗
PubMed2001

Y-chromosome variation in a Norwegian population sample.

Y-chromosome DNA profiles are promising tools in population genetics and forensic science. Here we present DNA profiles of 300 unrelated Y-chromosomes of Norwegian origin. The profile is composed of eight short tandem repeats (STRs) and one single nucleotide polymorphism (SNP). In more than 2/3 of the haplotypes the modular structure in the 5' end of the minisatellite locus DYF155S1 was revealed by minisatellite variant repeat PCR (MVR-PCR) These haplotypes were also typed for deletions of fragment 50f2C (DYF155S2). Allele distribution and paternity exclusion parameters are given for each marker. The degree of haplotype diversity and its implication for statistics are evaluated. In the 300 samples 177 different haplotypes were encountered, of which 137 were observed once only. Analysis showed that the main source of variation is within the population. The Fst values were less than 0.015 in general. Haplotype grouping by the SNP demonstrated two haplogroups (Tat/T and Tat/C). Haplogroup Tat/C--found in 5.7% of the present material - is the same haplogroup as encountered in 60% of Finnish males [Am. J. Hum. Genet. 62 (1998) 1171]. Mutation analysis in 150 father/son pairs (a total of 1200 meiotic events) revealed an average mutation frequency of 0.0042 (95% CI 0.0014-0.0097).

Alleles↗
PubMed2006

Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22.

Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.

Activin Receptors, Type II↗
PubMed2005

Analysis of single nucleotide polymorphisms in the promoter region of interleukin-10 by denaturing high-performance liquid chromatography.

Interleukin-10 (IL10), an anti-inflammatory cytokine, has been implicated in a variety of immune- and inflammatory-related diseases. We investigated the following SNPs: -1082, -819, -592 in the promoter region of IL10 in a normal (control) population and selected diseases: breast cancer (BrCa), systemic lupus erythematosus (SLE), and B-cell chronic lymphocytic leukemia (B-CLL) by denaturing high-performance liquid chromatography (DHPLC) and found distinct genotype and haplotype patterns. DHPLC was performed using the Transgenomic WAVE instrument, a mutational discovery tool that allows for high throughout analysis of SNPs. The principle of DHPLC is based on separation of homo- and heteroduplex formation of individual polymerase chain reaction products at specific melting temperatures and set gradients. The melting temperature selected for each SNP was based on size and sequence of the polymerase chain reaction product (for -1082, 57 degrees C; for -819, 58 degrees C; and for -592, 59.2 degrees C). Before fragment mutational analysis, all samples were denatured at 95 degrees C and slowly reannealed to allow for reassociation of different strands. Heteroduplex samples were easily distinguished from homoduplex samples. In order to identify wild type from homozygous mutant, two homoduplex polymerase chain reaction samples had to be mixed together, denatured at 95 degrees C and reannealed. The homozygous mutant, when combined with wild type, displayed a double peak on chromatogram. Once distinct chromatograms were established for each of the SNPs and the nucleotide changes confirmed by sequencing, genotype and haplotype frequencies were tabulated for the groups studied.

Base Sequence↗
PubMed2004

[Correlation analysis between single nucleotide polymorphism of the leptin receptor intron 8 and fatness traits in chickens].

Leptin receptor plays an important role in leptin functioning signal transduction and it may have direct effects on the deposition of adipose tissues and the body weight, the leptin receptor (OBR) gene, therefore, can be considered as a candidate gene in the study of fat deposition of the chicken. The function of OBR gene has been intensively studied in mammals, but study of OBR gene in the chicken is still rare. In this paper, the NEAU divergent selection broiler lines for abdominal fat were used. Body weight and fatness traits were measured in the sixth generation broiler population of the two lines at 7 week of age. Two pairs of primers for intron 8 of OBR gene were designed according to the database of chicken genomic sequence (Accession No. AF222783). The SNP was detected by DNA sequencing, and PCR-SSCP method was then developed to screen the population. The correlation analysis between the polymorphisms of the intron 8 of OBR gene and growth and fatness traits in the population was carried out using the appropriate statistical model. Two SNPs were found in the population. Those were T500C and G659A. The least square analysis showed that BB genotype birds had significant higher (P < 0.05) abdominal fat weight and percentage of abdominal fat than AA and AB genotype birds, and AA genotype birds had significant lower (P < 0.05) weights of livers than AB and BB genotype birds at the same time. From these results we can putatively drew the conclusion that OBR gene may be a major gene to affect the fatness traits or linked to the major gene, and the two polymorphisms found in OBR gene intron 8 region could be used to select the chicken for low abdominal fat in molecular marker-assisted selection programs.

Adipose Tissue↗
PubMed2003

Allowing for genotyping error in analysis of unmatched case-control studies.

A commonly-used method for testing for association between disease and a single-nucleotide polymorphism (SNP) is to compare the frequencies of the SNP genotypes in a sample of unrelated cases to those in a sample of unrelated controls drawn from the same population (an unmatched case-control study). A drawback of such a study is that it is impossible to detect genotyping errors, and few methods have been developed to allow for the presence of undetected genotyping errors. In this paper, we obtain analytic formulae for estimates of genotypic relative risks in terms of error probability (e). In general, e will be unknown. We investigate the effect of assuming both correct and incorrect values of e on power and type I error, and also on the genotypic relative risk estimates. The choice of e was found to have no effect on power or Type I error probability (provided a 2df test was used, allowing relative risks of homozygotes and heterozygotes to differ). However, overestimating e in the presence of a true association was found in general to bias relative risk estimates away from the null, with underestimates of e having the opposite effect. Although e is unknown, it may be estimated from an external "validation" study, such as genotyping a sample of unrelated individuals twice and counting the discrepancies. Simulation results suggest that, for such a study, 25 individuals would be sufficient to give approximately unbiased estimates of relative risks.

Case-Control Studies↗
PubMed2005

Cytokine gene polymorphisms in population of ethnic Macedonians.

AIM: To genotype cytokine polymorphisms in the Macedonian population as a part of the international project Cytokine Polymorphism Component (CPC). METHODS: The sample consisted of 125 healthy unrelated individuals, 46 men and 79 women, aged 20-35 years. All individuals were of Macedonian origin and nationality, Christian Orthodox religion, and residents of different regions of the Republic of Macedonia. Blood samples were collected after written consent was obtained, DNA was isolated from peripheral blood leukocytes by the phenol-chloroform extraction method, and the samples were stored in the Anthropology section of the Macedonian Human DNA Bank (hDNAMKD). Fourteen cytokine genes were identified as candidates: gamma-interferon (IFNgamma); interleukin (IL) 1 alpha (IL-1alpha); IL-1 beta (IL-1beta); IL-1 receptor (IL-1R); IL-1R antagonist (IL-1RA); IL-2; IL-4; IL-4 receptor alpha (IL-4Ralpha); IL-6; IL-10; IL-12B; TGF beta 1 (TGF-beta1); and TNF alpha (TNF-alpha). Cytokine genotyping for the anthropology samples was performed by polymerase chain reaction with sequence-specific priming (PCR-SSP) (Heidelberg kit). The population genetics analysis package, PyPop, was used for the analysis of the cytokine data for this report. RESULTS: The frequency of alleles for some single nucleotide polymorphisms (SNP) varied from 0.967 for TGF-beta1 cdn25/G and 0.920 for TNF-alpha -238/G, to 0.914 for IL-1alpha -889/C, indicating common "wild type" allele in those cytokines. For the most SNPs, the test of neutrality showed negative value for F(nd) statistic, which indicated balancing selection operating on the alleles at that locus. F(nd) was negative and significantly different from 0 for IFNgamma UTR5644 and TGF-beta1 cdn10 (P=0.006 and P=0.007, respectively). Most of SNPs showed a good fit with HWP expectations. A few SNPs (IL-1alpha -889, IL-1beta -511, IL-1beta+3962, and IFNgammaUTR5644) were not in HWP (P< or =0.005), and Guo and Thompson Hardy Weinberg Output (GTHWO) was significant (P< or =0.005). The most frequent haplotypes for TGF-beta1 were TG (0.491) and CG (0.476), with the absence of TGF-beta1/TC haplotype in the sample from the Macedonian population. Test of neutrality showed negative value for F(nd) statistic (Ewens-Watterson test of neutrality) which indicated balancing selection operating on the haplotypes at that locus, except for the IL-4 haplotypes, where it showed a positive value for F(nd) statistic, but without significance. F(nd) was negative and significantly different from 0 for IL-10 haplotypes (P=0.002). In the sample from the Macedonian population, D' was equal to 1 in all haplotypes with P values <0.0001, except for TNF-alpha (P< or =0.012), which indicated that one or more haplotypes were missing. CONCLUSION: The analysis of cytokine alleles, genotypes, and haplotypes in the sample from the Macedonian population showed a good fit with Hardy Weinberg equilibrium for most of SNPs and can be used for anthropological comparisons, as well as for association studies with different diseases.

Adult↗
PubMed2006

Interferon-gamma receptor-1 gene promoter polymorphisms (G-611A; T-56C) and susceptibility to tuberculosis.

We analysed frequencies of two single-nucleotide polymorphisms (SNP) in the interferon-gamma (IFN-gamma) receptor-1 (IFNGR1) gene promoter (G-611A, T-56C) in tuberculosis patients (n = 244) and compared them with controls (n = 521). These frequencies were not significantly different, whether analysed independently or as haplotypes. Because these SNP affect transcription, the results suggest that the expression of the IFNGR1 gene does not confer susceptibility to disease in patients from Croatia. Further analysis revealed a significant association between the protective (CA)(n) polymorphism (22 repeats, 192 FA(1)), located in the fifth intron of the IFNGR1 gene (+16682), and GT promoter haplotype (-611; -56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA)(22) allele was correlated in trans with an IFN-gamma SNP (IFNG G + 2109A), which might affect the transcription of the IFNG gene. These results suggest that a particular combination of IFNG and IFNGR1 SNP might offer a better protection against tuberculosis in this population.

Adult↗
PubMed2007

Type I error rates in association versus joint linkage/association tests in related individuals.

Positional gene discovery on pedigree data typically involves initial gross localization by linkage analysis with subsequent finer localization by association analysis in areas that show evidence of linkage. We examine the effect of including linkage information when testing for association in the context of variance-components-based pedigree analysis. We present simulation experiments showing that, at least in the extreme case of a rare private allele, failing to include the linkage variance component in the association model results in excessive Type I error that increases with allele copy number and/or quantitative trait locus (QTL) effect size. Joint estimation of the linkage variance component in the association model reduces Type I error to nominal expectations. This holds whether allele-sharing probabilities are estimated from a polymorphic marker or from the very single-nucleotide polymorphism (SNP) being tested for association, although the latter provides much less power. These results support the idea that an appropriate association analysis must test both the random effect of shared marker alleles (linkage) and the mean effects of the marker genotypes (association).

Alleles↗