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Tagging Single Nucleotide Polymorphisms (tagging + single_nucleotide_polymorphism)
Selected AbstractsQuantification and correction of bias in tagging SNPs caused by insufficient sample size and marker density by means of haplotype-dropping,GENETIC EPIDEMIOLOGY, Issue 1 2008Mark M. Iles Abstract Tagging single nucleotide polymorphisms (tSNPs) are commonly used to capture genetic diversity cost-effectively. It is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be inadequate and studies underpowered. Using data simulated under a coalescent model, we show that insufficient sample size can lead to overestimation of tSNP efficacy. Quantifying this we find that even when insufficient marker density is adjusted for, estimates of tSNP efficacy are up to 45% higher than the true values. Even with as many as 100 individuals, estimates of tSNP efficacy may be 9% higher than the true value. We describe a novel method for estimating tSNP efficacy accounting for limited sample size. The method is based on exclusion of haplotypes, incorporating a previous adjustment for insufficient marker density. We show that this method outperforms an existing Bootstrap approach. We compare the efficacy of multimarker and pairwise tSNP selection methods on real data. These confirm our findings with simulated data and suggest that pairwise methods are less sensitive to sample size, but more sensitive to marker density. We conclude that a combination of insufficient sample size and overfitting may cause overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel method corrects much of this bias and is superior to a previous method. However, sample sizes larger than previously suggested may be required for accurate estimation of tSNP efficacy. This has obvious ramifications for tSNP selection both in candidate regions and using HapMap or SNP chips for genomewide studies. Genet. Epidemiol. 31, 2007. © 2007 Wiley-Liss, Inc. [source] A sparse marker extension tree algorithm for selecting the best set of haplotype tagging single nucleotide polymorphismsGENETIC EPIDEMIOLOGY, Issue 4 2005Ke Hao Abstract Single nucleotide polymorphisms (SNPs) play a central role in the identification of susceptibility genes for common diseases. Recent empirical studies on human genome have revealed block-like structures, and each block contains a set of haplotype tagging SNPs (htSNPs) that capture a large fraction of the haplotype diversity. Herein, we present an innovative sparse marker extension tree (SMET) algorithm to select optimal htSNP set(s). SMET reduces the search space considerably (compared to full enumeration strategy), and therefore improves computing efficiency. We tested this algorithm on several datasets at three different genomic scales: (1) gene-wide (NOS3, CRP, IL6 PPARA, and TNF), (2) region-wide (a Whitehead Institute inflammatory bowel disease dataset and a UK Graves' disease dataset), and (3) chromosome-wide (chromosome 22) levels. SMET offers geneticists with greater flexibilities in SNP tagging than lossless methods with adjustable haplotype diversity coverage (,). In simulation studies, we found that (1) an initial sample size of 50 individuals (100 chromosomes) or more is needed for htSNP selection; (2) the SNP tagging strategy is considerably more efficient when the underlying block structure is taken into account; and (3) htSNP sets at 80,90% , are more cost-effective than the lossless sets in term of relative power, relative risk ratio estimation, and genotyping efforts. Our study suggests that the novel SMET algorithm is a valuable tool for association tests. Genet. Epidemiol. 29:336,352, 2005. © 2005 Wiley-Liss, Inc. [source] Genetic Polymorphism of KCNH2 Confers Predisposition of Acquired Atrial Fibrillation in ChineseJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2009QUN-SHAN WANG M.D. Introduction: Nonfamiliar atrial fibrillation (AF) is usually associated with acquired structural heart disease, including valvular heart disease, coronary artery disease, and hypertension. Suggestive evidence indicates that these forms of acquired AF are more likely to occur in individuals with a genetic predisposition. We investigated the effect of the potassium channel voltage-gated subfamily member 2 (KCNH2) gene on the prevalence of acquired AF in a Chinese population. Methods: In a pair-matched, hospital-based case control study (297 vs 297) conducted in Chinese Hans, we investigated 4 tagging single nucleotide polymorphisms (tSNPs), rs1805120, rs1036145, rs3807375, and rs2968857 in the KCNH2 gene, and determined their association with AF acquired from structural heart diseases. Results: We did not observe the association of rs1036145, rs3807375, and rs2968857 with AF. However, we determined that the tSNP, rs1805120, in exon 6 confers the risk of AF in Chinese Hans. Both genotype and allele frequencies of rs1805120 were distributed differently in cases and controls (P = 0.0289 and P = 0.0172, respectively). The most significant association was observed under a recessive model for the minor GG genotype with a 1.45-fold risk of developing AF (95% confidence interval 1.09,1.93, P = 0.012). The significance remained after controlling for the covariates of age, smoking, BMI, hypertension, and diabetes. Conclusion: We report a new genetic variation (rs1805120) in the KCNH2 gene that predisposes Chinese Han individuals to the risk of acquired AF. Further genetic and functional studies are required to identify the etiological variants in linkage disequilibrium with this polymorphism. [source] TLR-related pathway analysis: novel gene,gene interactions in the development of asthma and atopyALLERGY, Issue 2 2010N. E. Reijmerink To cite this article: Reijmerink NE, Bottema RWB, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, van Schayck CP, Smit HA, Brunekreef B, Koppelman GH, Postma DS. TLR-related pathway analysis: novel gene,gene interactions in the development of asthma and atopy. Allergy 2010; 65: 199,207. Abstract Background:, The toll-like receptor (TLR)-related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR-related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether gene,gene interactions in this pathway contribute to atopy and asthma development. Methods:, One hundred and sixty-nine haplotype tagging single nucleotide polymorphisms (SNPs) of 29 genes (i.e. membrane and intracellular receptors, TLR4 or lipopolysaccharide-binding/facilitating proteins, adaptors, interleukin-1 receptor associated kinases, kinases, chaperone molecules, transcription factors and inhibitors) were analysed for single- and multilocus associations with atopy [total and specific immunglobulin E (IgE) at 1,2 and 6,8 years] and asthma (6,8 years). A total of 3062 Dutch children from the birth cohorts PIAMA, PREVASC and KOALA (Allergenic study) were investigated. Chi-squared test, logistic regression and the data mining approach multifactor dimensionality reduction method (MDR) were used in analysis. Results:, Several genes in the TLR-related pathway were associated with atopy and/or asthma [e.g. IL1RL1, BPI, NOD1, NOD2 and MAP3K7IP1]. Multiple, single associations were found with the phenotypes under study. MDR analysis showed novel, significant gene,gene interactions in association with atopy and asthma phenotypes (e.g. IL1RL1 and TLR4 with sIgE to indoor allergens and IRAK1, NOD1 and MAP3K7IP1 with asthma). Interestingly, gene,gene interactions were identified with SNPs that did not have an effect on their own. Conclusion:, Our unbiased approach provided suggestive evidence for interaction between several TLR-related pathway genes important in atopy and/or asthma development and pointed to novel genes. [source] IL15 gene variants are not associated with asthma and atopyALLERGY, Issue 4 2009L. A. Pinto Background:, Interleukin 15 (IL15) promotes activation and proliferation of CD8+ T cells and enhances the differentiation into Th2 cells. A previous study described five polymorphisms in the IL15 gene to be associated with asthma in a haplotype analysis. Aim:, We selected HapMap tagging single nucleotide polymorphisms (SNPs) from IL15 to systematically investigate these IL15 associations in a large population-based sample. Methods:, Genotyping of seven IL15 SNPs was performed using MALDI-TOF MS in a cross-sectional study population of 3099 children from Dresden or Munich (age 9,11 years). All children were phenotyped by standardized and validated protocols for atopic phenotypes. Effects of single SNPs and haplotypes were studied using sas 9.1.3 and haploview. Equivalence tests were performed to prove the significance of negative results. Results:, Neither single IL15 polymorphisms nor haplotype analyses showed associations with asthma or atopy after correction for multiple testing. Conclusion:, These results do not confirm previous case,control studies and suggest that IL15 gene variants do not play an important role in the development for asthma or other atopic disorders. [source] Genetic Variation in the Paraoxonase-3 (PON3) Gene is Associated with Serum PON1 ActivityANNALS OF HUMAN GENETICS, Issue 1 2008Dharambir K. Sanghera Summary Low serum paraoxonase1 (PON1) activity determined by paraoxon substrate is associated with coronary heart disease (CHD), diabetes and systemic lupus erythematosus (SLE) risk. In this investigation, we have examined the role of genetic variation in the PON3 gene in relation to PON1 activity and SLE risk in a biracial sample comprising 377 SLE patients and 482 controls from US whites and blacks. We genotyped six PON3 tagging single nucleotide polymorphisms (tagSNPs) and examined their associations with PON1 activity, SLE risk, antiphopholipid autoantibodies (APA), lupus nephritis, carotid vascular disease, and inflammation. With the exception of PON1 activity, no other significant associations were found with PON3 SNPs. Multiple regression analysis including all six PON3 tagSNPs and PON1/Q192R and L55M SNPs revealed significant association of PON1 activity with 4 SNPs: PON3/A10340C (p < 0.0001), PON3/A2115T (p = 0.002), PON1/L55M (p < 0.0001) and PON1/Q192R (p < 0.0001). These four SNPs explained 2%, 1%, 8% and 19% of the variation in PON1 activity, respectively. In summary, our new data indicate that genetic variation in the PON3 gene influences serum PON1 activity independently of the known effect of PON1 genetic variation. To our knowledge, this is the first study reporting the association of the PON3 gene variants with PON1 activity. [source] Genetic variants in the Runt-related transcription factor 3 gene contribute to gastric cancer risk in a Chinese populationCANCER SCIENCE, Issue 9 2009Dongmei Wu Runt-related transcription factor 3 (RUNX3) is a well known gene for its functions in gastric cancer suppression, but the effect of its genetic variations on the risk of gastric cancer remains unclear. In this study, ten tagging single nucleotide polymorphisms (tSNPs) of the RUNX3 gene were selected and genotyped in a hospital-based case-control study of 312 gastric cancer patients and 329 cancer-free controls in a Chinese population. In the single-locus analysis, three RUNX3 intronic tSNPs associated with significantly increased risk of gastric cancer were observed: the SNP3 rs11249206 CC genotype (adjusted odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.03,2.99), compared with the TT genotype; the SNP7 rs760805 AA genotype (adjusted OR = 1.82, 95% CI = 1.14,2.92), compared with the TT genotype; and the SNP8 rs2236852 GG genotype (adjusted OR = 1.69, 95% CI = 1.05,2.72), compared with the AA genotype. In the combined analyses of these three tSNPs, we found that the combined genotypes with four to six variant (risk) alleles (i.e. SNP3 C, SNP7 A, and SNP8 G alleles) were associated with an increased risk of gastric cancer compared with those with one to three variant (risk) alleles (adjusted OR = 2.00, 95% CI = 1.41,2.85), and this increased risk was more pronounced among subgroups of age ,65 years, never smokers, and never drinkers. However, no significant association was observed in the clinicopathological features analyses. In conclusion, the RUNX3 genetic variants may modulate the risk of gastric cancer in a Chinese population. Further larger and functional studies are warranted to validate the findings. (Cancer Sci 2009; 100: 1688,1694) [source] | |||||||||||||