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Common Genetic Variation (common + genetic_variation)
Selected AbstractsRare TLR2 mutations reduce TLR2 receptor function and can increase atopy riskALLERGY, Issue 4 2009M. S. D. Kormann Background:, Common genetic variations in toll-like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases. Objective:, We investigated the functional properties of six rare amino acid changes in TLR2 (and one amino acid change in a TLR2 pseudogene) and studied their effect on atopic sensitization and disease. Methods:, We identified rare TLR2 mutations leading to amino acid changes from databases. Functional effects of TLR2 variants were analyzed by NF-,B-dependent luciferase reporter assay and interleukin-8 enzyme linked immunosorbent assay in vitro. The frequency of these mutations was determined in a random sample of the general population (n = 368). Association with atopic diseases were studied in a cross sectional German study population (n = 3099). Results:, Three out of six mutations in the TLR2 gene altered receptor activity in vitro. Out of these, only the minor allele of R753Q occurred reasonably frequent in the German population (minor allele frequency 3%). The risk to develop atopy increased by 50% in carriers of the 753Q allele (P = 0.021) and total (P = 0.040) as well as allergen specific serum IgE levels (P = 0.011) were significantly elevated. Conclusion:, The rare but functionally relevant mutation R753Q in TLR2 may significantly affect common conditions such as atopic sensitization in the general population. [source] Genetic variation, nucleotide diversity, and linkage disequilibrium in seven telomere stability genes suggest that these genes may be under constraint,,HUMAN MUTATION, Issue 4 2005Sharon A. Savage Abstract To maintain chromosomal integrity and to protect the ends of chromosomes against recognition as damaged DNA, end-to-end fusion, or recombination, a coordinated set of genes is required to stabilize the telomere. We surveyed common genetic variation in seven genes that are vital to telomere stability (TERT, POT1, TNKS, TERF1, TINF2, TERF2, and TERF2IP) and validated single nucleotide polymorphisms (SNPs) in four different ethnic groups (n=118 total). Overall, our data show limited degrees of nucleotide diversity in comparison with data from other gene families. We observed that these genes are highly conserved in sequence between species, and that for nearly all of the coding SNPs the most common allele is ancestral (i.e., it is observed in primate sequences). Our findings support the hypothesis that genetic variation in a pathway that is critical for telomere stability may be under constraint. These data establish a foundation for further investigation of these genes in population-genetics, evolution, and disease-association studies. Hum Mutat 26(4), 343,350, 2005. Published 2005, Wiley-Liss, Inc. [source] Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer riskINTERNATIONAL JOURNAL OF CANCER, Issue 11 2008Victoria L. Stevens Abstract Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29,38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations. © 2008 Wiley-Liss, Inc. [source] Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevityAGING CELL, Issue 4 2009Ludmila Pawlikowska Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan , 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan , 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68,0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15,1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. [source] Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non-Fatal Myocardial InfarctionANNALS OF HUMAN GENETICS, Issue 6 2008V. Meiner Summary Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP ,2708 G/A, ,971 A/G, ,629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (,2708 G, ,971 G, ,629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (,2708 G, ,971 A, ,629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4,14.8] and haplotype B (,2708 G, ,971 G, ,629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 , 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations. [source] Candidate Molecular Pathway Genes Related to Appetite Regulatory Neural Network, Adipocyte Homeostasis and Obesity: Results from the CARDIA StudyANNALS OF HUMAN GENETICS, Issue 5 2010Yechiel Friedlander Summary Appetite regulatory neural network and adipocyte homeostasis molecular pathways are critical to long-term weight maintenance. Associations between obesity-related phenotypes and four genes in these pathways , leptin (LEP), leptin receptor (LEPR), neuropeptide Y2 receptor (NPY2R) and peptide YY (PYY) were examined in CARDIA Study participants (aged 18,30 at recruitment in 1985,6). Weight, BMI and waist circumference were measured at baseline and at years 2, 5, 7, 10, 15, and 20. Genotyping was conducted using tag SNPs characterising common genetic variations in these genes. Generalized estimating equation (GEE) models estimated associations between SNPs and repeated anthropometric measurements, controlling for sex and age. False discovery rate was used to adjust for multiple testing. In African-Americans, SNPs across the LEP gene demonstrated significant overall associations with all obesity-related phenotypes. The associations between LEP rs17151919 with weight tended to strengthen with time , the difference in weight associated with each additional minor allele increased from 2.6 kg at baseline to 4.8 kg at year 20 (SNP*time interaction p = 0.0193). NPY2R gene SNPs were associated with waist circumference among African-American men (p = 0.0462). In Caucasians, LEP SNPs also tended to be associated with weight (p = 0.0471), and PYY rs11684664 was associated with obesity-related phenotypes in women only (p = 0.010,0.026). Several LEP, and NPY2R and PYY SNPs were associated with obesity-related phenotypes in young adults, particularly among African-Americans. [source] Haplotype Analysis of the Stromelysin-1 (MMP3) and Gelatinase B (MMP9) Genes in Relation to Coronary Heart DiseaseANNALS OF HUMAN GENETICS, Issue 4 2009Naqiong Wu Summary The functional genetic polymorphisms present in the promoters of stromelysin-1 (MMP3) and gelatinase B (MMP9) have been shown to be associated with angiographically measured atherosclerosis; however, haplotype analysis of the genetic polymorphisms occurring in the promoters and coding regions of MMP3 and MMP9 has been infrequently performed in the past. The aim of this study was to analyze the occurrence of the -1612 5A/6A, -376C/G, and Glu45Lys polymorphisms of MMP3 and the -1562C/T and R279Q polymorphisms of MMP9 and their relation to the risk of coronary heart disease (CHD; stenosis ,50% of the diameter in at least one major coronary artery) in a Chinese Han population. The present study involved 1373 patients with CHD and 695 healthy controls. The Glu45Lys polymorphism of MMP3 was significantly associated with an increased risk of CHD. Compared with the 45Glu homozygotes, 45Lys allele carriers had a significantly elevated risk of CHD (adjusted OR = 1.50; 95%CI 1.11,2.03; p= 0.008). Moreover, haplotype analysis identified both the 6A-C-Lys (-1612 6A, -376C, 45Lys) haplotype and the 6A-G-Lys (-1612 6A,-376G, 45Lys) haplotype of MMP3 as associated with an increased risk of CHD. Our study suggests that common genetic variations in the MMP3 gene may affect the risk of CHD in the Chinese population. [source] | |||||||||||||