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Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.

ABSTRACT: Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV1 and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.

SUBMITTER: Lange NE

PROVIDER: S-EPMC3048492 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.

Lange Nancy E NE Zhou Xiaobo X Lasky-Su Jessica J Himes Blanca E BE Lazarus Ross R Soto-Quirós Manuel M Avila Lydiana L Celedón Juan C JC Hawrylowicz Catherine M CM Raby Benjamin A BA Litonjua Augusto A AA

BMC medical genetics 20110215

<h4>Background</h4>Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.<h4>Methods</h4>rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were ...[more]

PMID: 21324137

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Project description:BackgroundTo a great extent, genetic factors contribute to the susceptibility to type 1 diabetes (T1D) development, and by triggering immune imbalance, Toll-like receptor (TLR) 9 is involved in the development of T1D. However, there is a lack of evidence supporting a genetic association between polymorphisms in the TLR9 gene and T1D.MethodsIn total, 1513 individuals, including T1D patients (n=738) and healthy control individuals (n=775), from the Han Chinese population were recruited for an association analysis of the rs352140 polymorphism of the TLR9 gene and T1D. rs352140 was genotyped by MassARRAY. The allele and genotype distributions of rs352140 in the T1D and healthy groups and those in different T1D subgroups were analyzed by the chi-squared test and binary logistic regression model. The chi-square test and Kruskal-Wallis H test were performed to explore the association between genotype and phenotype in T1D patients.ResultsThe allele and genotype distributions of rs352140 were significantly different in T1D patients and healthy control individuals (p=0.019, p=0.035). Specifically, the T allele and TT genotype of rs352140 conferred a higher risk of T1D (OR=1.194, 95% CI=1.029-1.385, p=0.019, OR=1.535, 95% CI=1.108-2.126, p=0.010). The allele and genotype distributions of rs352140 were not significantly different between childhood-onset and adult-onset T1D and between T1D with a single islet autoantibody and T1D with multiple islet autoantibodies (p=0.603, p=0.743). rs352140 was associated with T1D susceptibility according to the recessive and additive models (p=0.015, p=0.019) but was not associated with T1D susceptibility in the dominant and overdominant models (p=0.117, p=0.928). Moreover, genotype-phenotype association analysis showed that the TT genotype of rs352140 was associated with higher fasting C-peptide levels (p=0.017).ConclusionIn the Han Chinese population, the TLR9 polymorphism rs352140 is associated with T1D and is a risk factor for susceptibility to T1D.

Project description:A single nucleotide polymorphism (SNP) rs2853669 (A>G) in the telomerase reverse transcriptase (TERT) promoter has recently been reported in chr5:1,295,349 T>C (T349C), and was shown to be associated with increased cancer risk and poor survival in a specific population. However, at present, the role of this particular SNP with TERT promoter driver mutations and its genetic association with human papilloma virus (HPV) in patients with cervical cancer has not been determined. In the present study, the genetic association of the functional SNP rs2853669 in the presence/absence of TERT promoter hotspot mutations and HPV in patients with cervical cancer of South Indian origin was evaluated. To understand and compare the frequency of the variant allele and its risk association in different cancer types of various populations, the SNP was genotyped in 257 cervical cancer samples and 295 controls, and its associations with TERT promoter hotspot mutations and HPV were analyzed. Furthermore, an extensive search of previously published articles in PubMed, Embase and Web of Science was conducted; a meta-analysis was carried out to elucidate the association of the SNP with different cancer types in global populations. The SNP analysis showed significantly high frequency (41%) of homozygous variant allele rs2853669 (GG) in patients with cervical cancer compared with control samples [Recessive allele model odds ratio (OR)=1.71; 95% CI=1.20-2.43; P=0.003]. No significant interaction was observed between the TERT SNP rs2853669 and HPV status as well as other hotspot TERT promoter (C228T and C250T) mutations determined in our previous study. In addition, the overall meta-analysis revealed a significant association of the SNP rs2853669 with other cancer types in different ethnic populations (OR=1.09; 95% CI=1.03-1.16; P=0.004). The present results suggested that the TERT SNP rs2853669 could play an important role in the risk of cervical cancer in a South Indian population.

Dataset Information

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.

Publications

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.

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