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Correlation of human telomerase reverse transcriptase single nucleotide polymorphisms with in vitro fertilisation outcomes.

ABSTRACT: PURPOSE:To explore whether it is possible to predict the number and quality of the embryo using a few particular hTERT SNPs. METHODS:We included 997 Han Chinese women who were genetically unrelated and underwent assisted reproduction using IVF from September 2014 to December 2015. DNA was genotyped by using TaqMan real-time quantitative PCR. RESULTS:Among the 997 patients, individuals with the CC genotype of rs2075786 had a significantly lower number of good-quality embryos than those with the TT+TC genotypes. Compared with the CT+CC genotype carriers, patients carrying the TT genotype of rs2853677 had a significantly lower number of oocytes retrieved, mature oocytes and available embryos. Among the 750 patients aged ??35 years, individuals with the AA+AG genotypes of rs2853691 had a significantly higher number of good-quality embryos than those with the GG genotype. The haplotype analysis showed that the TTTG (rs2853672/rs2853669/rs2735940/rs2736108) haplotype was more likely to lead to more than three good-quality embryos in patients aged ??35 years. CONCLUSIONS:Our study suggests that the hTERT SNP is associated with IVF outcomes.

SUBMITTER: Dai K

PROVIDER: S-EPMC6439048 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Correlation of human telomerase reverse transcriptase single nucleotide polymorphisms with in vitro fertilisation outcomes.

Dai Kailing K Xu Hongmei H Ouyang Nengyong N Li Ying Y Yuan Ping P Wang Liangan L Zhao Xiaomiao X Wang Wenjun W

Journal of assisted reproduction and genetics 20181210 3

<h4>Purpose</h4>To explore whether it is possible to predict the number and quality of the embryo using a few particular hTERT SNPs.<h4>Methods</h4>We included 997 Han Chinese women who were genetically unrelated and underwent assisted reproduction using IVF from September 2014 to December 2015. DNA was genotyped by using TaqMan real-time quantitative PCR.<h4>Results</h4>Among the 997 patients, individuals with the CC genotype of rs2075786 had a significantly lower number of good-quality embryos ...[more]

PMID: 30535641

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Project description:BackgroundTelomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated.Methodology/principal findingsTo understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function.Conclusions/significanceWe provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention.

Project description:Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer.A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association.Eighty-five studies enrolling 490?901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types.To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.

Dataset Information

Correlation of human telomerase reverse transcriptase single nucleotide polymorphisms with in vitro fertilisation outcomes.

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Correlation of human telomerase reverse transcriptase single nucleotide polymorphisms with in vitro fertilisation outcomes.

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