Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.

A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations

Phenotypic and genetic analyses of four cases of coagulation factor XII deficiency

Objectives To identify the clinical phenotypic and molecular pathogeneses of four cases of coagulation factor XII deficiency and to deepen the cognition of this disease.Methods Coagulation tests were performed through one stage of coagulation on a STAGO coagulation analyser. Coagulation factor XII antigen was detected using enzyme-linked immunosorbent assay. The species conservatism and structural change of mutant proteins were analysed using MegAlign and PYMOL. Meanwhile, missense variants and a novel splice site variant were identified using PolyPhen2 and NetGene2.Results The four cases had an observably prolonged activated partial thromboplastin time but without obvious bleeding tendency. Their coagulation factor XII activity (FⅫ:C) and antigen (FXII:Ag) were greatly reduced. Six mutations were detected: NM_000505.4:c.398-1G>A, NP_000496.2:p.(Pro182Leu), NP_000496.2:p.(Ser479Ter), NP_000496.2:p.(Cys559Arg), NC_000005.10:g.7217_7221delinsGTCTA and NM_000505.4:c.1681-1G>A. The first five are newly discovered mutations. The two missense mutation sites were highly conservative, and their protein secondary structure changes may occur not only on the mutation sites but also on other domains. In silico analysis revealed that NP_000496.2:p.(Pro182Leu) may be BENIGN, NP_000496.2:p.(Cys559Arg) may be damaging, and that NM_000505.4:c.398-1G>A and NM_000505.4:c.1681-1G>A are crucial for splicing.Conclusion We found six types of mutations, of which five were novel. The two missense mutation sites might be closely related to the function of coagulation factor XII. The mutations were the primary culprits of factor XII deficiency

Marker-free carotenoid-enriched rice generated through targeted gene insertion using CRISPR-Cas9.

Targeted insertion of transgenes at pre-determined plant genomic safe harbors provides a desirable alternative to insertions at random sites achieved through conventional methods. Most existing cases of targeted gene insertion in plants have either relied on the presence of a selectable marker gene in the insertion cassette or occurred at low frequency with relatively small DNA fragments (<1.8 kb). Here, we report the use of an optimized CRISPR-Cas9-based method to achieve the targeted insertion of a 5.2 kb carotenoid biosynthesis cassette at two genomic safe harbors in rice. We obtain marker-free rice plants with high carotenoid content in the seeds and no detectable penalty in morphology or yield. Whole-genome sequencing reveals the absence of off-target mutations by Cas9 in the engineered plants. These results demonstrate targeted gene insertion of marker-free DNA in rice using CRISPR-Cas9 genome editing, and offer a promising strategy for genetic improvement of rice and other crops

Marker-free carotenoid-enriched rice generated through targeted gene insertion using CRISPR-Cas9.

Targeted insertion of transgenes at pre-determined plant genomic safe harbors provides a desirable alternative to insertions at random sites achieved through conventional methods. Most existing cases of targeted gene insertion in plants have either relied on the presence of a selectable marker gene in the insertion cassette or occurred at low frequency with relatively small DNA fragments (<1.8 kb). Here, we report the use of an optimized CRISPR-Cas9-based method to achieve the targeted insertion of a 5.2 kb carotenoid biosynthesis cassette at two genomic safe harbors in rice. We obtain marker-free rice plants with high carotenoid content in the seeds and no detectable penalty in morphology or yield. Whole-genome sequencing reveals the absence of off-target mutations by Cas9 in the engineered plants. These results demonstrate targeted gene insertion of marker-free DNA in rice using CRISPR-Cas9 genome editing, and offer a promising strategy for genetic improvement of rice and other crops

Telomere length and risk of lung cancer: results for overall study and stratifying by years from enrollment to case diagnosis.

†<p>Telomere length categorized using tertiles in controls as cut-points.</p>*<p>N_Co indicates number of controls; and N_Ca, number of cases.</p>£<p>Odds ratios computed using conditional logistic regression adjusted for age and ever smoking.</p>‡<p>P trend calculated by using log transformed telomere length as continuous variable, adjusted for age and ever smoking.</p

Mean telomere length in association with rs2736100 (<i>CLPTM1L-TERT</i>), by case-control status in the Shanghai Women’s Health Study^*(All cases and controls).

*<p>log transformed telomere length as continuous variable was used.</p>‡<p>mean (SD).</p>†<p>P for trend calculated by using linear regression and rs2736100 by assigning the ordinal values 1, 2, and 3 for TT, GT, and GG respectively, adjusted for age and ever smoking.</p>£<p>P value from spearman correlation test.</p

Selected characteristic of lung cancer cases and individually matched controls selected from the Shanghai Women’s Health Study (recruited between 1997–2000).

$<p>Spearman correlation (r) with telomere length in controls is −0.41(P<0.0001).</p>£<p>P value of spearman r with telomere length in controls >0.05.</p>‡<p>Family history of lung cancer in first degree relatives.</p>*<p>NOS indicates not otherwise specified.</p>†<p>NA indicates not available.</p>††<p>NA indicates not available, as only never-smoking subjects were genotyped.</p

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

International audienceBACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation. Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the