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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
European Urology ( IF 25.3 ) Pub Date : 2017-08-07 , DOI: 10.1016/j.eururo.2017.07.015 Mitchell J Machiela 1 , Jonathan N Hofmann 1 , Robert Carreras-Torres 2 , Kevin M Brown 1 , Mattias Johansson 2 , Zhaoming Wang 3 , Matthieu Foll 2 , Peng Li 2 , Nathaniel Rothman 1 , Sharon A Savage 1 , Valerie Gaborieau 2 , James D McKay 2 , Yuanqing Ye 4 , Marc Henrion 5 , Fiona Bruinsma 6 , Susan Jordan 7 , Gianluca Severi 8 , Kristian Hveem 9 , Lars J Vatten 10 , Tony Fletcher 11 , Kvetoslava Koppova 12 , Susanna C Larsson 13 , Alicja Wolk 13 , Rosamonde E Banks 14 , Peter J Selby 14 , Douglas F Easton 15 , Paul Pharoah 15 , Gabriella Andreotti 1 , Laura E Beane Freeman 1 , Stella Koutros 1 , Demetrius Albanes 1 , Satu Mannisto 16 , Stephanie Weinstein 1 , Peter E Clark 17 , Todd E Edwards 17 , Loren Lipworth 17 , Susan M Gapstur 18 , Victoria L Stevens 18 , Hallie Carol 19 , Matthew L Freedman 19 , Mark M Pomerantz 19 , Eunyoung Cho 20 , Peter Kraft 21 , Mark A Preston 22 , Kathryn M Wilson 21 , J Michael Gaziano 23 , Howard S Sesso 21 , Amanda Black 1 , Neal D Freedman 1 , Wen-Yi Huang 1 , John G Anema 24 , Richard J Kahnoski 24 , Brian R Lane 25 , Sabrina L Noyes 26 , David Petillo 26 , Leandro M Colli 1 , Joshua N Sampson 1 , Celine Besse 27 , Helene Blanche 28 , Anne Boland 27 , Laurie Burdette 1 , Egor Prokhortchouk 29 , Konstantin G Skryabin 29 , Meredith Yeager 1 , Mirjana Mijuskovic 30 , Miodrag Ognjanovic 31 , Lenka Foretova 31 , Ivana Holcatova 32 , Vladimir Janout 33 , Dana Mates 34 , Anush Mukeriya 35 , Stefan Rascu 36 , David Zaridze 35 , Vladimir Bencko 37 , Cezary Cybulski 38 , Eleonora Fabianova 12 , Viorel Jinga 37 , Jolanta Lissowska 39 , Jan Lubinski 40 , Marie Navratilova 32 , Peter Rudnai 41 , Neonila Szeszenia-Dabrowska 42 , Simone Benhamou 43 , Geraldine Cancel-Tassin 44 , Olivier Cussenot 45 , H Bas Bueno-de-Mesquita 46 , Federico Canzian 47 , Eric J Duell 48 , Börje Ljungberg 49 , Raviprakash T Sitaram 49 , Ulrike Peters 50 , Emily White 50 , Garnet L Anderson 50 , Lisa Johnson 50 , Juhua Luo 51 , Julie Buring 21 , I-Min Lee 52 , Wong-Ho Chow 4 , Lee E Moore 1 , Christopher Wood 53 , Timothy Eisen 54 , James Larkin 55 , Toni K Choueiri 19 , G Mark Lathrop 56 , Bin Tean Teh 26 , Jean-Francois Deleuze 57 , Xifeng Wu 4 , Richard S Houlston 58 , Paul Brennan 2 , Stephen J Chanock 1 , Ghislaine Scelo 2 , Mark P Purdue 1
European Urology ( IF 25.3 ) Pub Date : 2017-08-07 , DOI: 10.1016/j.eururo.2017.07.015 Mitchell J Machiela 1 , Jonathan N Hofmann 1 , Robert Carreras-Torres 2 , Kevin M Brown 1 , Mattias Johansson 2 , Zhaoming Wang 3 , Matthieu Foll 2 , Peng Li 2 , Nathaniel Rothman 1 , Sharon A Savage 1 , Valerie Gaborieau 2 , James D McKay 2 , Yuanqing Ye 4 , Marc Henrion 5 , Fiona Bruinsma 6 , Susan Jordan 7 , Gianluca Severi 8 , Kristian Hveem 9 , Lars J Vatten 10 , Tony Fletcher 11 , Kvetoslava Koppova 12 , Susanna C Larsson 13 , Alicja Wolk 13 , Rosamonde E Banks 14 , Peter J Selby 14 , Douglas F Easton 15 , Paul Pharoah 15 , Gabriella Andreotti 1 , Laura E Beane Freeman 1 , Stella Koutros 1 , Demetrius Albanes 1 , Satu Mannisto 16 , Stephanie Weinstein 1 , Peter E Clark 17 , Todd E Edwards 17 , Loren Lipworth 17 , Susan M Gapstur 18 , Victoria L Stevens 18 , Hallie Carol 19 , Matthew L Freedman 19 , Mark M Pomerantz 19 , Eunyoung Cho 20 , Peter Kraft 21 , Mark A Preston 22 , Kathryn M Wilson 21 , J Michael Gaziano 23 , Howard S Sesso 21 , Amanda Black 1 , Neal D Freedman 1 , Wen-Yi Huang 1 , John G Anema 24 , Richard J Kahnoski 24 , Brian R Lane 25 , Sabrina L Noyes 26 , David Petillo 26 , Leandro M Colli 1 , Joshua N Sampson 1 , Celine Besse 27 , Helene Blanche 28 , Anne Boland 27 , Laurie Burdette 1 , Egor Prokhortchouk 29 , Konstantin G Skryabin 29 , Meredith Yeager 1 , Mirjana Mijuskovic 30 , Miodrag Ognjanovic 31 , Lenka Foretova 31 , Ivana Holcatova 32 , Vladimir Janout 33 , Dana Mates 34 , Anush Mukeriya 35 , Stefan Rascu 36 , David Zaridze 35 , Vladimir Bencko 37 , Cezary Cybulski 38 , Eleonora Fabianova 12 , Viorel Jinga 37 , Jolanta Lissowska 39 , Jan Lubinski 40 , Marie Navratilova 32 , Peter Rudnai 41 , Neonila Szeszenia-Dabrowska 42 , Simone Benhamou 43 , Geraldine Cancel-Tassin 44 , Olivier Cussenot 45 , H Bas Bueno-de-Mesquita 46 , Federico Canzian 47 , Eric J Duell 48 , Börje Ljungberg 49 , Raviprakash T Sitaram 49 , Ulrike Peters 50 , Emily White 50 , Garnet L Anderson 50 , Lisa Johnson 50 , Juhua Luo 51 , Julie Buring 21 , I-Min Lee 52 , Wong-Ho Chow 4 , Lee E Moore 1 , Christopher Wood 53 , Timothy Eisen 54 , James Larkin 55 , Toni K Choueiri 19 , G Mark Lathrop 56 , Bin Tean Teh 26 , Jean-Francois Deleuze 57 , Xifeng Wu 4 , Richard S Houlston 58 , Paul Brennan 2 , Stephen J Chanock 1 , Ghislaine Scelo 2 , Mark P Purdue 1
Affiliation
BACKGROUND
Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
OBJECTIVE
We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
DESIGN, SETTING, AND PARTICIPANTS
Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
RESULTS AND LIMITATIONS
Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).
CONCLUSIONS
Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
PATIENT SUMMARY
Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
中文翻译：
与较长端粒长度相关的遗传变异与肾细胞癌风险增加有关。
背景 在多项研究中，外周血白细胞的相对端粒长度已被评估为肾细胞癌（RCC）风险的潜在生物标志物，但结果相互矛盾。目的 我们对与白细胞端粒长度相关的遗传变异进行了分析，以使用孟德尔随机化评估端粒长度与肾细胞癌风险之间的关系，这种方法不受可能影响早期研究的时间变异性和反向因果关系偏差的影响。设计、设置和参与者 来自 6 项 RCC 全基因组关联研究 (GWAS) 的 10 784 例病例和 20 406 例无癌对照的 9 种端粒长度相关变异的基因型被汇总成加权遗传风险评分 (GRS)，预测白细胞端粒长度。结果测量和统计分析 在各个 GWAS 数据集中计算与 GRS 和 RCC 风险相关的优势比 (OR)，并通过荟萃分析进行合并。结果和局限性 基因推断端粒长度较长与 RCC 风险增加相关（每预测千碱基增加 OR=2.07，95% 置信区间 [CI]:=1.70-2.53，p<0 id=31>0.5），GWAS-从端粒长度 GRS 中识别出 RCC 风险变异（rs10936599 和 rs9420907）；尽管排除了这一因素，GRS 和 RCC 风险之间仍然存在统计学上显着的关联（OR=1.73，95% CI=1.36-2.21，p<0.0001）。对各个组织学亚型的探索性分析表明，透明细胞 (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001)、乳头状细胞 (N=573, OR=1.96, 95) 与端粒长度 GRS 具有可比较的相关性% CI=1.01-3.81，p=0.046）和嫌色肾细胞癌（N=203，OR=2.37，95% CI=0.78-7.17，p=0.13）。 结论 我们的调查增加了越来越多的证据表明端粒长度较长的某些方面对于 RCC 风险很重要。患者摘要 端粒是染色体末端的 DNA 片段，可维持染色体稳定性。我们的研究调查了与端粒长度相关的遗传变异与肾细胞癌风险之间的关系。我们发现的证据表明，具有较长端粒长度遗传倾向的个体患肾细胞癌的风险增加。
更新日期：2017-08-07
中文翻译：
与较长端粒长度相关的遗传变异与肾细胞癌风险增加有关。
背景 在多项研究中，外周血白细胞的相对端粒长度已被评估为肾细胞癌（RCC）风险的潜在生物标志物，但结果相互矛盾。目的 我们对与白细胞端粒长度相关的遗传变异进行了分析，以使用孟德尔随机化评估端粒长度与肾细胞癌风险之间的关系，这种方法不受可能影响早期研究的时间变异性和反向因果关系偏差的影响。设计、设置和参与者 来自 6 项 RCC 全基因组关联研究 (GWAS) 的 10 784 例病例和 20 406 例无癌对照的 9 种端粒长度相关变异的基因型被汇总成加权遗传风险评分 (GRS)，预测白细胞端粒长度。结果测量和统计分析 在各个 GWAS 数据集中计算与 GRS 和 RCC 风险相关的优势比 (OR)，并通过荟萃分析进行合并。结果和局限性 基因推断端粒长度较长与 RCC 风险增加相关（每预测千碱基增加 OR=2.07，95% 置信区间 [CI]:=1.70-2.53，p<0 id=31>0.5），GWAS-从端粒长度 GRS 中识别出 RCC 风险变异（rs10936599 和 rs9420907）；尽管排除了这一因素，GRS 和 RCC 风险之间仍然存在统计学上显着的关联（OR=1.73，95% CI=1.36-2.21，p<0.0001）。对各个组织学亚型的探索性分析表明，透明细胞 (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001)、乳头状细胞 (N=573, OR=1.96, 95) 与端粒长度 GRS 具有可比较的相关性% CI=1.01-3.81，p=0.046）和嫌色肾细胞癌（N=203，OR=2.37，95% CI=0.78-7.17，p=0.13）。 结论 我们的调查增加了越来越多的证据表明端粒长度较长的某些方面对于 RCC 风险很重要。患者摘要 端粒是染色体末端的 DNA 片段，可维持染色体稳定性。我们的研究调查了与端粒长度相关的遗传变异与肾细胞癌风险之间的关系。我们发现的证据表明，具有较长端粒长度遗传倾向的个体患肾细胞癌的风险增加。
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