The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium.
The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium.
复制标题
DOI：
10.1007/s10552-015-0654-9
复制
发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Martin RM
中科院分区：
文献类型：
--
作者：
Davies NM;Gaunt TR;Lewis SJ;Holly J;Donovan JL;Hamdy FC;Kemp JP;Eeles R;Easton D;Kote-Jarai Z;Al Olama AA;Benlloch S;Muir K;Giles GG;Wiklund F;Gronberg H;Haiman CA;Schleutker J;Nordestgaard BG;Travis RC;Neal D;Pashayan N;Khaw KT;Stanford JL;Blot WJ;Thibodeau S;Maier C;Kibel AS;Cybulski C;Cannon-Albright L;Brenner H;Park J;Kaneva R;Batra J;Teixeira MR;Pandha H;PRACTICAL consortium;Lathrop M;Smith GD;Martin RM
流行病学研究表明，肥胖和成年身高的决定因素在前列腺癌的风险和死亡率中具有潜在的作用，但文献中描述的关系是复杂的。为了解决先前观察结果因果关系的不确定性，我们研究了身高和肥胖相关的遗传变异与前列腺癌风险和死亡率的关系。我们进行了一项病例对照研究，该研究基于PRACTICAL联盟的22项研究中的20，848例前列腺癌和20，214例欧洲血统对照。我们构建了遗传风险评分，将每个人的身高和BMI增加等位基因的数量相加，这些等位基因跨越多个单核苷酸多态性，这些多态性与已发表的全基因组关联研究中的每个表型密切相关。遗传风险评分分别解释了身高和BMI变异性的6.31%和1.46%。只有微弱的证据表明，先前与BMI增加相关的遗传变异与前列腺癌风险降低相关（BMI遗传评分每标准差增加的比值比为0.98; 95% CI 0.96，1.00; p = 0.07）。与身高增加相关的遗传变异与前列腺癌发病率无关（OR 0.99; 95% CI 0.97，1.01; p = 0.23），但与低级别疾病中前列腺癌死亡率增加（OR 1.13; 95% CI 1.08，1.20）相关（p异质性，低与高级别<0.001）。与BMI增加相关的遗传变异与轻度疾病男性的全因死亡率增加（OR 1.08; 95% CI 1.03，1.14）相关（p异质性= 0.03）。我们发现几乎没有证据表明遗传性身高或BMI升高对前列腺癌风险有实质性影响，这表明先前报道的观察性关联可能反映了身高或BMI和前列腺癌风险的共同环境决定因素。遗传性升高的身高和BMI与低级别疾病男性的死亡率（分别为前列腺癌特异性和全因死亡率）增加相关，这是一个潜在的信息，但需要复制的新发现。本文的在线版本（doi：10.1007/s10552-015-0654-9）包含补充材料，可供授权用户使用。
Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication. The online version of this article (doi:10.1007/s10552-015-0654-9) contains supplementary material, which is available to authorized users.