成人身体质量指数与不同亚型卵巢癌风险：一项孟德尔随机化研究
Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.
作者信息
Dixon Suzanne C, Nagle Christina M, Thrift Aaron P, Pharoah Paul Dp, Pearce Celeste Leigh, Zheng Wei, Painter Jodie N, Chenevix-Trench Georgia, Fasching Peter A, Beckmann Matthias W, Lambrechts Diether, Vergote Ignace, Lambrechts Sandrina, Van Nieuwenhuysen Els, Rossing Mary Anne, Doherty Jennifer A, Wicklund Kristine G, Chang-Claude Jenny, Rudolph Anja, Moysich Kirsten B, Odunsi Kunle, Goodman Marc T, Wilkens Lynne R, Thompson Pamela J, Shvetsov Yurii B, Dörk Thilo, Park-Simon Tjoung-Won, Hillemanns Peter, Bogdanova Natalia, Butzow Ralf, Nevanlinna Heli, Pelttari Liisa M, Leminen Arto, Modugno Francesmary, Ness Roberta B, Edwards Robert P, Kelley Joseph L, Heitz Florian, Karlan Beth Y, Kjær Susanne K, Høgdall Estrid, Jensen Allan, Goode Ellen L, Fridley Brooke L, Cunningham Julie M, Winham Stacey J, Giles Graham G, Bruinsma Fiona, Milne Roger L, Southey Melissa C, Hildebrandt Michelle A T, Wu Xifeng, Lu Karen H, Liang Dong, Levine Douglas A, Bisogna Maria, Schildkraut Joellen M, Berchuck Andrew, Cramer Daniel W, Terry Kathryn L, Bandera Elisa V, Olson Sara H, Salvesen Helga B, Thomsen Liv Cecilie, Kopperud Reidun K, Bjorge Line, Kiemeney Lambertus A, Massuger Leon F A G, Pejovic Tanja, Cook Linda S, Le Nhu D, Swenerton Kenneth D, Brooks-Wilson Angela, Kelemen Linda E, Lubiński Jan, Huzarski Tomasz, Gronwald Jacek, Menkiszak Janusz, Wentzensen Nicolas, Brinton Louise, Yang Hannah, Lissowska Jolanta, Høgdall Claus K, Lundvall Lene, Song Honglin, Tyrer Jonathan P, Campbell Ian, Eccles Diana, Paul James, Glasspool Rosalind, Siddiqui Nadeem, Whittemore Alice S, Sieh Weiva, McGuire Valerie, Rothstein Joseph H, Narod Steven A, Phelan Catherine, Risch Harvey A, McLaughlin John R, Anton-Culver Hoda, Ziogas Argyrios, Menon Usha, Gayther Simon A, Ramus Susan J, Gentry-Maharaj Aleksandra, Wu Anna H, Pike Malcolm C, Tseng Chiu-Chen, Kupryjanczyk Jolanta, Dansonka-Mieszkowska Agnieszka, Budzilowska Agnieszka, Spiewankiewicz Beata, Webb Penelope M
机构信息
Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia The University of Queensland, School of Public Health, Brisbane, QLD, Australia
Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia The University of Queensland, School of Public Health, Brisbane, QLD, Australia.
出版信息
Int J Epidemiol. 2016 Jun;45(3):884-95. doi: 10.1093/ije/dyw158. Epub 2016 Jul 10.
BACKGROUND
Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.
METHODS
We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.
RESULTS
Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).
CONCLUSIONS
Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
背景
观察性研究报告称体重指数（BMI）与卵巢癌风险之间存在正相关。然而，这是否代表因果效应，或者是否适用于所有组织学亚型，仍存在疑问。例如，浆液性癌缺乏相关性可能是由于疾病相关的体重减轻。孟德尔随机化（MR）使用基因标记作为风险因素的替代指标，以克服观察性研究的局限性。我们使用MR来阐明BMI与卵巢癌之间的关系，假设基因预测的BMI与非高级别浆液性卵巢癌（non-HGSC）风险增加相关，但与HGSC无关。
方法
我们汇总了卵巢癌协会联盟中39项研究（14047例病例，23003例对照）的数据。我们构建了一个加权遗传风险评分（GRS，部分F统计量=172），将先前与BMI相关的87个单核苷酸多态性的等位基因相加，并根据其与BMI的已发表关联强度进行加权。应用两阶段预测变量替代MR，我们使用逻辑回归来估计基因预测的BMI与风险之间关联的研究特异性比值比（OR）和95%置信区间（CI），并使用随机效应荟萃分析对这些结果进行汇总。
结果
基因预测的较高BMI与non-HGSC风险增加相关（每5个BMI单位的汇总OR=1.29，95%CI为1.03-1.61），但与HGSC无关（汇总OR=1.06，95%CI为0.88-1.27）。按行为/亚型分层的二次分析表明，与观察性数据一致，该关联在低级别/交界性浆液性癌中最强（OR=1.93，95%CI为1.33-2.81）。
结论
我们的数据表明，较高的BMI会增加non-HGSC的风险，但不会增加更常见且侵袭性更强的HGSC亚型的风险，这证实了观察性证据。
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