TY - JOUR
T1 - Using Mendelian randomization to investigate etiologic heterogeneity across renal cell carcinoma subtypes
AU - The Renal Cancer Genetics Consortium
AU - Winter, Timothy D.
AU - Jahagirdar, Om
AU - Johansson, Mattias
AU - Brennan, Paul
AU - Machiela, Mitchell J.
AU - Chanock, Stephen J.
AU - Purdue, Mark P.
AU - Dutta, Diptavo
AU - Purdue, Mark P.
AU - Machiela, Mitchell J.
AU - Gorman, Bryan R.
AU - Winter, Timothy
AU - Okuhara, Dayne
AU - Cleland, Sara
AU - Ferreiro-Iglesias, Aida
AU - Scheet, Paul
AU - Liu, Aoxing
AU - Wu, Chao
AU - Antwi, Samuel O.
AU - Larkin, James
AU - Zequi, Stênio C.
AU - Sun, Maxine
AU - Hikino, Keiko
AU - Hajiran, Ali
AU - Lawson, Keith A.
AU - Cárcano, Flavio
AU - Blanchet, Odile
AU - Shuch, Brian
AU - Nepple, Kenneth G.
AU - Margue, Gaëlle
AU - Sundi, Debasish
AU - Diver, W. Ryan
AU - Folgueira, Maria A.A.K.
AU - Van Bokhoven, Adrie
AU - Neffa, Florencia
AU - Brown, Kevin M.
AU - Hofmann, Jonathan N.
AU - Rhee, Jongeun
AU - Yeager, Meredith
AU - Cole, Nathan R.
AU - Hicks, Belynda D.
AU - Manning, Michelle R.
AU - Hutchinson, Amy A.
AU - Rothman, Nathaniel
AU - Huang, Wen Yi
AU - Linehan, W. Marston
AU - Lori, Adriana
AU - Connolly, Denise C.
AU - Uzzo, Robert G.
AU - Abbosh, Philip H.
N1 - Published by Oxford University Press on behalf of the International Epidemiological Association 2025.
PY - 2025/12/1
Y1 - 2025/12/1
N2 - Background Renal cell carcinoma (RCC) histological subtypes clear cell RCC (ccRCC; >75% of cases) and papillary RCC (papRCC; ∼15%) exhibit distinct molecular and genetic profiles, patient demographics, and prognoses. Previous epidemiologic studies have identified several risk factors for overall RCC, although few have explored differences in etiology across subtypes. Methods For this study, we applied two-sample Mendelian randomization (MR) to findings from a genome-wide association study of RCC (27 213 cases, 488 019 controls) to investigate the effects of RCC risk factors with ccRCC (15 507 cases) and papRCC (2103 cases). We also conducted case-only MR analyses contrasting ccRCC and papRCC cases to test for heterogeneity in risk factor effects across subtypes. Results MR for overall RCC confirmed associations with obesity, blood pressure, smoking, and several other suspected risk factors. In subtype-specific analyses, we observed stronger associations with ccRCC than for papRCC for anthropometric measures such as body mass index [ccRCC odds ratio (ORccRCC) = 1.58 per standard deviation increase, 95% confidence interval (CI) = 1.50-1.68; papRCC odds ratio (ORpapRCC) = 1.24, 95% CI = 1.07-1.42; Pheterogeneity = 2.7 × 10-4], while stronger associations with papRCC were observed for chronic kidney disease (ORccRCC = 1.07, 95% CI = 0.99-1.15; ORpapRCC = 1.39, 95% CI = 1.16-1.66; Pheterogeneity = 5.42 × 10-5), creatinine-based estimated glomerular filtration rate (ORccRCC = 0.96, 95% CI = 0.92-1.01; ORpapRCC = 0.71, 95% CI = 0.64-0.79; Pheterogeneity = 7.76 × 10-5), and telomere length (ORccRCC = 1.98, 95% CI = 1.93-2.06; ORpapRCC = 2.50, 95% CI = 2.28-2.72; Pheterogeneity = 6.2 × 10-3). Further analysis identified the colocalization of significant RCC risk loci and 20 risk factors along with potential target genes through transcriptomic analysis. Conclusion These results highlight the heterogeneous nature of RCC etiology and the importance of considering histologic subtypes in etiologic and genetic studies.
AB - Background Renal cell carcinoma (RCC) histological subtypes clear cell RCC (ccRCC; >75% of cases) and papillary RCC (papRCC; ∼15%) exhibit distinct molecular and genetic profiles, patient demographics, and prognoses. Previous epidemiologic studies have identified several risk factors for overall RCC, although few have explored differences in etiology across subtypes. Methods For this study, we applied two-sample Mendelian randomization (MR) to findings from a genome-wide association study of RCC (27 213 cases, 488 019 controls) to investigate the effects of RCC risk factors with ccRCC (15 507 cases) and papRCC (2103 cases). We also conducted case-only MR analyses contrasting ccRCC and papRCC cases to test for heterogeneity in risk factor effects across subtypes. Results MR for overall RCC confirmed associations with obesity, blood pressure, smoking, and several other suspected risk factors. In subtype-specific analyses, we observed stronger associations with ccRCC than for papRCC for anthropometric measures such as body mass index [ccRCC odds ratio (ORccRCC) = 1.58 per standard deviation increase, 95% confidence interval (CI) = 1.50-1.68; papRCC odds ratio (ORpapRCC) = 1.24, 95% CI = 1.07-1.42; Pheterogeneity = 2.7 × 10-4], while stronger associations with papRCC were observed for chronic kidney disease (ORccRCC = 1.07, 95% CI = 0.99-1.15; ORpapRCC = 1.39, 95% CI = 1.16-1.66; Pheterogeneity = 5.42 × 10-5), creatinine-based estimated glomerular filtration rate (ORccRCC = 0.96, 95% CI = 0.92-1.01; ORpapRCC = 0.71, 95% CI = 0.64-0.79; Pheterogeneity = 7.76 × 10-5), and telomere length (ORccRCC = 1.98, 95% CI = 1.93-2.06; ORpapRCC = 2.50, 95% CI = 2.28-2.72; Pheterogeneity = 6.2 × 10-3). Further analysis identified the colocalization of significant RCC risk loci and 20 risk factors along with potential target genes through transcriptomic analysis. Conclusion These results highlight the heterogeneous nature of RCC etiology and the importance of considering histologic subtypes in etiologic and genetic studies.
KW - Aged
KW - Body Mass Index
KW - Carcinoma, Renal Cell/genetics
KW - Female
KW - Genome-Wide Association Study
KW - Humans
KW - Kidney Neoplasms/genetics
KW - Male
KW - Mendelian Randomization Analysis
KW - Middle Aged
KW - Obesity/epidemiology
KW - Risk Factors
KW - Smoking/epidemiology
UR - https://www.scopus.com/pages/publications/105020651858
U2 - 10.1093/ije/dyaf177
DO - 10.1093/ije/dyaf177
M3 - Article
C2 - 41170685
AN - SCOPUS:105020651858
SN - 0300-5771
VL - 54
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
IS - 6
M1 - dyaf177
ER -
