| Title: | Using Mendelian randomization to investigate etiologic heterogeneity across renal cell carcinoma subtypes |
| Journal: | International Journal of Epidemiology |
| Published: | 14 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41170685/ |
| DOI: | https://doi.org/10.1093/ije/dyaf177 |
Publication 19181
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Abstract
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.</p>
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.</p>
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.</p>
CONCLUSION: These results highlight the heterogeneous nature of RCC etiology and the importance of considering histologic subtypes in etiologic and genetic studies.</p>
13 Keywords
- Aged
- Body Mass Index
- Carcinoma, Renal Cell
- Female
- Genome-Wide Association Study
- Humans
- Kidney Neoplasms
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Obesity
- Risk Factors
- Smoking
141 Authors
- Timothy D Winter
- Om Jahagirdar
- Mark P Purdue
- Diptavo Dutta
- Mitchell J Machiela
- Bryan R Gorman
- Timothy Winter
- Dayne Okuhara
- Sara Cleland
- Aida Ferreiro-Iglesias
- Paul Scheet
- Aoxing Liu
- Chao Wu
- Samuel O Antwi
- James Larkin
- Stênio C Zequi
- Maxine Sun
- Keiko Hikino
- Ali Hajiran
- Keith A Lawson
- Flavio Cárcano
- Odile Blanchet
- Brian Shuch
- Kenneth G Nepple
- Gaëlle Margue
- Debasish Sundi
- W Ryan Diver
- Maria A A K Folgueira
- Adrie van Bokhoven
- Florencia Neffa
- Kevin M Brown
- Jonathan N Hofmann
- Jongeun Rhee
- Meredith Yeager
- Nathan R Cole
- Belynda D Hicks
- Michelle R Manning
- Amy A Hutchinson
- Nathaniel Rothman
- Wen-Yi Huang
- W Marston Linehan
- Adriana Lori
- Matthieu Ferragu
- Merzouka Zidane-Marinnes
- Sérgio Serrano
- Wesley J Magnabosco
- BioBank Japan Project Consortium
- Ana Vilas
- Ricardo Decia
- Florencia Carusso
- Laura S Graham
- Kyra Anderson
- Mehmet A Bilen
- Cletus Arciero
- Isabelle Pellegrin
- Solène Ricard
- Ghislaine Scelo
- Rosamonde E Banks
- Naveen S Vasudev
- Naeem Soomro
- Grant D Stewart
- Adebanji Adeyoju
- Stephen Bromage
- David Hrouda
- Norma Gibbons
- Poulam Patel
- Mark Sullivan
- Andrew Protheroe
- Francesca I Nugent
- Michelle J Fournier
- Xiaoyu Zhang
- Lisa J Martin
- Maria Komisarenko
- Timothy Eisen
- Sonia A Cunningham
- Denise C Connolly
- Robert G Uzzo
- David Zaridze
- Anush Mukeria
- Ivana Holcatova
- Anna Hornakova
- Lenka Foretova
- Vladimir Janout
- Dana Mates
- Viorel Jinga
- Stefan Rascu
- Mirjana Mijuskovic
- Slavisa Savic
- Sasa Milosavljevic
- Valérie Gaborieau
- Behnoush Abedi-Ardekani
- James McKay
- Mattias Johansson
- Larry Phouthavongsy
- Lindsay Hayman
- Jason Li
- Ilinca Lungu
- Stephania M Bezerra
- Aline G de Souza
- Claudia T G Sares
- Rodolfo B Reis
- Fabio P Gallucci
- Mauricio D Cordeiro
- Mark Pomerantz
- Gwo-Shu M Lee
- Matthew L Freedman
- Anhyo Jeong
- Samantha E Greenberg
- Alejandro Sanchez
- R Houston Thompson
- Vidit Sharma
- David D Thiel
- Colleen T Ball
- Diego Abreu
- Elaine T Lam
- William C Nahas
- Viraj A Master
- Alpa V Patel
- Jean-Christophe Bernhard
- Neal D Freedman
- Pierre Bigot
- Rui M Reis
- Leandro M Colli
- Antonio Finelli
- Brandon J Manley
- Chikashi Terao
- Toni K Choueiri
- Dirce M Carraro
- Richard Houlston
- Jeanette E Eckel-Passow
- Philip H Abbosh
- Andrea Ganna
- Paul Brennan
- Jian Gu
- Stephen J Chanock
- Mattias Johansson
- Paul Brennan
- Mitchell J. Machiela
- Stephen J. Chanock
- Mark P. Purdue
- Diptavo Dutta
1 Application
| Application ID | Title |
|---|---|
| 86140 | Genome-wide association study of renal cell carcinoma |
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