Circulating Inflammatory Markers and Mammographic Density Phenotypes: a Mendelian Randomization Analysis
- 1Department of Epidemiology, University of Washington School of Public Health
Abstract
Observational studies have identified associations between circulating inflammatory markers (CIMs) and mammographic density (MD) phenotypes, but whether these associations reflect causal effects remains unclear. We utilized two-sample Mendelian randomization (MR) to assess relationships between 60 CIMs and MD phenotypes in individuals of European genetic ancestry by examining associations between genetically predicted CIM concentrations and three MD phenotypes (dense area, DA: N = 13,965; non-dense area, NDA: N = 14,036; percent density, PMD: N = 17,841). Primary analyses were conducted using the inverse variance weighted MR method. No CIM-MD phenotype associations reached statistical significance after correction for multiple testing. At a nominal significance level of p < 0.05, we observed suggestive evidence for eight associations represented by six unique CIMs (MD phenotype/direction of association): CCL23 (DA/+), CD40 (NDA/-), GDNF (DA/+ & PMD/+), MMP-10 (DA/+ & PMD/+), TRANCE (DA/-), and TWEAK (NDA/+). In multivariable MR analyses accounting for body mass index (BMI), we observed six nominal associations represented by six unique CIMs, although most instruments demonstrated weak conditional instrument strength after inclusion of BMI. Overall, our comprehensive analysis of 60 CIMs provides limited evidence supporting broad causal effects of circulating inflammatory markers contributing to variation in MD phenotypes.
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BibTeX
@misc{suger2026circulating,
title = {{Circulating Inflammatory Markers and Mammographic Density Phenotypes: a Mendelian Randomization Analysis}},
author = {A. Hammermeister Suger and T. A. Harrison and C. B. Haas and H. Chen and S. Fan and M. K. Bolla and Q. Wang and J. Dennis and K. Michailidou and A. M. Dunning and D. F. Easton and M. C. Southey and P. A. Fasching and L. Haeberle and J. Stone and M. Gago-Dominguez and J. E. Castelao and K. Aronson and R. A. Murphy and D. G. Evans and S. Loi and kConFab Investigators and F. J. Couch and S. Yadav and R. L. Milne and C. A. Haiman and C. G. Scott and A. Norman and E. M. John and A. M. Mulligan and V. N. Kristensen and A. H. Eliassen and I. L. Andrulis and J. D. Figueroa and S. Astley and K. Czene and P. D. P. Pharoah and A. C. Antoniou and M. Garcia-Closas and Berrington},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362541},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362541v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Circulating Inflammatory Markers and Mammographic Density Phenotypes: a Mendelian Randomization Analysis
AU - A. Hammermeister Suger
AU - T. A. Harrison
AU - C. B. Haas
AU - H. Chen
AU - S. Fan
AU - M. K. Bolla
AU - Q. Wang
AU - J. Dennis
AU - K. Michailidou
AU - A. M. Dunning
AU - D. F. Easton
AU - M. C. Southey
AU - P. A. Fasching
AU - L. Haeberle
AU - J. Stone
AU - M. Gago-Dominguez
AU - J. E. Castelao
AU - K. Aronson
AU - R. A. Murphy
AU - D. G. Evans
AU - S. Loi
AU - kConFab Investigators
AU - F. J. Couch
AU - S. Yadav
AU - R. L. Milne
AU - C. A. Haiman
AU - C. G. Scott
AU - A. Norman
AU - E. M. John
AU - A. M. Mulligan
AU - V. N. Kristensen
AU - A. H. Eliassen
AU - I. L. Andrulis
AU - J. D. Figueroa
AU - S. Astley
AU - K. Czene
AU - P. D. P. Pharoah
AU - A. C. Antoniou
AU - M. Garcia-Closas
AU - Berrington
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362541
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362541v1
AB - Observational studies have identified associations between circulating inflammatory markers (CIMs) and mammographic density (MD) phenotypes, but whether these associations reflect causal effects remains unclear. We utilized two-sample Mendelian randomization (MR) to assess relationships between 60 CIMs and MD phenotypes in individuals of European genetic ancestry by examining associations between genetically predicted CIM concentrations and three MD phenotypes (dense area, DA: N = 13,965; non-dense area, NDA: N = 14,036; percent density, PMD: N = 17,841). Primary analyses were conducted using the inverse variance weighted MR method. No CIM-MD phenotype associations reached statistical significance after correction for multiple testing. At a nominal significance level of p < 0.05, we observed suggestive evidence for eight associations represented by six unique CIMs (MD phenotype/direction of association): CCL23 (DA/+), CD40 (NDA/-), GDNF (DA/+ & PMD/+), MMP-10 (DA/+ & PMD/+), TRANCE (DA/-), and TWEAK (NDA/+). In multivariable MR analyses accounting for body mass index (BMI), we observed six nominal associations represented by six unique CIMs, although most instruments demonstrated weak conditional instrument strength after inclusion of BMI. Overall, our comprehensive analysis of 60 CIMs provides limited evidence supporting broad causal effects of circulating inflammatory markers contributing to variation in MD phenotypes.
ER -