TY - JOUR
T1 - Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk
AU - Jordahl, Kristina M.
AU - Phipps, Amanda I.
AU - Randolph, Timothy W.
AU - Tinker, Lesley F.
AU - Nassir, Rami
AU - Hou, Lifang
AU - Anderson, Garnet L.
AU - Kelsey, Karl T.
AU - White, Emily
AU - Bhatti, Parveen
N1 - Funding Information:
The WHI program collected the questionnaire data and specimens for the current study and was funded by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.
Funding Information:
This study was supported by the American Cancer Society under Grant 125299-RSG-13-100-01-CCE; and Kristina M. Jordahl was also supported by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) under Training Grants R25 CA094880 and T32 CA094880 for the data analysis, interpretation of data, and writing of the manuscript. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - Background: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). Methods: Among 412 bladder cancer cases and 424 controls from the Women’s Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. Results: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. Conclusions: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.
AB - Background: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). Methods: Among 412 bladder cancer cases and 424 controls from the Women’s Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. Results: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. Conclusions: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.
KW - Bladder cancer
KW - Bladder cancer risk SNPs
KW - DNA methylation
KW - Mediation analysis
UR - http://www.scopus.com/inward/record.url?scp=85096296680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096296680&partnerID=8YFLogxK
U2 - 10.1186/s12881-020-01172-1
DO - 10.1186/s12881-020-01172-1
M3 - Article
C2 - 33213418
AN - SCOPUS:85096296680
VL - 21
JO - BMC Medical Genomics
JF - BMC Medical Genomics
SN - 1755-8794
IS - 1
M1 - 228
ER -
