Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk

Kristina M. Jordahl; Amanda I. Phipps; Timothy W. Randolph; Lesley F. Tinker; Rami Nassir; Lifang Hou; Garnet L. Anderson; Karl T. Kelsey; Emily White; Parveen Bhatti

doi:10.1186/s12881-020-01172-1

Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk

Kristina M. Jordahl^*, Amanda I. Phipps, Timothy W. Randolph, Lesley F. Tinker, Rami Nassir, Lifang Hou, Garnet L. Anderson, Karl T. Kelsey, Emily White, Parveen Bhatti

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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 (OR^NIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (OR^NIE = 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.

Original language	English (US)
Article number	228
Journal	BMC Medical Genetics
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12881-020-01172-1
State	Published - Dec 2020

Funding

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. 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.

Keywords

Bladder cancer
Bladder cancer risk SNPs
DNA methylation
Mediation analysis

ASJC Scopus subject areas

Genetics(clinical)
Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s12881-020-01172-1

Cite this

@article{3266532dc4514bf391900ed2886645bd,

title = "Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk",

abstract = "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{\textquoteright}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.",

keywords = "Bladder cancer, Bladder cancer risk SNPs, DNA methylation, Mediation analysis",

author = "Jordahl, {Kristina M.} and Phipps, {Amanda I.} and Randolph, {Timothy W.} and Tinker, {Lesley F.} and Rami Nassir and Lifang Hou and Anderson, {Garnet L.} and Kelsey, {Karl T.} and Emily White and Parveen Bhatti",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1186/s12881-020-01172-1",

language = "English (US)",

volume = "21",

journal = "BMC Medical Genetics",

issn = "1755-8794",

publisher = "BioMed Central",

number = "1",

}

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

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

SN - 1755-8794

VL - 21

JO - BMC Medical Genetics

JF - BMC Medical Genetics

IS - 1

M1 - 228

ER -

Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this