Antihypertensive drug targets and breast cancer risk : a two-sample Mendelian randomization study
Zheng, Guoqiao LU ; Chattopadhyay, Subhayan LU
; Sundquist, Jan
LU
; Sundquist, Kristina
LU
and Ji, Jianguang
LU
(2024)
In European Journal of Epidemiology
- Abstract
Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects... (More)
Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects on BC risk. We further performed sensitivity analyses to confirm the discovered MR associations such as assessment of horizontal pleiotropy, colocalization, and multiple tissue enrichment analyses. The overall BC risk was only associated with SLC12A2 gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of SLC12A2 gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80-1.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06-1.28). This signal was further observed for estrogen receptor positive (ER +) BC (1.17, 1.06-1.28). In addition, one SD decrease in expression of PDE1B in blood was associated with 7% decreased risk of ER + BC (0.93, 0.90-0.97). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5, 40.5 and 66.8%, respectively. No significant association was observed between other target gene expressions and BC risk. Changes in expression of SLC12A2 and PDE1B mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.
(Less)
- author
- Zheng, Guoqiao
LU
; Chattopadhyay, Subhayan
LU
; Sundquist, Jan
LU
; Sundquist, Kristina
LU
and Ji, Jianguang
LU
- organization
- publishing date
- 2024-02-24
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- European Journal of Epidemiology
- publisher
- Springer
- external identifiers
-
- scopus:85185932767
- pmid:38396187
- ISSN
- 1573-7284
- DOI
- 10.1007/s10654-024-01103-x
- language
- English
- LU publication?
- yes
- additional info
- © 2024. The Author(s).
- id
- 46bf6ef1-2695-43a7-a117-a96b18d6d5a7
- date added to LUP
- 2024-02-26 14:36:51
- date last changed
- 2024-04-17 15:23:37
@article{46bf6ef1-2695-43a7-a117-a96b18d6d5a7,
abstract = {{<p>Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects on BC risk. We further performed sensitivity analyses to confirm the discovered MR associations such as assessment of horizontal pleiotropy, colocalization, and multiple tissue enrichment analyses. The overall BC risk was only associated with SLC12A2 gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of SLC12A2 gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80-1.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06-1.28). This signal was further observed for estrogen receptor positive (ER +) BC (1.17, 1.06-1.28). In addition, one SD decrease in expression of PDE1B in blood was associated with 7% decreased risk of ER + BC (0.93, 0.90-0.97). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5, 40.5 and 66.8%, respectively. No significant association was observed between other target gene expressions and BC risk. Changes in expression of SLC12A2 and PDE1B mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.</p>}},
author = {{Zheng, Guoqiao and Chattopadhyay, Subhayan and Sundquist, Jan and Sundquist, Kristina and Ji, Jianguang}},
issn = {{1573-7284}},
language = {{eng}},
month = {{02}},
publisher = {{Springer}},
series = {{European Journal of Epidemiology}},
title = {{Antihypertensive drug targets and breast cancer risk : a two-sample Mendelian randomization study}},
url = {{http://dx.doi.org/10.1007/s10654-024-01103-x}},
doi = {{10.1007/s10654-024-01103-x}},
year = {{2024}},
}