Causal Relationship of Nitrogen Dioxides Air Pollution with Risk of Breast Cancer: A Two-sample Mendelian Randomization Study

doi:10.21203/rs.3.rs-4831686/v1

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Causal Relationship of Nitrogen Dioxides Air Pollution with Risk of Breast Cancer: A Two-sample Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-4831686/v1

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Background

Whether nitrogen dioxides (NO₂) air pollution genetically regulate the risk of breast cancer (BC) remains unknown. This study aims to investigate the cause-and-effect relationship of NO₂ air pollution with risk of BC.

Methods

A two-sample Mendelian randomization (MR) analysis was performed. The inverse-variance weighted (IVW) method and the weighted median (WM) method were applied to analyze the causal relationship. Cochran's Q statistic method and MR-Egger intercept test were used to assess heterogeneity and pleiotropy. MR-Egger regression and leave-one-out analysis were performed to assess sensitivity.

Results

IVW and WM methods demonstrated that NO₂ air pollution (with any potential confounders) was significantly associated with higher odds of BC overall [OR (95%CI): 1.69 (1.13, 2.54); 1.70 (1.02, 2.86)] (P = 0.01; 0.04). No significant heterogeneity (P = 0.33) and horizontal pleiotropy (P = 0.19) were present in the correlation analysis of NO₂ air pollution and risk of BC overall. After excluding SNPs of NO₂ with any potential confounders, IVW model demonstrated that NO₂ air pollution was still significantly associated with higher odds of BC overall [OR (95%CI): 4.15 (1.52, 11.31)] (P = 0.005). In the subtype analysis for ER + BC and ER- BC, causal relationship between NO₂ air pollution (removing any potential confounders) and estrogen receptor negative (ER-) BC was observed [OR (95%CI): 4.15 (1.52, 11.31)] (P = 0.005).

Conclusion

Increased exposure of NO₂ air pollution causally raises the chance of BC independent of ER, providing a recommendation to reduce NO₂ air pollution for future BC prevention.

human

nitrogen dioxide

air pollution

breast cancer

genetic association

Breast cancer (BC) is a type of malignant neoplasm of breast caused by acquired DNA lesion and gene alterations, or inherited DNA deficiencies or tumor-promoting genes[1]. BC mainly originates from ducts or lobules in situ[2]. As course advances, BC cells can go out of ducts and lobules into nearby adipose and connective tissues of mammary gland in an invasive form[2]. With further deterioration, invasive BC can diffuse to adjacent lymphonodus and other organs, named regional metastasis and distant metastasis, respectively[3]. The global number of BC estimated by GLOBOCAN 2020 stood at 2.261 million fresh events and 685,000 death tolls, listed first among malignant tumors[4]. As is well known, one-eighth of female is affected by hereditary and environmental factors in evolution of BC[5]. Thereby, discerning relative weights and secular inclination of variable environmental risk drivers is crucial for BC controlling[6].

Nitrogen dioxides (NO₂) is a pollutant gas with properties of reddish-brown color, strong- oxidant, toxic and irritating[7]. NO₂ is the main raw material for nitrate aerosols, which are notable piece for the formation of particulate matter (PM)_2.5 and ozone[8]. NO₂ in environment is mainly from quick oxidization of nitric oxide (NO) by oxidants during fuels burning[9]. The outdoor and indoor source of NO₂ are vehicle exhaust, and tobacco smoke and gas-, wood-, oil-, kerosene- and coal-burning appliances, respectively[9]. NO₂ typically represents the mingle of contaminants related to traffic in epidemiological studies[10, 11]. In published epidemiological literatures, some have found NO₂ exposure was proportional to risk of breast cancer, while others exhibited no significant correlation between the two[12–16]. The discrepancy of these results could possibly attribute to reverse causality and confounders, such as heterogenous evaluation method for NO₂ exposure, spatial and temporal instability for NO₂ concentration, heterogeneity in research design, and small sample size[17]. To address shortcomings of traditional epidemiological studies conducted in an observational manner, mendelian randomization (MR) is a test measuring the casual impact of exposure on outcome from an epigenetic perspective, unaffected by reverse causality and confounders[18]. To date, the casual impact of NO₂ air pollution on BC has not yet been described.

In this study, a two-sample MR design was adopted to assess possible causal relationships of NO₂ air pollution with risk of BC.

An overview of the study design is shown in Fig. 1. A two-sample MR design based on public summary-level data derived from genome-wide association studies (GWASs) was adopted to evaluate the possible causal relationship of NO₂ air pollution with risk of BC.

Instrumental Variable Selection

Summary-level data of NO₂ air pollution (GWAS ID: ukb-b-9942) were obtained from UK Biobank conducted among individuals of European ancestry (N = 456,380) (Table S2). The summary data is available on the website (https://gwas.mrcieu.ac.uk/datasets/ukb-b-9942/). Single nucleotide polymorphisms (SNPs) associated with NO₂ were selected at the genome-wide significance level of P < 5×10^− 8. When the r² of SNPs was less than 0.001 within a 10 Mb window, the SNP with a higher significant P-value was removed from the analysis. The SNPs with a minor allele frequency (MAF) < 0.01 were also excluded. An overview of these data has been shown in the Table S1.

Outcome Data Source

The genetic variants of BC (combined Oncoarray; iCOGS; GWAS meta-analysis) were enrolled from Breast Cancer Association Consortium (BCAC) conducted among individuals of European ancestry. Three datasets of BC overall, estrogen receptor positive (ER+) BC and estrogen receptor negative (ER-) BC (GWAS ID: ieu-a-1126; ieu-a-1127; ieu-a-1128) were included (N = 228,951; 175,475; 127,442) (Table S2)[19]. The summary data is available on the website (https://gwas.mrcieu.ac.uk/datasets/ieu-a-1126/; https://gwas.mrcieu.ac.uk/datasets/ ieu-a-1127/; https://gwas.mrcieu.ac.uk/datasets/ieu-a-1128/).

Statistical analyses

The MR method was used to explore the causal associations of genetically predicted difference of the per one standard deviation (SD) increase in NO₂ air pollution with risk of BC by reporting odds ratios (ORs). Importantly, the conventional inverse-variance weighted (IVW) method and the weighted median (WM) method were used in the primary analysis[20]. The Cochran’s Q test under the IVW model was used to quantify heterogeneity[21]. The MR-Egger regression model was used to check for unknown pleiotropic effects. A non-zero intercept from MR-Egger indicates that the IVW estimate may be invalid due to horizontal pleiotropy[22]. Sensitivity analysis based on the MR-Egger regression model and leave-one-out sensitivity analysis were also performed[22]. Furthermore, the PhenoScanner database was searched to see whether the selected SNPs were associated with possible pleiotropy, such as BMI, blood pressure, fat percentage, alcohol intake and etc., at a genome-wide significance level of P < 5×10^− 8 and the analysis based on IVW model was repeated after removing these SNPs[23, 24].

All statistical analyses were conducted by R software (R 4.0.5, The R Foundation for Statistical Computing) and “TwoSampleMR” package[25]. The two-sided significance level was set at 0.05 for all analyses.

The Genetic Variants Associated with NO₂ air pollution

In the NO₂ variants, and 8 SNPs associated with NO₂ air pollution were obtained from 9,851,867 SNPs (all P < 5×10^− 8, r² < 0.001, 10000 kb, MAF > 0.01) (Table S1).

Cause-and-Effect Relationship of NO₂ air pollution with Risk of Breast Cancer

First of all, the analysis was performed in SNPs of NO₂ air pollution with potential confounders. According to the IVW and WM models, NO₂ air pollution was significantly associated with higher odds of BC overall [OR (95%CI): 1.69 (1.13, 2.54); 1.70 (1.02, 2.86);] (P = 0.01; 0.04) (Table 1). No significant heterogeneity (P = 0.33) and horizontal pleiotropy (P = 0.19) were present in the correlation analysis of NO₂ air pollution and risk of BC overall (Table 2). In the leave-one-out sensitivity analyses, the correlation of NO₂ air pollution with BC overall did not remain by leaving rs79475047 out (Figure S2). In the analysis of BC classified by ER, NO₂ air pollution was roughly significantly associated with higher odds of ER + BC according to the IVW model [OR (95%CI): 1.63 (1.03, 2.56)] (P = 0.04) (Table 1).

Table 1

Inverse variance-weighted, weighted median analyses and sensitivity analysis of NO₂ air pollution and the risks of breast cancer.
Exposure	Outcome	Inverse variance-weighted method			Weighted median method			Sensitivity analysis^※
Exposure	Outcome	SNPs, n	OR (95%CI)	P-value	SNPs, n	OR (95%CI)	P-value	SNPs, n	OR (95%CI)	P-value
NO₂ air pollution	Breast cancer overall	8	1.69 (1.13, 2.54)	0.01	8	1.70 (1.02, 2.86)	0.04	4	4.15 (1.52, 11.31)	0.005
	ER + Breast cancer	8	1.63 (1.03, 2.56)	0.04	8	1.60 (0.90, 2.82)	0.11	4	1.77 (0.92, 3.42)	0.09
	ER- Breast cancer	8	1.24 (0.47, 3.24)	0.66	8	1.55 (0.57, 4.21)	0.39	4	4.15 (1.52, 11.31)	0.005
^※Sensitivity analysis were performed after removing the SNPs that were significantly associated with potential confounders under the inverse-variance weighted model.

Table 2

Cochran’s Q test, MR–Egger intercept, MR–Egger regression and sensitivity analysis of NO₂ air pollution and the risks of breast cancer.
Exposure	Outcome	Cochran’s Q test^†	MR-Egger intercept^‡			MR-Egger regression				Sensitivity analysis^※
Exposure	Outcome	P-value	β	SE	P-value	SNPs, n	β	SE	P-value	SNPs, n	β	SE		P-value
NO₂ air pollution	Breast cancer overall	0.33	-0.02	0.01	0.19	8	1.74	0.85	0.09	4	1.42		0.51	0.005
	ER + Breast cancer	0.79	-0.02	0.02	0.28	8	1.68	1.02	0.15	4	0.57		0.34	0.09
	ER- Breast cancer	0.06	-0.02	0.04	0.57	8	1.56	2.27	0.52	4	1.42		0.51	0.005
^†The Cochran’s Q test is a statistical test for heterogeneity.
^‡The intercept term from the MR–Egger regression method is a statistical test of horizontal pleiotropy.
^※Sensitivity analysis were performed after removing the SNPs that were significantly associated with potential confounders under the inverse-variance weighted mode.

Then, the analysis based on IVW model was repeated in SNPs of NO₂ air pollution removing any potential confounders. The results showed that NO₂ air pollution was significantly associated with higher odds of BC overall and ER- BC [OR (95%CI): 4.15 (1.52, 11.31); 4.15 (1.52, 11.31)] (P = 0.005; 0.005) (Table 1). Besides, there were no causal relationship of NO₂ air pollution on risk of ER + BC (P > 0.05) (Table 1).

The cause-and-effect relationships between NO₂ air pollution and risk of BC were evaluated for the first time in this study. Rough examination for the causal relationship was performed in SNPs of NO₂ with any potential confounders, and followed confirmation was rerun in SNPs of NO₂ without any potential confounders using IVW model.

In majority multi-step pathology of BC, ER is one of classic hormone receptors contributing to tumorigenesis and deterioration in ligand-dependent and -independent pathways[26, 27]. In ligand-dependent mechanism, ER works through genomic, tethered, and non-genomic pathways[27]. In genomic mode, after tight binding with estrogen, nuclear ER undergoes a conformational shift into a bioactive pattern, which then transfers into nucleus to facilitate transcription of target genes by intertwining with estrogen responsive elements (EREs), or cross-talking with activator protein 1 (AP1) and specific protein 1 (SP1) through serum responsive elements (SERs)[5]. In tethered mode, the direct coupling between DNA and ERE occurs followed by ligand activation[27]. In non-genomic mode, estrogen links with membranous ER to stimulate kinase pathways outside of nucleus, such as Ras-Raf-MEK-MAPK (mitogen-activated protein kinase), PI3K (phosphatidylinositide 3-kinase)-AKT (serine/threonine kinase)-rapamycin (mTOR), and PLC (phospholipase C)-inositol 1,4,5-trisphosphate (IP3)-IP3 receptors (IP3R)-Ca²⁺[26]. Distinctively, in ligand-independent mechanism, ER is triggered by insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and intracellular effector analog 8-bromo-cyclic adenosine monophosphate for dimerization, which anchors with DNA to regulate gene[27]. In clinic, ER + and ER- are two outline subtypes of BC according to breast cancer consensus subtypes (BCCS) [28]. In this MR analysis for estimating the causal relationship between NO₂ air pollution and risk of BC, three datasets (combined Oncoarray; iCOGS; GWAS meta-analysis) of BC overall and two subtypes of BC (ER + BC and ER- BC) were included as outcome variables.

In the NO₂ variants, clumping analysis extracted 8 SNPs associated with NO₂ air pollution from total 9,851,867 SNPs. In the initial analysis for SNPs of NO₂ (with any potential confounders), NO₂ air pollution was found positively associate with higher odds of BC overall according to IVW and WM models. No significant heterogeneity and horizontal pleiotropy were present in the correlation analysis of NO₂ air pollution and risk of BC overall. After removing SNPs of NO₂ with any potential confounders, IVW results displayed that NO₂ air pollution was still significantly associated with higher odds of BC overall. For inspecting the triggers of BC, analysis was conducted between NO₂ air pollution and ER + BC / ER- BC, separately. Consequently, causal relationship between NO₂ air pollution (removing any potential confounders) and ER- BC was observed.

Our result is consistent with some published findings. A California multiethnic cohort (CA MEC) study (57,589 female, from recruitment (1993–1996) through 2010), using land use regression (LUR) model, found positive effect of NO₂ air pollution on risk of ER- BC incidence in Japanese Americans [HR (95%CI): 3.81 (1.47–9.88)][29]. Another CA MEC study (3,089 breast cancer cases diagnosed from 1993 to 2013) revealed that NO₂ air pollution increased risk of ER- BC death by Empirical Bayesian kriging interpolation [HR (95%CI): 2.63 (1.19–5.83)][30]. The operative mechanism of NO₂ air pollution on ER- BC gets uncomplete interpretation. First, NO₂ is capable of promoting risk of breast cancer by elevating density of breast as a tumor-promoting agent, which is in line with the report by Perry et al. that breast density in urban women is higher than rural women[17, 31]. Second, NO₂ is able to upregulate risk of breast cancer by mitigating the methylation of protumorigenic genes including ephrin type-B receptor 2 (EPHB2) and mitochondrial lon protease (LonP1)[32]. Third, NO₂ can directly both interfere with endocrine and play carcinogenic effects[33]. Forth, NO₂ is closely related to else air pollutants, which possess underlying biological toxicity for BC incidence, such as ultra-fine particles (UFPs) or polycyclic aromatic hydrocarbons (PAHs)[34]. Altogether, heightened risk of BC, particular in BC independent of ER, will benefit from NO₂ air pollution via synergistic effect of elevated density of breast, mitigated methylation of EPHB2 and LonP1, direct role of interference with endocrine and promotion of cancer, and intimacy to other air pollutants.

This study has several advantages. First, this is the far-reaching population study to analyze the cause-and-effect relationships between NO₂ air pollution and risk of BC from an epigenetic perspective. Second, NO₂ air pollution was found causally associated with risk of BC, particular in BC independent of ER. Third, this result is reliable and valid because this MR study not only covaried out reverse causality and confounders in traditional epidemiological studies, but also avoided bias in individual studies by using the outcome datasets of BC combined Oncoarray, iCOGS and GWAS meta-analysis. However, there are also several limitations. First, outcome datasets of BC overall, ER + BC and ER- BC were available from only females. The causal effect of NO₂ air pollution on risk of BC in males were not presented this time, calling for establishment of specialized genomic datasets for male cases with BC in the future. Second, members of ER falls into nuclear ER (ERα and ERβ) and membranous G protein-coupled estrogen receptor 1 (GPER1, also named GPR30)[35]. However, ER-subclasses of BC were not analyzed in this MR study because of none sequencing datasets, this gap of which will be filled in the future. Third, this MR study did not consider other risk factors of BC including progesterone (PR), prolactin receptors, human epidermal growth factor receptor 2 (HER2), lifestyle (smoking and physical activity), reproductive factors (ages at menarche and menopause, use of exogenous hormones, number of children, age at first full-term pregnancy, and breastfeeding), anthropometric measurements (height, weight, waist and hip circumference), previous medical history (benign breast disease and gynecological screening), familial history of cancer, and urban / rural conditions[5, 36], which will be validated in the future. Forth, the reasonable mechanistic foundation about the causal effect of NO₂ air pollution on ER- BC will be shed light on in vivo and in vitro in foreseeable future.

Increased exposure of NO₂ air pollution causally raises the chance of BC independent of ER, providing a recommendation to reduce NO₂ air pollution for future BC prevention.

Financial support: This study was supported by grants from the National Natural Science Foundation of China (No. 82370847; 82000804, G.W.).

Disclosure Statement: The authors have nothing to disclose.

Conflicts of Interests: None declared.

Ethical consideration

This study utilized publicly available data from UK Biobank and BCAC that had already received ethical approval from a committee responsible for human experimentation. No additional ethical approval was necessary for this particular study.

Availability of data and materials

The data presented in this study are openly available in Table S2.

Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding sources

This study was supported by grants from the National Natural Science Foundation of China (No. 82370847; 82000804, G.W.).

Credit authorship contribution statement

LL: Conceptualization, Methodology, Software, Resources, Supervision, Project administration, Writing - Original Draft and Writing - Review & Editing. CZ: Formal analysis, Data Curation, Writing - Original Draft and Writing - Review & Editing. GW: Funding acquisition, Writing - Original Draft and Writing - Review & Editing.

Acknowledgements

We thank UK Biobank and BCAC, all the organizations and participants for the dataset in this study.

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No competing interests reported.

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You are reading this latest preprint version

Causal Relationship of Nitrogen Dioxides Air Pollution with Risk of Breast Cancer: A Two-sample Mendelian Randomization Study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Instrumental Variable Selection

Outcome Data Source

Statistical analyses

Results

The Genetic Variants Associated with NO₂ air pollution

Cause-and-Effect Relationship of NO₂ air pollution with Risk of Breast Cancer

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

Causal Relationship of Nitrogen Dioxides Air Pollution with Risk of Breast Cancer: A Two-sample Mendelian Randomization Study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Instrumental Variable Selection

Outcome Data Source

Statistical analyses

Results

The Genetic Variants Associated with NO2 air pollution

Cause-and-Effect Relationship of NO2 air pollution with Risk of Breast Cancer

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

The Genetic Variants Associated with NO₂ air pollution

Cause-and-Effect Relationship of NO₂ air pollution with Risk of Breast Cancer