Dataset Information

Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.

ABSTRACT:

Background

Immune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.

Methods

We used individual-level data obtained from 10,179 women, including 537 who developed breast cancer, from the Women's Health Initiative Database for Genotypes and Phenotypes Study, which consists of five genome-wide association (GWA) studies. We examined 61 GWA single-nucleotide polymorphisms (SNPs) previously associated with CRP. We employed weighted/penalized weighted-medians and MR gene-environment interactions that allow instruments' invalidity to some extent and attenuate the heterogeneous estimates of outlying SNPs.

Results

In lifestyle-stratification analyses, genetically elevated CRP decreased risk for breast cancer in exogenous estrogen-only, estrogen + progestin, and past oral contraceptive (OC) users, but only among relatively short-term users (<5 years). Estrogen-only users for ?5 years had more profound CRP-decreased breast cancer risk in dose-response fashion, whereas past OC users for ?5 years had CRP-increased cancer risk. Also, genetically predicted CRP was strongly associated with increased risk for hormone-receptor positive or human epidermal growth factor receptor-2 negative breast cancer.

Conclusions

Our findings may provide novel evidence on the immune-related molecular pathways linking to breast cancer risk and suggest potential clinical use of CRP to predict the specific cancer subtypes. Our findings suggest potential interventions targeting CRP-inflammatory markers to reduce breast cancer risk.

SUBMITTER: Jung SY

PROVIDER: S-EPMC7888276 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.

Jung Su Yon SY Papp Jeanette C JC Sobel Eric M EM Pellegrini Matteo M Yu Herbert H Zhang Zuo-Feng ZF

Frontiers in oncology 20210203

<h4>Background</h4>Immune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.<h4>Methods</h4>We used individual-level data obtained from 10,179 women, including 537 who devel ...[more]

PMID: 33614510

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Project description:ObjectivesPrevious observational studies have suggested associations between concentrations of several circulating micronutrients and sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Therefore, we aimed to examine the causal effects of the levels of genetically predicted serum micronutrients on sarcopenia.MethodsSingle nucleotide polymorphisms (SNPs) were chosen from large-scale genome-wide association studies of participants only with European descent and were used as genetic instruments for the levels of 10 serum micronutrients (calcium, magnesium, selenium, copper, iron, zinc, Vitamin A, Vitamin B12, Vitamin D, and Vitamin E). Sarcopenia was defined by referencing to the 2019 definition given by the European Working Group on Sarcopenia in Older People (EWGSOP). A two-sample Mendelian randomization (MR) analysis was carried out to examine the associations between the levels of genetically predicted serum micronutrients and the risk of sarcopenia. Then, sensitivity analyses (including weighted median, MR-Egger and leave-one-out sensitivity analyses) were performed to evaluate the robustness of study findings. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs) per one standard deviation (SD) increase in the exposures.ResultsA total of 378,635 UK Biobank participants, including 572 participants who were identified with sarcopenia, were included in this study. The iron status was shown to have a clear effect on the risk of sarcopenia based on MR analyses. The per one SD increment in the genetically-determined serum iron level corresponded to a 53% increase in the risk of sarcopenia (OR = 1.53, 95% CI: 1.31-1.78, P = 0.001). The exclusion of SNPs of the circulating iron level (i.e., rs1799945 SNP, rs1800562 SNP or rs855791 SNP) did not attenuate the magnitude of the signal in MR analysis. There was little evidence supporting the associations between other remaining micronutrients and sarcopenia.ConclusionsAn increased risk of sarcopenia was observed with a genetically higher concentration of iron, suggesting that iron may play a role in the occurrence or development of sarcopenia.

Dataset Information

Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.

Background

Methods

Results

Conclusions

Publications

Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.

Similar Datasets

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