Abstract
Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.
Highlights
Homocysteine is derived from the essential amino acid methionine [1] and functions as a metabolic intermediate of the methionine cycle that is essential for one-carbon metabolism [2]
All the results confirmed no pleiotropy effects on our estimated associations. This two-sample Mendelian randomization (MR) study suggested no putative relationships between plasma homocysteine levels and the risk of breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC)
Higher plasma homocysteine levels tend to be associated with metabolic disorders, even cancer; but the conclusions drawn from previous observational studies on associations between levels of plasma homocysteine with cancer risk are controversial given that other studies found no evidence for casual associations between genetically-determined plasma homocysteine levels with risk of hormone-related cancers
Summary
Homocysteine is derived from the essential amino acid methionine [1] and functions as a metabolic intermediate of the methionine cycle that is essential for one-carbon metabolism [2]. Activated by ATP, methionine is converted to S-adenosyl methionine (SAM), a donor for DNA methylation [3] that leads to producing homocysteine as a crucial intermediate for methionine regeneration This process requires a 5methyl-tetra-hydrogen-folate (5-MTHF) unit and a specialized methyltransferase that uses vitamin B12 as a coenzyme [4]. Reduced plasma homocysteine levels had been reported in some clinical cases of patients who received hormone replacement therapy for post-menopause or severe hypothyroidism [10, 11] On one hand, this negative correlation between hormone and homocysteine levels may be explained by the effects of hormones (estrogen or thyroid hormones) on various enzymes including those involved in methionine metabolism. Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. We investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses
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