Dataset Information

The impact of homocysteine on the risk of coronary artery diseases in individuals with diabetes: a Mendelian randomization study.

ABSTRACT:

Aims

Observational studies have reported that homocysteine (Hcy) is associated with an increased risk of coronary artery disease (CAD) in individuals with diabetes, though controversy remains. The present study aimed to investigate the causal association between Hcy and CAD in individuals with diabetes.

Methods

A 2-sample Mendelian randomization (MR) study was designed to infer causality. Genetic summary data on the association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) of up to 44,147 individuals of European ancestry. SNP-CAD data were obtained from another recently published GWAS which included 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The fixed-effects inverse variance-weighted method was employed to calculate the effect estimates. Other robust methods and leave-one-out analyses were used in the follow-up sensitivity analyses. Potential pleiotropy was assessed with the MR-Egger intercept test.

Results

The 2-sample MR analysis suggested no evidence of an association between genetically predicted plasma Hcy levels and CAD risk in individuals with diabetes (odds ratio = 1.14, 95% confidence interval: 0.82-1.58, p = 0.43) using 9 SNPs as instrumental variables. Similar results were observed in the follow-up sensitivity analyses. The MR-Egger intercept test indicated no evidence of directional pleiotropy (intercept = 0.03, 95% confidence interval: - 0.08-0.03, p = 0.35).

Conclusion

This 2-sample MR analysis found no evidence of a causal association between plasma Hcy levels and CAD risk in individuals with diabetes.

SUBMITTER: Xu T

PROVIDER: S-EPMC7907016 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Observational studies have reported that childhood obesity is positively associated with risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in adults; however, whether this association is causal is still unclear. In the present study, we conducted the 2-sample Mendelian randomization (MR) studies to investigate whether childhood obesity is causally associated with T2D and CAD in adults.Seven single-nucleotide polymorphisms (SNPs) that significantly associated with childhood obesity were used as instrumental variables. The 2-sample MR analyses were performed with the summary-level data of large-sample genome-wide association studies to evaluate the causal effects of childhood obesity on adult T2D and CAD and the levels of cardiometabolic traits.The 2-sample MR analyses suggested that each 1-unit increase in the log-odds of having childhood obesity was causally associated with an increased risk of adult T2D (odds ratio [OR] = 1.16, 95% confidential interval [CI] = 1.06-1.28; P = 1.0 × 10) and CAD (OR = 1.07, 95% CI = 1.02-1.12; P = 4.0 × 10) based on the inverse-variance weighted method. The MR analyses also suggested that childhood obesity was positively associated with the levels of adult body mass index, waist circumference, hip circumference, waist and hip ratio, log-transformed fasting glucose, log-transformed homeostatic model assessment (HOMA) of insulin resistance (%), and triglycerides. The childhood obesity was negatively associated with the adult high-density lipoprotein cholesterol level; however, there was no evidence of a causal association between childhood obesity and the levels of fasting glucose, 2-hour glucose, HbA1c (%), log-transformed HOMA of ß-cell function (%), low-density lipoprotein cholesterol, or total cholesterol in adults.In conclusion, a genetic predisposition to childhood obesity was associated with an increased risk of adult T2D and CAD, providing causal relations between childhood obesity and the risks of T2D and CAD in adults; however, the results need to be validated with larger-scale intervention studies.

Project description: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.