Polymorphisms in PARK2 and MRPL37 are associated with higher risk of recurrent venous thromboembolism in a sex-specific manner

Abstract

Recent studies indicate that mitochondrial DNA (mtDNA) dysfunction is a biomarker of oxidative stress and can predict the risk of cardiovascular diseases (CVDs). Genetic variants in PARK2 (rs4708928) and MRPL37 (rs10888838) genes have been shown to be associated with altered levels of mtDNA in a sex-specific manner. However, the role of these genetic variants in risk assessment of recurrent venous thromboembolism (VTE) is unknown. We investigated the role of these polymorphisms in VTE recurrence in patients from the Malmö thrombophilia study (MATS, n = 1465), followed for ~ 10 years. Genotyping was performed by TaqMan polymerase chain reaction. Female patients with PARK2 polymorphism had significantly higher risk of VTE recurrence (Hazard ratio [HR] = 2.39, 95% confidence interval [CI] 1.09-5.24) and male patients with MRPL37 polymorphism had a significantly higher risk of VTE recurrence (HR = 1.79, 95% CI 1.01-3.17) on multivariate Cox regression analysis. Combined analysis of these polymorphism with factor V Leiden (FVL) showed that female patients with both, FVL and PARK2 polymorphism had even higher risk of VTE recurrence (HR = 4.49, 95% CI 1.58-12.75) compared to FVL or PARK2 polymorphism alone or both wild-type (reference). Similarly, male patients with both FVL and MRPL37 polymorphism had significantly higher risk of VTE recurrence (HR = 2.97, 95% CI 1.45-6.08) compared to those with FVL or MRPL37 polymorphisms alone or the reference group. Polymorphisms in nuclear genome regulating mtDNA together with FVL may be promising biomarkers for predicting VTE recurrence in a sex specific manner. The abstract should be followed by 3-4 bullet points that highlight the major findings. The final bullet point should address future research.Keywords Factor V Leiden · Genetic risk factor · Mitochondria · Predictive biomarkers · Recurrent VTE Highlights• Genetic variants in PARK2 and MRPL37 are associated with increased risk of VTE recurrence in a sex-specific manner • Combined analyses of PARK2 and MRPL37 variants with FVL increase the risk of VTE recurrence several fold in female and male patients respectively • Our results warrant further investigation in these potentially important variants associated with VTE recurrence

Risk prediction of recurrent venous thromboembolism: a multiple genetic risk model

“…Similarly, PAI-1 polymorphism has been reported by us to be associated with an increased risk of VTE recurrence in the presence of FVL [35]. We have recently shown an association between risk of VTE recurrence and SNPs in mitochondrial regulating genes, suggesting a potential role of mitochondrial function in VTE [36]. Mitochondrial transcription factor A ( TFAM ) has been shown to be involved in mitochondrial biogenesis that in turn affects inflammation; a well-known mechanism in thrombosis [37–39].…”

Abnormal Expression of Mitochondrial Ribosomal Proteins and Their Encoding Genes with Cell Apoptosis and Diseases

“…Cri-du-chat syndrome [36] MRPL37 mL37 Venous thromboembolism [37] MRPL38 mL38 Liver cancer [38] MRPL39 mL39 Gastric cancer [39] ↓ MRPL40 mL40 Schizophrenia [40][41][42] ↓…”

“…mrpl16 has been shown to be significantly associated with septic cardiomyopathy [17]. The genetic variation in MRPL37 was linked to an increased risk of venous thromboembolism recurrence [37]. Meng et al designed the cardiac hypertrophy cells by culturing the cardiac cells with 25 mmol/L D-glucose for 48 h. With the help of quantitative real-time PCR, it was confirmed that the expressions of mrpl50, mrps2 and mrps21 were upregulated, and mrpl34 was downregulated [33].…”

Correlation and integration of circulating miRNA and peripheral whole blood gene expression profiles in patients with venous thromboembolism

“…For example, ribosomal protein S6K1 and SLFN14 are present in circulating platelets and exert their unique effects in the process of hemostasis and thrombosis [ 21 , 22 ]. The polymorphism of ribosomal protein MRPL37 predisposes to recurrent venous thromboembolism [ 23 ]. In our study, the Hub genes RPS27A, MRPL13, RPL9, RPS23, and RPS24 belong to the ribosomal protein family.…”