Endothelial progenitor cell-derived extracellular vesicles: the world of potential prospects for the treatment of cardiovascular diseases.

Cardiovascular diseases (CVDs) have emerged as a predominant threat to human health, surpassing the incidence and mortality rates of neoplastic diseases. Extracellular vesicles (EVs) serve as vital mediators in intercellular communication and material exchange. Endothelial progenitor cells (EPCs), recognized as precursors of vascular endothelial cells (ECs), have garnered considerable attention in recent years due to the potential therapeutic value of their derived extracellular vesicles (EPC-EVs) in the context of CVDs. This comprehensive review systematically explores the origins, characteristics, and functions of EPCs, alongside the classification, properties, biogenesis, and extraction techniques of EVs, with particular emphasis on their protective roles in CVDs. Additionally, we delve into the essential bioactive components of EPC-EVs, including microRNAs, long non-coding RNAs, and proteins, analyzing their beneficial effects in promoting angiogenesis, anti-inflammatory and anti-oxidant activities, anti-fibrosis, anti-apoptosis, and myocardial regeneration. Furthermore, this review comprehensively investigates the therapeutic potential of EPC-EVs across various CVDs, encompassing acute myocardial infarction, myocardial ischemia-reperfusion injury, atherosclerosis, non-ischemic cardiomyopathies, and diabetic cardiovascular disease. Lastly, we summarize the potential challenges associated with the clinical application of EPC-EVs and outline future directions, aiming to offer a valuable resource for both theoretical insights and practical applications of EPC-EVs in managing CVDs.

Homocysteine, hyperhomocysteinemia and H-type hypertension.

Homocysteine (Hcy) is a sulfur-containing nonessential amino acid derived from the intermediate metabolites of methionine. Methionine is obtained from dietary proteins, such as poultry, meat, eggs, seafood, and dairy products. Abnormalities in Hcy metabolic pathways, deficiencies in dietary methionine, folate, and vitamins B12, B6 and B2 and genetic defects, polymorphisms, or mutations in Hcy metabolism-related enzymes may lead to an increase in plasma Hcy levels. Generally, a plasma Hcy level higher than 10 µmol/L or 15 µmol/L has been defined as hyperhomocysteinemia (HHcy). An individual with essential hypertension complicated with HHcy is considered to have H-type hypertension (HTH). Currently, HHcy is considered a novel independent risk factor for various cardiovascular diseases. To provide a useful reference for clinicians, the research progress on Hcy, HHcy and HTH in recent years was systematically reviewed here, with a focus on the source and metabolic pathways of Hcy, plasma Hcy levels and influencing factors, detection methods for plasma Hcy levels, relationship between Hcy concentration and hypertension, pathogenesis of HTH, cardiovascular complications of HTH, and treatment of HTH.

Relationship between the methylenetetrahydrofolate reductase (MTHFR) rs1801133 SNP and serum homocysteine levels of Zhuang hypertensive patients in the central region of Guangxi.

BACKGROUND: The relationship between the methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphism (SNP) and serum homocysteine (Hcy) levels or H-type hypertension in different populations is inconsistent. This study aimed to explore the association between the MTHFR rs1801133 SNP and serum Hcy levels of Zhuang hypertensive patients in the central region of Guangxi. METHODS: A total of 606 Zhuang inpatients with essential hypertension were recruited in our hospital from August 2016 to December 2018. The patients were divided into H-type hypertension (Hcy > 10 µmol/L, n = 528) and non-H-type hypertension (Hcy ≤ 10 µmol/L, n = 78) groups. At the same time, an age- and sex-matched group of 379 subjects with normal physical examination in our hospital were selected as the control group. Blood biochemical measurements and genotyping of the MTHFR rs1801133 SNP were performed. RESULTS: The prevalence of H-type hypertension was 87.13%. The levels of serum Hcy in patients with hypertension were higher than those in control group (14.20 ± 5.78 µmol/L vs. 11.97 ± 5.39 µmol/L, P < 0.001), especially in patients with H-type hypertension (15.08 ± 5.65 µmol/L, P < 0.001). The frequencies of TT genotype (22.73%) and T allele (46.21%) in patients with H-type hypertension were significantly higher than those in control group (11.35% and 30.47%, respectively) and non-H-type hypertension group (10.26% and 28.85%, respectively; P < 0.001 for all). Multivariate linear regression analysis showed that serum Hcy levels were significantly correlated with creatinine, low-density lipoprotein cholesterol, endogenous creatinine clearance rate, and the MTHFR rs1801133 genotypes in control group, while serum Hcy levels were significantly correlated with creatinine, triglyceride, low-density lipoprotein cholesterol, endogenous creatinine clearance rate, glycosylated hemoglobin, and the MTHFR rs1801133 genotypes in H-type hypertension group (P < 0.05-0.001). Serum Hcy levels in the T allele carriers were higher than those in the T allele noncarriers in both H-type hypertension and control groups. CONCLUSIONS: There was closely related between the MTHFR rs1801133 SNP and serum Hcy levels in Zhuang patients with H-type hypertension in the central region of Guangxi. The MTHFR SNP may be an important reason for the increase of serum Hcy levels in Zhuang patients with H-type hypertension in this region.

Recent progress in epigenetics of obesity.

Nowadays, obesity is one of the largest public health problems worldwide. In the last few decades, there has been a marked increase in the obesity epidemic and its related comorbidities. Worldwide, more than 2.2 billion people (33%) are affected by overweight or obesity (712 million, 10%) and its associated metabolic complications. Although a high heritability of obesity has been estimated, the genetic variants conducted from genetic association studies only partially explain the variation of body mass index. This has led to a growing interest in understanding the potential role of epigenetics as a key regulator of gene-environment interactions on the development of obesity and its associated complications. Rapid advances in epigenetic research methods and reduced costs of epigenome-wide association studies have led to a great expansion of population-based studies. The field of epigenetics and metabolic diseases such as obesity has advanced rapidly in a short period of time. The main epigenetic mechanisms include DNA methylation, histone modifications, microRNA (miRNA)-mediated regulation and so on. DNA methylation is the most investigated epigenetic mechanism. Preliminary evidence from animal and human studies supports the effect of epigenetics on obesity. Studies of epigenome-wide association studies and genome-wide histone modifications from different biological specimens such as blood samples (newborn, children, adolescent, youth, woman, man, twin, race, and meta-analysis), adipose tissues, skeletal muscle cells, placenta, and saliva have reported the differential expression status of multiple genes before and after obesity interventions and have identified multiple candidate genes and biological markers. These findings may improve the understanding of the complex etiology of obesity and its related comorbidities, and help to predict an individual's risk of obesity at a young age and open possibilities for introducing targeted prevention and treatment strategies.

Association of RDW, NLR, and PLR with Atrial Fibrillation in Critical Care Patients: A Retrospective Study Based on Propensity Score Matching.

Objective: Previous studies have shown inconsistent results in relation to the red cell distribution width (RDW), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) of atrial fibrillation (AF). This retrospective study is aimed at detecting the association of RDW, NLR, and PLR with AF. Methods: A total of 4717 critical care patients were screened from the Medical Information Mart for Intensive Care- (MIMIC-) III database. The patients were separated into the non-AF and AF groups. The imbalances between the groups were reduced using propensity score matching (PSM). ROC curves were generated to detect the diagnostic value of RDW, NLR, and PLR. Logistic regression analysis was used to detect the risk factors for AF. Results: A total of 991 non-AF patients paired with 991 AF patients were included after PSM in this study. The RDW level in the AF group was significantly higher than that in the non-AF group (15.09 ± 1.93vs. 14.89 ± 1.91, P = 0.017). Neither NLR nor PLR showed any significant difference between the two groups (P > 0.05 for each). According to ROC curve, RDW showed a very low diagnostic value of AF (AUC = 0.5341), and the best cutoff of RDW was 14.1 (ACU = 0.5257, sensitivity = 0.658, specificity = 0.395). Logistic regression analysis showed that an elevated RDW level increased 1.308-fold (95%CI = 1.077-1.588, P = 0.007) risk of AF. Neither elevated NLR nor elevated PLR was a significant risk factor for AF (OR = 0.993, 95%CI = 0.802-1.228, P = 0.945 for NLR; OR = 0.945, 95%CI = 0.763-1.170, P = 0.603 for PLR). Conclusions: Elevated RDW level but not NLR or PLR levels is associated with AF. RDW > 14.1 is a risk factor for AF, but its diagnostic capacity for AF is not of great value.

EHBP1, TUBB, and WWOX SNPs, Gene-Gene and Gene-Environment Interactions on Coronary Artery Disease and Ischemic Stroke.

The associations among the EH domain-binding protein 1 (EHBP1), tubulin beta class I (TUBB), and WW domain-containing oxidoreductase (WWOX) single nucleotide polymorphisms (SNPs) and coronary artery disease (CAD) and ischemic stroke (IS) are not yet understood. This study aimed to detect the associations of these SNPs, gene-gene and gene-environment interactions and CAD and IS in the Guangxi Han population. A total of 1853 unrelated subjects were recruited into normal control (n = 638), CAD (n = 622), and IS (n = 593) groups. Related genotypes were determined by high-throughput sequencing. The genotypic and minor allelic frequencies of rs2278075 were different between the CAD and control groups, and those of rs2710642, rs3130685, and rs2278075 were also different between the IS and control groups. The rs2278075T allele, rs3130685-rs2222896-rs2278075, rs3130685-rs2222896-diabetes, rs3130685-rs2222896-drinking, and haplotype rs2710642A-rs10496099C-diabetes interactions were associated with increased risk, while G-T-G-C-G-A and G-T-T-T-G-T-drinking were associated with reduced risk of CAD. The rs2278075T and rs2710642G alleles, rs2710642G-rs10496099C haplotype, rs3130685-rs2278075-rs2222896, and rs2710642-rs2278075-hypertension interactions aggravated the association with IS, whereas the rs3130685T allele, rs2710642A-rs10496099C haplotype and the interactions of H1 (s2710642A-rs10496099C)-H2 (rs2710642G-rs10496099C)-drinking and I1 (A-C-G-C-A-A)-I3 (A-C-G-T-A-A)-I4 (A-C-G-T-G-A)-I5 (G-T-G-C-G-A) diminished the association with IS. Carrying WWOX rs2278075T was strongly associated with CAD or IS, while EHBP1 rs2710642 and TUBB rs3130685 might alter the association of IS by modifying the serum lipid profile. This study demonstrates that the EHBP1, TUBB, and WWOX SNPs, gene-gene and gene-environment interactions are associated with the risk of CAD and IS in the Guangxi Han population.

DGAT2-MOGAT2 SNPs and Gene-Environment Interactions on Serum Lipid Profiles and the Risk of Ischemic Stroke.

Background: The genetic susceptibility to ischemic stroke (IS) is still not well-understood. Recent genome-wide association studies (GWASes) found that several single nucleotide polymorphisms (SNPs) in the Diacylglycerol acyltransferase 2 gene (DGAT2) and monoacylglycerol O-acyltransferase 2 (MOGAT2) cluster were associated with serum lipid levels. However, the association between the DGAT2-MOGAT2 SNPs and serum lipid phenotypes has not yet been verified in the Chinese people. Therefore, the present study was to determine the DGAT2-MOGAT2 SNPs and gene-environment interactions on serum lipid profiles and the risk of IS. Methods: Genotyping of 5 SNPs (DGAT2 rs11236530, DGAT2 rs3060, MOGAT2 rs600626, MOGAT2 rs609379, and MOGAT2 rs10899104) in 544 IS patients and 561 healthy controls was performed by the next-generation sequencing technologies. The association between genotypes and serum lipid data was determined by analysis of covariance, and a corrected P-value was adopted after Bonferroni correction. Unconditional logistic regression analysis was performed to assess the association between genotypes and the risk of IS after adjustment of potential confounders. Results: The rs11236530A allele was associated with increased risk of IS (CA/AA vs. CC, OR = 1.45, 95%CI = 1.12-1.88, P = 0.0044), whereas the rs600626G-rs609379A-rs10899104G haplotype was associated with decreased risk of IS (adjusted OR = 0.67, 95% CI = 0.48-0.93, P = 0.018). The rs11236530A allele carriers had lower high-density lipoprotein cholesterol (HDL-C) concentrations than the rs11236530A allele non-carriers (P < 0.001). The interactions of rs11236530-smoking, rs3060-smoking and rs10899104-smoking influenced serum apolipoprotein B levels, whereas the interactions of rs11236530- and rs3060-alcohol affected serum HDL-C levels (P I < 0.004-0.001). The interaction of rs600626G-rs609379A-rs10899104G-alcohol (OR = 0.41, 95% CI = 0.22-0.76) and rs600626G-rs609379C-rs10899104T-alcohol (OR = 0.12, 95% CI = 0.04-0.36) decreased the risk of IS (P I < 0.0001). Conclusions: The rs11236530A allele was associated with decreased serum HDL-C levels in controls and increased risk of IS in patient group. The rs600626G-rs609379A-rs10899104G haplotype, the rs600626G-rs 609379A-rs10899104G-alcohol and rs600626G-rs609379C-rs10899104T-alcohol interactions were associated with decreased risk of IS. The rs11236530 SNP may be a genetic marker for IS in our study populations.

CYP17A1-ATP2B1 SNPs and Gene-Gene and Gene-Environment Interactions on Essential Hypertension.

Background: The association between the CYP17A1 and ATP2B1 SNPs and essential hypertension (referred to as hypertension) is far from being consistent. In addition to the heterogeneity of hypertension resulting in inconsistent results, gene-gene and gene-environment interactions may play a major role in the pathogenesis of hypertension rather than a single gene or environmental factor. Methods: A case-control study consisting of 1,652 individuals (hypertension, 816; control, 836) was conducted in Maonan ethnic minority of China. Genotyping of the four SNPs was performed by the next-generation sequencing technology. Results: The frequencies of minor alleles and genotypes of four SNPs were different between the two groups (p < 0.001). According to genetic dominance model analysis, three (rs1004467, rs11191548, and rs17249754) SNPs and two haplotypes (CYP17A1 rs1004467G-rs11191548C and ATP2B1 rs1401982G-rs17249754A) were negatively correlated, whereas rs1401982 SNP and the other two haplotypes (CYP17A1 rs1004467A-rs11191548T and ATP2B1 rs1401982A-rs17249754G) were positively associated with hypertension risk (p ≤ 0.002 for all). Two best significant two-locus models were screened out by GMDR software involving SNP-environment (rs11191548 and BMI ≥ 24 kg/m2) and haplotype-environment (CYP17A1 rs1004467G-rs11191548C and BMI ≥ 24 kg/m2) interactions (p ≤ 0.01). The subjects carrying some genotypes increased the hypertension risk. Conclusions: Our outcomes implied that the rs1004467, rs11191548, and rs17249754 SNPs and CYP17A1 rs1004467G-rs11191548C and ATP2B1 rs1401982G-rs17249754A haplotypes have protective effects, whereas the rs1401982 SNP and CYP17A1 rs1004467A-rs11191548T and ATP2B1 rs1401982A-rs17249754G haplotypes showed adverse effect on the prevalence of hypertension. Several SNP-environment interactions were also detected.

SYTL3-SLC22A3 Single-Nucleotide Polymorphisms and Gene-Gene/Environment Interactions on the Risk of Hyperlipidemia.

The current study aims to further delineate the associations between the synaptotagmin-like 3 (SYTL3) and solute carrier family 22 member 3 (SLC22A3) single-nucleotide polymorphisms (SNPs) and their haplotypes and gene-gene (G × G)/environment (G × E) interactions on the risk of hyperlipidemia (HLP) in the Maonan and Han ethnic groups. Genotype distribution among the SYTL3-SLC22A3 SNPs in 2,829 individual patients bearing no relationship to each other (Han, 1,436; Maonan, 1,393) was analyzed utilizing next-generation sequencing techniques. The genotype frequencies of the rs6455600, rs2129209, and rs446809 SNPs were varied between the two ethnic groups (P < 0.05-0.001). Various SNPs were correlated with serum levels of triglyceride (TG; rs446809), total cholesterol (TC; rs6455600, rs2129209, and rs539298), and low-density lipoprotein cholesterol (LDL-C; rs446809) among the Han population, whereas various SNPs were also correlated with TC (rs6455600 and rs539298), TG (rs446809), and LDL-C (rs446809) levels in the Maonan ethnic group (P < 0.008-0.001). One part of haplotypes resulted in worsened HLP-related morbidity in the Han (SYTL3 A-C-A-A; SLC22A3 A-A and A-G; and SYTL3-SLC22A3 A-C-A-A-A-A and A-C-A-A-A-G) and Maonan (SYTL3 A-C-A-A; SLC22A3 A-A and A-G; and SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-A-A-A, and G-T-C-A-C-A) ethnic groups, whereas another part of haplotypes lowered HLP-related health risks in the Han (SLC22A3 C-A and C-G and SYTL3-SLC22A3 A-C-A-A-C-A, A-C-A-A-C-G, and G-T-C-A-C-A) and Maonan (SLC22A3 C-G and SYTL3-SLC22A3 A-C-A-A-C-G) ethnic groups. We discovered that the SYTL3-SLC22A3 SNPs and their haplotypes were associated with serum lipid levels and the risk of HLP in our studied populations.

Effect of SYTL3-SLC22A3 Variants, Their Haplotypes, and G × E Interactions on Serum Lipid Levels and the Risk of Coronary Artery Disease and Ischaemic Stroke.

Background: The current study aimed to investigate the effects of synaptotagmin-like 3 (SYTL3) and solute carrier family 22 member 3 (SLC22A3) single nucleotide polymorphisms (SNPs) and gene-environment (G × E) interactions on blood lipid levels as well as the risk of coronary artery disease (CAD) and ischaemic stroke (IS) in the Southern Chinese Han population. Methods: The genetic makeup of 6 SYTL3-SLC22A3 SNPs in 2269 unrelated participants (controls, 755; CAD, 758 and IS, 756) of Chinese Han ethnicity was detected by the next-generation sequencing techniques. Results: The allele and genotype frequencies of the SYTL3 rs2129209 and SLC22A3 rs539298 SNPs were significantly different between the case and control groups. The SLC22A3 rs539298 SNP was correlated with total cholesterol (TC) levels in controls, the rs539298G allele carriers maintained lower TC levels than the rs539298G allele non-carriers. At the same time, the SLC22A3 rs539298 SNP interacted with alcohol consumption reduced the risk of CAD and IS. The SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-C-A and A-T-A-A-C-A haplotypes increased and the A-C-A-A-C-G haplotype reduced the risk of CAD, whereas the SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-A-G and A-T-A-A-C-A haplotypes increased and the A-C-A-A-A-G and A-C-A-A-C-G haplotypes reduced the risk of IS. In addition, several SNPs interacted with alcohol consumption, body mass index ≥ 24 kg/m2 and cigarette smoking to affect serum lipid parameters such as triglyceride, high-density lipoprotein cholesterol, TC, and apolipoprotein A1 levels. Conclusions: Several SYTL3-SLC22A3 variants, especially the rs539298 SNP, several haplotypes, and G × E interactions, were related to blood lipid parameters and the risk of CAD and IS in the Southern Chinese Han population.

Association between the PLTP rs4810479 SNP and Serum Lipid Traits in the Chinese Maonan and Han Populations.

The association between the phospholipid transfer protein (PLTP) gene rs4810479 single-nucleotide polymorphism (SNP) and serum lipid levels is largely unknown. This investigation aimed to evaluate the relationship between the PLTP rs4810479 SNP, several environmental risk factors, and serum lipid parameters in the Chinese Maonan and Han nationalities. Polymerase chain reaction-restriction fragment length polymorphism, gel electrophoresis, and direct sequencing were employed to determine the PLTP rs4810479 genotypes in 633 Maonan and 646 Han participants. The frequencies of CC, CT, and TT genotypes and the C allele were different between Maonan and Han groups (29.07%, 53.08%, 17.85%, and 55.61% vs. 35.60%, 49.70%, 14.70%, and 60.45%, respectively, P < 0.05). The C allele carriers in the Maonan group had higher high-density lipoprotein cholesterol levels than the C allele noncarriers, but this finding was only found in Maonan males but not in females. The C allele carriers in Han males had lower total cholesterol and low-density lipoprotein cholesterol levels than the C allele noncarriers. Serum lipid profiles were also affected by several traditional cardiovascular risk factors in both populations. There might be an ethnic- and/or sex-specific association between the PLTP rs4810479 SNP and serum lipid traits.

No causal effects of plasma homocysteine levels on the risk of coronary heart disease or acute myocardial infarction: A Mendelian randomization study.

BACKGROUND: Although many observational studies have shown an association between plasma homocysteine levels and cardiovascular diseases, controversy remains. In this study, we estimated the role of increased plasma homocysteine levels on the etiology of coronary heart disease and acute myocardial infarction. METHODS: A two-sample Mendelian randomization study on disease was conducted, i.e. "coronary heart disease" (n = 184,305) and "acute myocardial infarction" (n = 181,875). Nine single nucleotide polymorphisms, which were genome-wide significantly associated with plasma homocysteine levels in 57,644 subjects from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium genome-wide association study and were known to be associated at p < 5×10-8, were used as an instrumental variable. RESULTS: None of the nine single nucleotide polymorphisms were associated with coronary heart disease or acute myocardial infarction (p > 0.05 for all). Mendelian randomization analysis revealed no causal effects of plasma homocysteine levels, either on coronary heart disease (inverse variance weighted; odds ratio = 1.015, 95% confidence interval = 0.923-1.106, p = 0.752) or on acute myocardial infarction (inverse variance weighted; odds ratio = 1.037, 95% confidence interval = 0.932-1.142, p = 0.499). The results were consistent in sensitivity analyses using the weighted median and Mendelian randomization-Egger methods, and no directional pleiotropy (p = 0.213 for coronary heart disease and p = 0.343 for acute myocardial infarction) was observed. Sensitivity analyses confirmed that plasma homocysteine levels were not significantly associated with coronary heart disease or acute myocardial infarction. CONCLUSIONS: The findings from this Mendelian randomization study indicate no causal relationship between plasma homocysteine levels and coronary heart disease or acute myocardial infarction. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

Associations between TUBB-WWOX SNPs, their haplotypes, gene-gene, and gene-environment interactions and dyslipidemia.

In this study, we investigated associations between single nucleotide polymorphisms (SNPs) in the tubulin beta class I (TUBB) and WW domain-containing oxidoreductase (WWOX) genes, gene-gene interactions, and gene-environment interactions and dyslipidemia in the Chinese Maonan ethnic group. Four SNPs (rs3132584, rs3130685, rs2222896, and rs2548861) were genotyped in unrelated subjects with normal lipid levels (864) or dyslipidemia (1129). While 5.0% of Maonan subjects carried the rs3132584TT genotype, none of the Chinese Han in Beijing subjects did. Allele and genotype frequencies differed between the normal and dyslipidemia groups for three SNPs (rs3132584, rs3130685, and rs2222896). rs2222896G allele carriers in the normal group had higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol levels. The rs3132584GG, rs3130685CC+TT, and rs2222896GG genotypes as well as the rs2222896G-rs2548861G and rs2222896G-rs2548861T haplotypes were associated with an elevated risk of dyslipidemia; the rs2222896A-rs2548861T and rs2222896A-rs2548861G haplotypes were associated with a reduced risk of dyslipidemia. Among the thirteen TUBB-WWOX interaction types identified, rs3132584T-rs3130685T-rs2222896G-rs2548861T increased the risk of dyslipidemia 1.371-fold. Fourteen two- to four-locus optimal interactive models for SNP-SNP, haplotype-haplotype, gene-gene, and gene-environment interactions exhibited synergistic or contrasting effects on dyslipidemia. Finally, the interaction between rs3132584 and rs2222896 increased the risk of dyslipidemia 2.548-fold and predicted hypertension.

Association between SLC44A4-NOTCH4 SNPs and serum lipid levels in the Chinese Han and Maonan ethnic groups.

BACKGROUND: The current research was to assess the relationship of the solute carrier family 44 member 4 (SLC44A4) rs577272, notch receptor 4 (NOTCH4) rs3134931 SNPs and serum lipid levels in the Han and Maonan ethnic groups. METHODS: The genetic makeup of the SLC44A4 rs577272 and NOTCH4 rs3134931 SNPs in 2467 unrelated subjects (Han, 1254; Maonan,1213) was obtained by using polymerase chain reaction and restriction fragment length polymorphism technique, combined with gel electrophoresis, and confirmed by direct sequencing. RESULTS: The genotype frequencies of SLC44A4 rs577272 and NOTCH4 rs3134931 SNPs were different between Han and Maonan populations (P < 0.05); respectively. The SLC44A4 rs577272 SNP was associated with total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels in Maonan group. The NOTCH4 rs3134931 SNP was associated with triglyceride (TG) in Han; and TG and low-density lipoprotein cholesterol (LDL-C) levels in Maonan groups (P < 0.025-0.001). Stratified analysis according to gender showed that the SLC44A4 rs577272 SNP was associated with TC and HDL-C in Han and Maonan females; TC in Maonan males, meanwhile, the NOTCH4 rs3134931 SNP was associated with TG and HDL-C in Han males; TG in Han females; TG and LDL-C in Maonan males; and TG, HDL-C and LDL-C in Maonan females. Linkage disequilibrium analysis showed that the most common haplotype was rs577272G-rs3134931A (> 50%) in both Han and Maonan groups. The haplotype of rs577272G-rs3134931A was associated with TG and HDL-C in Han; and TC, TG and HDL-C in Maonan ethnic groups. CONCLUSIONS: These results suggest that the relationship among SLC44A4 rs577272, NOTCH4 rs3134931 SNPs and serum lipid parameters may vary depending on the gender and/or ethnicity/race in some populations. Haplotypes could explain more changes in serum lipid parameters than any single SNP alone particularly for TC, TG and HDL-C.

CMIP SNPs and their haplotypes are associated with dyslipidaemia and clinicopathologic features of IgA nephropathy.

The relationship between serum lipid profiles and related clinicopathologic features of IgA nephropathy (IgAN) and c-Maf-inducing protein (CMIP) gene polymorphisms is unclear. The present study was designed to examine the effect of CMIP single-nucleotide polymorphisms (SNPs) on dyslipidaemia and clinicopathologic features of IgAN. Clinical and pathological data from patients with IgAN diagnosed at the First Affiliated Hospital of Guangxi Medical University were collected. DNA was extracted from blood samples. CMIP rs2925979 and CMIP rs16955379 genotypes were determined by PCR and direct sequencing. Among 543 patients, 281 had dyslipidaemia (51.7%). Compared with the non-dyslipidaemia group, the dyslipidaemia group exhibited higher blood pressure, blood urea nitrogen, uric acid, and body mass index; higher prevalence of oedema, haematuria, tubular atrophy, and interstitial fibrosis; and lower albumin and estimated glomerular filtration rate. In the dyslipidaemia group, the frequency of C allele carriers was higher than that of non-C allele carriers for rs16955379. Multivariate linear regression analysis showed that total cholesterol, low-density lipoprotein and high-density lipoprotein were associated with rs16955379C allele carriers. Apolipoprotein B was associated with A allele carriers of rs2925979. Linkage disequilibrium was observed between rs16955379 and rs2925979, and rs2925979G-rs16955379T was the most common haplotype. The frequencies of the four CMIP SNP haplotypes differed between dyslipidaemia and non-dyslipidaemia groups in IgAN (P<0.05, for all above). Dyslipidaemia is a common complication in IgAN patients, and those with dyslipidaemia present poor clinicopathologic features. CMIP SNPs and their haplotypes are closely correlated with the occurrence of dyslipidaemia and clinicopathologic damage in IgAN patients.

Potential Molecular Mechanism of the NPPB Gene in Postischemic Heart Failure with and without T2DM.

BACKGROUND: This study is aimed at investigating natriuretic peptide B (NPPB) coexpression genes and their pathways involved in heart failure (HF) among patients both with and without type 2 diabetes mellitus (T2DM). METHODS: The microarray dataset GSE26887, containing 19 postischemic HF patients' peripheral blood samples (7 with T2DM and 12 without T2DM), was examined to detect the genes coexpressed with NPPB using the corr.test function in the R packet. Furthermore, using online analytical tools, we determined the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) annotation, and protein-protein interaction (PPI) network of the coexpression genes. The modules and hub genes of the PPI network were then identified using the Cytoscape software. RESULTS: In patients with T2DM, a total of 41 biological processes (BP), 20 cellular components (CC), 13 molecular functions (MF), and 41 pathways were identified. Furthermore, a total of 61 BPs, 16 CCs, 13 MFs, and 22 pathways in patients without T2DM were identified. In both groups of patients, 17 BPs, 10 CCs, 6 MFs, and 13 pathways were enriched. We also identified 173 intersectional coexpression genes (63 positively, 106 negatively, and 4 differently coexpressed in patients with and without T2DM, respectively) in both types of patients, which were enriched in 16 BPs, 8 CCs, 3 MFs, and 8 KEGG pathways. Moreover, the PPI network (containing 237 edges and 170 nodes) with the top module significantly enriched in 4 BPs (tricarboxylic acid metabolic process, citrate metabolic process, tricarboxylic acid cycle, and aerobic respiration) and 3 pathways (citrate cycle, malaria parasite metabolic pathway, and AGE-RAGE signaling pathway in diabetic complications) was constructed. DECR1, BGN, TIMP1, VCAN, and CTCF are the top hub genes. CONCLUSIONS: Our findings may elucidate the functions and roles of the NPPB gene in patients with postischemic HF and facilitate HF management.

The MC4R SNPs, their haplotypes and gene-environment interactions on the risk of obesity.

BACKGROUND: Little is known about the correlation between the melanocortin 4 receptor gene (MC4R) single nucleotide polymorphisms (SNPs) and the risk of obesity. This research sought to test the MC4R rs17782313, rs476828 and rs12970134 SNPs, their haplotypes and gene-environment interactions on the risk of obesity in the Maonan ethnic group, an isolated minority in China. METHODS: A case-control study comprised of 1836 participants (obesity group, 858; and control group, 978) was conducted. Genotypes of the three SNPs were determined by the next-generation sequencing (NGS) technology. RESULTS: The genotypic frequencies of the three SNPs were different between the obesity and control groups (P <  0.05 for all). The minor allelic frequency of the MC4R rs17782313C, rs476828C and rs12970134A was higher in obesity than in control groups (13.8% vs. 8.3%, P <  0.001, 17.1% vs. 10.9%, P <  0.001; and 15.5% vs. 11.5%, P <  0.001; respectively). Additionally, the dominant model of rs17782313 and rs476828 SNPs revealed an increased morbidity function on the risk of obesity (P <  0.05). A correlation between SNP-environment and the risk of obesity was also observed. The rs17782313C-rs476828C-rs12970134A haplotype was associated with high risk of obesity (OR = 1.796, 95% CI = 1.447-2.229), whereas the rs17782313T-rs476828T-rs12970134G and rs17782313T-rs476828T-rs12970134A haplotypes were associated with low risk of obesity (OR = 0.699, 95% CI = 0.586-0.834 and OR = 0.620, 95% CI = 0.416-0.925; respectively). The interactions between haplotype and waist circumference on the risk of obesity were also noted. CONCLUSIONS: We discovered that the MC4R rs17782313, rs476828 and rs12970134 SNPs and their haplotypes were associated with the risk of obesity in the Chinese Maonan population.

Associations of PRKN-PACRG SNPs and G × G and G × E interactions with the risk of hyperlipidaemia.

This research aimed to assess the associations of 7 parkin RBR E3 ubiquitin protein ligase (PRKN) and 4 parkin coregulated gene (PACRG) single-nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G) and gene-environment (G × E) interactions with hyperlipidaemia in the Chinese Maonan minority. The genotypes of the 11 SNPs in 912 normal and 736 hyperlipidaemic subjects were detected with next-generation sequencing technology. The genotypic and allelic frequencies of the rs1105056, rs10755582, rs2155510, rs9365344, rs11966842, rs6904305 and rs11966948 SNPs were different between the normal and hyperlipidaemic groups (P < 0.05-0.001). Correlations between the above 7 SNPs and blood lipid levels were also observed (P < 0.0045-0.001, P < 0.0045 was considered statistically significant after Bonferroni correction). Strong linkage disequilibrium was found among the 11 SNPs (r2 = 0.01-0.64). The most common haplotypes were PRKN C-G-T-G-T-T-C (> 15%) and PACRG A-T-A-T (> 40%). The PRKN C-G-C-A-T-T-C and PRKN-PACRG C-G-T-G-T-T-C-A-T-A-T haplotypes were associated with an increased risk of hyperlipidaemia, whereas the PRKN-PACRG C-G-T-G-C-T-C-A-T-C-T and C-G-T-G-T-T-C-A-T-C-T haplotypes provided a protective effect. Association analysis based on the haplotypes and G × G interaction could improve the power to detect the risk of hyperlipidaemia over the analysis of any one SNP alone. The differences in serum lipid parameters between the hyperlipidaemic and normal groups might partly be due to the effects of the PRKN-PACRG SNPs and their haplotypes.

Association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels.

This study investigated the association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels in the population of Southwest China. Genotyping of 12 SNPs (i.e., rs2238675, rs2228603, rs58542926, rs735273, rs16996148, rs968525, rs17216525, rs12610185, rs10401969, rs8102280, rs73001065 and rs150268548) was performed in 1248 hyperlipidemia patients and 1248 normal subjects. The allelic and genotypic frequencies of the detected SNPs differed substantially between the normal and hyperlipidemia groups (P < 0.05-0.001), and the association of the 12 SNPs and hyperlipidemia was also observed (P < 0.004-0.0001). Four haplotypes (i.e., NCAN C-C, CILP2 G-T, PBX4-SUGP1 G-C, and MAU2 C-A-G-T) and 5 gene-gene interaction haplotypes (i.e., rs2238675C-rs2228603C, rs16996148G-rs17216525T, rs12610185G-rs10401969C, rs73001065G-rs8102280A-rs150268548G-rs968525C and rs73001065C-rs8102280A-rs150268548G-rs96852）showed a protective effect, whereas four other haplotypes (i.e., TM6SF2 T-A, TM6SF2 C-A, MAU2 G-G-G-C and MAU2 C-G-A-T), as well as 4 gene-gene interaction haplotypes (i.e., rs58542926C-rs735273A, rs58542926T-rs735273A, rs73001065G-rs8102280G-rs150268548G-rs968525C, and rs73001065C-rs8102280G-rs150268548A-rs968525T), exhibited an inverse effect on hyperlipidemia (P < 0.05-0.0001). There were notable three-locus models comprising SNP-SNP, SNP-environment, and haplotype-haplotype interactions (P < 0.05-0.0001). The individuals with some genotypes and haplotypes reduced the prevalence of hyperlipidemia, whereas the individuals with some other genotypes and haplotypes augmented the prevalence of hyperlipidemia. The NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions on hyperlipidemia were observed in the population of Southwest China.

SYNE1-QK1 SNPs, G × G and G × E interactions on the risk of hyperlipidaemia.

This study aimed to assess the relationship of 3 spectrin repeat containing nuclear envelope protein 1 (SYNE1) and 4 KH domain containing RNA binding (QK1) single nucleotide polymorphisms (SNPs), their haplotypes, gene-gene (G × G), gene-environment (G × E) interactions and hypercholesterolaemia (HCH) and hypertriglyceridaemia (HTG) in the Chinese Maonan minority. The genetic make-up of the SYNE1-QK1 SNPs in 1932 unrelated subjects (normal, 641; HCH, 649; and HTG, 642) was obtained by next-generation sequencing technologies. The genotypic frequencies of following SNPs were suggestively distinctive between the control and HCH groups (rs2623963, rs7745725, rs9459317, rs16897566), or between the control and HTG groups (rs2623963, rs1358317, rs7745725, rs1923608, rs16897566 SNPs; P < .05, respectively). Multiple-locus linkage disequilibrium analysis indicated that the identified SNPs were not inherited independently. Several haplotypes and gene-gene interaction haplotypes among the detected SNPs may be related with an increased morbidity of HCH (C-G-A, C-G-G and C-G-G-T-C-A-T) and HTG (C-G-G, G-T-G-C, C-G-G-G-T-G-C and C-G-G-T-C-A-T), whereas others may be related with an decreased risk of HCH (G-A-A, G-C-A-T, C-A-A-T-C-A-T and G-A-A-G-C-A-T) and HTG (G-A-A, G-C-A-T, C-A-A-T-C-A-T and G-A-A-G-C-A-T). The association evaluation based on haplotypes and gene-gene interactions could improve the power of detecting the risk of dyslipidaemia than anyone of SNP alone. There was significant three-locus model involving SNP-SNP, haplotype-haplotype/environment and G × G interactions (P < .05-0.001) that were detected by GMDR in HCH and HTG groups. Different interactions between genetic and environmental factors would produce different redundancy or synergy effects on the morbidity of HCH and/or HTG.