The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Discovery of novel selective phosphodiesterase­1 inhibitors for the treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Association of CHI3L1 gene variants with YKL-40 levels and hypertension incidence: A population-based nested case-control study in China.

YKL-40 was reported to be associated with the risk of hypertension. Whether the variants of CHI3L1 gene were associated with both YKL-40 levels and hypertension needs to be further elucidated. In a 1:1 matched case-control study of 507 pairs with available YKL-40 levels and DNA samples nested in a prospective cohort of Chinese subjects, the 15 tag single nucleotide polymorphisms (SNPs) of CHI3L1 gene were genotyped. The levels of YKL-40 among different genotypes of each SNP were compared after false discovery rate adjustment. Multivariable conditional logistic regression analyses were used to explore the association between the genotypes and the risk of hypertension. Subjects with the genetic variants for rs10399931, rs1538372, rs2071580, rs2297839 and rs4950928 had lower YKL-40 levels. The genetic variant for rs10399805 was associated with higher YKL-40 level. Subjects with the genotype of GA/AA of rs10399805 had a 1.34-fold risk of hypertension compared with those with GG genotype in the total population (P = .05). Subjects with heterozygote/rare homozygote genotype of rs4950928 and rs2297839 both had a significantly lower risk of hypertension compared with those with major homozygote genotype among men. The ORs (95% CIs) were 0.46 (0.23-0.89) and 0.49 (0.26-0.91), respectively. The above three SNPs could significantly improve the accuracy of risk prediction for hypertension based on the conventional factors. The genotypes of rs10399805, rs4950928 and rs2297839 may hopefully become stable biomarkers for predicting the risk of hypertension.

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

Associations between potentially functional CORIN SNPs and serum corin levels in the Chinese Han population.

BACKGROUND: Corin is an important convertase involved in the natriuretic peptide system and may indirectly regulate blood pressure. Genetic factors relate to corin remain unclear. The purpose of the current study was to comprehensively examine the associations among CORIN SNPs, methylations, serum corin levels and hypertension. RESULTS: We genotyped 9 tag-SNPs in the CORIN gene and measured serum corin levels in 731 new-onset hypertensive cases and 731 age- and sex-matched controls. DNA methylations were tested in 43 individuals. Mendelian randomization was used to investigate the causal associations. Under additive models, we observed associations of rs2289433 (p.Cys13Tyr), rs6823184, rs10517195, rs2271037 and rs12509275 with serum corin levels after adjustment for covariates (P = 0.0399, 0.0238, 0.0016, 0.0148 and 0.0038, respectively). The tag-SNP rs6823184 and SNPs that are in strong linkage disequilibrium with it, i.e., rs10049713, rs6823698 and rs1866689, were associated with CORIN gene expression (P = 2.38 × 10- 24, 5.94 × 10- 27, 6.31 × 10- 27 and 6.30 × 10- 27, respectively). Neither SNPs nor corin levels was found to be associated with hypertension. SNP rs6823184, which is located in a DNase hypersensitivity cluster, a CpG island and transcription factor binding sites, was significantly associated with cg02955940 methylation levels (P = 1.54 × 10- 7). A putative causal association between cg02955940 methylation and corin levels was detected (P = 0.0011). CONCLUSION: This study identified potentially functional CORIN SNPs that were associated with serum corin level in the Chinese Han population. The effect of CORIN SNPs on corin level may be mediated by DNA methylation.

Detection of Putative Functional Single Nucleotide Polymorphisms in Blood Pressure Loci and Validation of Association Between Single Nucleotide Polymorphism in WBP1L and Hypertension in the Chinese Han Population.

We have performed a gene-based association study and detected several important blood pressure (BP)-associated genes. In this study, we explored functional variants in these genes by bioinformatics analysis and validated the associations between the functional single nucleotide polymorphisms (SNPs) and hypertension with public data and our in-house data of 857 cases and 927 controls. We found various functional variants in the BP-associated genes, including missense mutations and phosphorylation-related SNPs. Most of these SNPs were associated with expressions of the local genes. Some of these SNPs were associated with coronary artery disease or ischemic stroke. The associations between 12 functional SNPs in 7 genes and BP were validated (P < 5 × 10). The intronic SNP rs176185, which may influence promoter histone, enhancer histone, DNase and regulatory motifs and showed cis-eQTL effect on WBP1L, was associated with hypertension in the Chinese Han population (P = 0.0119). Our study detected plenty of potential functional SNPs in the BP-associated genes and demonstrated that rs176185 may be associated with hypertension in the Chinese Han population.

SNPs rs10224002 in PRKAG2 may disturb gene expression and consequently affect hypertension.

Genome-wide association studies have identified a large number of genetic loci for blood pressure in European populations. The associations in other populations are needed to determine. The purpose of this study was to examine the associations between the single nucleotide polymorphisms (SNPs) identified in European populations and hypertension in the Chinese Han population, and highlight the potential roles. Seven tag-SNPs were genotyped in 857 hypertension cases and 927 controls to test the associations. The intronic SNP rs10224002 (PRKAG2) which could affect DNase and regulatory motif was associated with hypertension (P = 0.024). This SNP was also found to be associated with coronary artery disease and stroke. We searched for potential functional variants by bioinformatics analysis and found various kinds of variants such as missense mutations, phosphorylation-related SNPs and SNPs that have regulatory potentials in the blood pressure loci. We performed expression quantitative trait locus (eQTL) and differential expression analyses for the identified variants and genes. eQTL analysis found that rs10224002 was associated with PRKAG2 gene expression in peripheral blood (P = 0.0016). PRKAG2 was differentially expressed between hypertension cases and controls (P = 0.0133), coronary artery disease cases and controls (P = 0.02112) and stroke cases and controls (P = 0.0059). Our study demonstrated that SNPs rs10224002 may be associated with hypertension in the Chinese Han population and PRKAG2 may play a role in the etiology of hypertension and cardiovascular diseases.

Risk of reduced platelet counts in patients with nonalcoholic fatty liver disease (NAFLD): a prospective cohort study.

BACKGROUND: The production of peripheral platelet is mainly regulated by thrombopoietin, which is a glycoprotein hormone predominantly synthesized in the liver. Previously, many studies have reported that there was an inverse correlation between the degree of chronic viral hepatitis and the peripheral platelet count. However, the effect of nonalcoholic fatty liver disease (NAFLD) on the peripheral platelet counts remains unclear. METHODS: With 1303 participants from "The prevention of MS and multi-metabolic disorders in Jiangsu province of China (PMMJS)" cohort study, we investigated the associations between NAFLD and the risk of platelet counts reduction in Chinese adults. The paired-samples T test was used to explore the platelet counts changes between baseline and follow-up. Multivariate logistic regression was used to examine the association between presence of NAFLD and the risk of platelet reduction by calculating the odds ratios (ORs) and 95% confidence interval (CI). RESULTS: After five years of follow-up, platelet counts were markedly reduced from 220.6 ± 42.22 (109/L) at baseline to 208.41 ± 40.70 (109/L) at follow-up in NAFLD group (P < 0.0001). However, platelet counts were slightly lowered from 213.2 ± 43.26(109/L) at baseline to 211.8 ± 41.65 (109/L) at follow-up in non-NAFLD people (P = 0.2349). Meanwhile, there was a significant association between NAFLD and the risks of platelet count reduction, even after adjustment for confounding variables (OR: 1.68, 95% CI: 1.06-2.67). Additionally, among the participants with BMI ≤ 23 kg/m2 and SUA ≤ 344.3 µmol/L, the NAFLD participants have an increased risk of platelet count reduction compared to the persons in non-NAFLD group. CONCLUSIONS: Our present results suggested that NAFLD individuals have an increased risk of platelet counts reduction.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension.

Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.

A population association study of PPAR δ gene rs2016520 and rs9794 polymorphisms and haplotypes with body mass index and waist circumference in a Chinese population.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR) gene plays an important role in obesity and PPAR δ protein is a potent inhibitor; however, few previous studies have focused on this gene. AIM: To investigate the association of haplotypes of PPAR δ gene rs2016520 and rs9794 with abnormal weight (BMI ≥ 24 kg/m(2)) and abdominal obesity (WC ≥ 90 cm for males and ≥ 80 cm for females) in a Chinese Han population. SUBJECTS AND METHODS: In total, 820 subjects (270 men, 550 women) were randomly selected from the PMMJS cohort population and no individuals were related. rs2016520 and rs9794 were detected by TaqMan fluorescence probe. Hardy-Weinberg equilibrium (HWE) was used to detect genotype typing errors by Fisher's exact test. Linkage disequilibrium (LD) between polymorphisms was estimated by using SHEsis. Two PPAR δ SNPs (rs2016520 and rs9794) were analysed by using the logistic regression model. RESULTS: After adjustment for covariates, the haplotype containing the rs1026520-C and rs9794-C alleles was associated with a statistically significant decreased risk of obesity (OR = 0.64; 95% CI = 0.48-0.84, p = 0.0015). Coincidentally, the haplotype containing the rs1026520-C and rs9794-C alleles was also associated with a statistically decreased risk of abdominal obesity after covariate adjustment (OR = 0.59, 95% CI = 0.45-0.77, p < 0.001). CONCLUSION: C-C haplotype, constructed from rs2016520 and rs9794 alleles, showed a significant protective effect for both abnormal weight and abdominal obesity.

[Impact of dynamic changes of waist circumference and body mass index on type 2 diabetes mellitus risk].

OBJECTIVE: To investigate the impact of dynamic change of waist circumference or body mass index (BMI) on type 2 diabetes mellitus (T2DM) populations in a cohort study. METHODS: We not only obtained the baseline survey data from program 'Prevention of Multiple Metabolic Disorders and metabolic syndrome (MS) in Jiangsu Province'(PMMJS) which started in 1994, and we conducted twice follow-ups from January 2002 to August 2003, and March 2006 to November 2007. After excluding subjects who were found to have T2DM at baseline, cardiovascular disease(CVD), and BMI<18.5 kg/m(2) , and loss to follow up because of relocation, death or other reasons, a total of 3 461 subjects were included in this analysis. They received investigation including questionnaires investigation, measurement and laboratory examination. The differences of gender, smoking, alcohol drinking and T2DM family history in different groups were examined using χ(2)-test, median and inter-quartile range were calculated for TG, and they were examined by rank test. Four equal parts of the differences of waist circumference and BMI were carried out in the COX regression model, to investigate the association between 2 years change of waist circumference or BMI and incidence of T2DM. We also examined the association between BMI and waist circumference modification and incident risk of T2DM in subjects with normal baseline BMI, baseline obese subjects, subjects with normal baseline waist circumference and baseline abdominal obese subjects. RESULTS: A total of 3 461 participants (1 406 males, 2 055 females) were investigated, including 160 new T2DM cases (60 males, 100 females) who were from between baseline and the second following up. The accumulative incidence was 4.6% (60/3 461). Multivariate COX regression model analysis results showed that the T2DM risk was relatively high in the highest quartile of waist circumference D-value group(HR=2.06, 95% CI: 1.27-3.16), the T2DM risk was also high in the highest quartile of BMI D-value group (HR=1.30, 95% CI: 0.86-1.95). In subjects with abdominal obesity and normal waist circumference at baseline, the incidence rate of T2DM in non-control group was 7.1% (40/565) , 6.3% (45/645), higher than that in control group (3.4%(71/2 096), 4.5%(4/155)) (χ(2) values were 3.98 and 15.18, P values were 0.043 and <0.001). In subjects with normal waist circumference, T2DM risk was higher in non-control group than that in control group (HR=2.12, 95% CI: 1.40-3.22). In abdominal obese subjects, T2DM risk was also higher in non-control group than that in control group (HR=1.14, 95% CI: 1.04-1.92). If waist circumference was not controlled, T2DM risk was high, no matter BMI controlled or not (HR(95% CI) were 1.73(1.17-2.54), 2.45(1.63-3.69) respectively). CONCLUSION: Controlling the waistline could reduce the risk of diabetes, and once waist circumference was not controlled, T2DM risk would be increased no matter BMI was controlled or not.

[The impact of interaction between alcohol consumption and obesity on incident hypertension].

OBJECTIVE: To investigate the combined effects of alcohol consumption and obesity hypertension risk. METHODS: Based on data from program "Prevention of multiple metabolic disorders and metabolic syndrome in Jiangsu province", Baseline data were obtained in April 1999 to Jun 2004, we conducted the follow up investigation from March 2006 to October 2007 for subjects, those follow up time meet 5 years. A total of 4 083 participants completed the follow-up survey, and 2 778 eligible participants for final analysis. In the baseline and follow up survey, participants returned a completed questionnaire with information on diet, education, occupation, lifestyle factors, and medical history. Data on demographic characteristics, physical examination and laboratory tests were also obtained. Cox proportional hazards regression model was used to investigate the association between body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR). Logistic regression model was used to examine the interaction of alcohol consumption with WC, BMI and WHtR on risk of hypertension and the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergy index (SI) were calculated. If the 95% CI of SI do not include 1, the 95% CI of RERI and AP do not include 0, the interactions are statistically significant. RESULTS: In the study subjects, 660 patients (254 males and 406 females) were new cases, who developed hypertension by the follow-up investigation. The mean of WC, BMI and WHtR were (23.3 ± 3.2) kg/m(2), (77.7 ± 9.0) cm and 0.49 ± 0.06, were higher than that in normal subjects ((22.4 ± 3.0) kg/m², (74.8 ± 8.5) cm and 0.47 ± 0.05, all P values < 0.001). After adjustment for age, sex, smoking status, family history of hypertension, the hazard ratio of EH for participants with obesity, high WC, high WHtR and alcohol consumption were higher, the HR (95% CI) were 2.12 (1.46-3.10), 1.64 (1.32-2.03), 2.80 (1.73-4.59) and 1.65 (1.29-2.12). HR (95% CI) of subjects with both abnormal BMI and current alcohol consumption was 2.76 (2.45-3.17), SI (95% CI) was 1.60 (0.48-5.28), RERI(95%CI) was 0.66 (-0.47-1.79) and AP was 0.24 (-0.22-0.69), HR (95% CI) of subjects with both high WC and current alcohol consumption was 4.93 (2.87-8.49), SI(95% CI) was 4.49(1.97-10.22), RERI (95%CI) was 3.06 (0.48-5.64) and AP(95% CI) was 0.62 (0.41-0.83), HR (95% CI) of subjects with both high WHtR and current alcohol consumption was 2.80 (1.73-4.59), SI (95% CI) was 2.14 (0.88-5.17), RERI was 0.96 (0.48-5.64) and AP (95% CI) was 0.34 (0.03-0.68). CONCLUSION: Both obesity, high WC, high WHtR, and alcohol consumption were strong risk factors of EH, and impact of an additive interaction of alcohol consumption and high WC on EH risk existed.

[Association and interaction between 10 SNP of peroxisome proliferator-activated receptor and non-HDL-C].

OBJECTIVE: To examine the main effect of 10 Peroxisome proliferators-activated receptor (PPAR) SNP in contribution to non-HDL-C and study whether there is an interaction in the 10 SNPs. METHODS: Participants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort-population-survey, which was initiated from April 1999 to June 2004, and 5-year follow-up data from total 4 582 subjects were obtained between March 2006 and October 2007. A total of 4 083 participants received follow-up examination. After excluding subjects who had experienced stroke or exhibited cardiovascular disease, type 2 diabetes or a BMI <18.5 kg/m(2), a total of 820 unrelated individual subjects were selected from 3 731 subjects on October of 2009. Blood samples which were collected at the baseline were subjected to PPARα, PPARδ and PPARγ 10 SNPs genotype analysis. Logistic regression model was used to examine the association between 10 SNPs in the PPARs and non-HDL-C. Interactions within the 10 SNP were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: A total of 820 participants (mean age was 50.05±9.41) were included in the study and 270 were males and 550 were females. Single-locus analysis showed that after adjusting gender, age, smoking, alcohol consumption, physical activity, high-fat diet and low-fiber diet factors, rs1800206-V and rs3856806-T were significantly associated with higher non-HDL-C levels. V allele (LV + VV genotype) carriers of rs1800206 have a average non-HDL-C levels on (3.15 ± 0.89)mg/L (F = 15.01, P = 0.002); T allele (CT+TT genotype) carriers of rs3856806 have a average non-HDL-C levels on (3.03±1.01) mg/L (F = 9.87, P = 0.005). GMDR model analysis showed that after adjusting the same factors, two-locus model, five-locus model, six-locus model and seven-order interaction models were all statistically significant (P<0.05), and the seven-locus model (rs1800206, rs3856806, rs135539, rs4253778, rs2016520, rs1805192, rs709158) was the best model (P = 0.001), the cross-validation consistency was 10/10 and testing accuracy was 0.656. CONCLUSION: Rs1800206 and rs3856806 were significantly associated with non-HDL-C. And there was an gene-gene interaction among rs1800206, rs3856806, rs1800206, rs135539, rs4253778, rs2016520, rs1805192, rs3856806 and rs709158 which could influence the non-HDL-C levels.

[Association between peroxisome proliferator-activated receptor and gene-gene interactions with the apolipoprotein A I/apolipoprotein B100 ratio].

OBJECTIVE: To investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARα, ß, γ) with apolipoprotein A I/apolipoprotein B100 (ApoA I/ApoB100) ratio and the additional role of a gene-gene interactions among the 10 SNPs. METHODS: Participants were recruited under the framework of the Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province (PMMJS) cohort population survey in the urban community of Jiangsu province of China.A total of 630 subjects were randomly selected and no individual was related.Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were selected from the HapMap database,which covered PPARα, PPARß and PPARγ. A linear regression model was used to analyze the relations between ten SNPs in the PPARs and ApoA I/ApoB100 ratio level. Mean difference and 95% CI were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: After adjusting for age, gender, smoking status, alcohol consumption, occupational physical activity, high-fat diet as well as low-fiber diet, both rs1800206 and rs3856806 were significantly associated with a decreased level of ApoA I/ApoB100 ratio, mean difference (95% CI) values were -1.19 (-1.88 to -0.50) and -0.77 (-1.40 to -0.14). Whereas rs4253778 was significantly associated with an increased level of ApoA I/ApoB100 ratio, Mean difference (95% CI) values was 0.80 (0.08 to 1.52). GMDR analysis showed a significant gene-gene interaction among rs4253778, rs1800206 of PPARα, rs9794, rs2016520 of PPARß and rs10865710, rs3856806, rs709158, rs1805192 of PPARγ for eight-dimension models (P = 0.01), in which prediction accuracy was 0.624 and cross-validation consistency was 7/10. CONCLUSIONS: The rs1800206 of PPARα and rs3856806 of PPARγ are significantly associated with a decreased level of ApoA I/ApoB100 ratio while rs4253778 of PPARα is associated with an increased level of ApoA I/ApoB100 ratio. There is a gene-gene interaction between multiple SNPs.

Analysis on the association between PPARα/γ polymorphisms and lipoprotein(a) in a Chinese Han population.

Lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle, is recognized as an independent risk factor for atherosclerosis, cardiovascular diseases, and diabetic vascular diseases. Our recent studies revealed that the single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors (PPARα/δ/γ) gene are involved in the regulation of lipid storage and metabolism. In order to investigate the relationships between the SNPs of PPARα/γ gene and plasma levels of Lp(a), 644 participants were randomly selected from Chinese Han population in the present study. As the results shown, Lp(a) was significantly associated with L162V (rs1800206) in PPARα. Compared with those subjects with widetype (LL), significantly higher Lp(a) concentration was determined in the individuals with mutant (LV + VV) (mean difference: 49.07 mg/l, 95% CI 23.32-74.82 mg/l, p = 0.0002). Moreover, with generalized multifactor dimensionality reduction analysis, our present results indicated that there was a significant association between plasma Lp(a) level and gene-gene interaction among the polymorphisms rs1800206, rs135539 in PPARα and rs10865710, rs1805192, and rs4684847 in PPARγ. Therefore, our presented study indicated that PPARα/γ polymorphisms should be involved in the regulation of plasma Lp(a) in independently and/or in an interactive manner, suggesting that PPARα/γ gene may influence the risk of hypertension, cardiovascular diseases, and dyslipidemia by regulating Lp(a) level.

The application of visceral adiposity index in identifying type 2 diabetes risks based on a prospective cohort in China.

BACKGROUND: Visceral adiposity index (VAI), a novel sex-specific index for visceral fat measurement, has been proposed recently. We evaluate the efficacy of VAI in identifying diabetes risk in Chinese people, and compare the predictive ability between VAI and other body fatness indices, i.e., waist circumference (WC), body mass index (BMI) and waist- to- height ratio (WHtR). METHODS: Participants (n=3,461) were recruited from an ongoing cohort study in Jiangsu Province, China. Hazard ratio (HR) and corresponding 95% confidence interval (CI) between diabetes risk and different body fatness indices were evaluated by Cox proportional hazard regression model. Receiver operating characteristic (ROC) curve and area under curve (AUC) were applied to compare the ability of identifying diabetes risk between VAI, WC, WHtR and BMI. RESULTS: A total number of 160 new diabetic cases occurred during the follow-up, with an incidence of 4.6%. Significant positive associations were observed for VAI with blood pressure, fasting plasma glucose, triglyceride, WC, BMI and WHtR. Moreover, increased VAI was observed to be associated with higher diabetes risk with a positive dose-response trend (p for trend<0.001). As compared to individuals with the lowest VAI, those who had the highest VAI were at 2.55-fold risk of diabetes (95% CI: 1.58-4.11). The largest AUC was observed for VAI, following by WC, WHtR and BMI. CONCLUSIONS: VAI is positively associated with the risk of diabetes. Compared to other indices for body fatness measurements, VAI is a better and convenience surrogate marker for visceral adipose measurement and could be used in identifying the risk of diabetes in large-scale epidemiologic studies.

PPAR α and PPAR γ polymorphisms as risk factors for dyslipidemia in a Chinese Han population.

BACKGROUND: The PPAR α and PPAR γ are the key messengers responsible for the translation of nutritional stimuli into changes for the expression of genes, particularly genes involved in lipid metabolism. However, the associations between PPAR α/γ polymorphisms and lipid serum levels in the general population were rarely studied, and the conclusions were conflicting. The objective was to investigate the associations of the PPAR α and PPAR γ polymorphisms with dyslipidemia. METHODS: 820 subjects were randomly selected from the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort populations. The logistic regression model was used to examine the association between these polymorphisms and dyslipidemia. SNPstats was used to explore the haplotype association analyses. RESULTS: In the codominant and log-additive models, rs1800206, rs1805192 and rs3856806 were all associated with dyslipidemia (P < 0.005). When the most common haplotype L-G (established by rs1800206, rs4253778) was treated as the reference group, the V-G haplotype was associated with dyslipidemia (P < 0.001), higher TC and TG levels (P < 0.01). Moreover, when compared to Pro-C haplotype (established by rs1805192, rs3856806), the Pro-T, Ala-C, Ala-T haplotypes were associated with dyslipidemia (p < 0.001). A-T haplotype was associated with higher TC levels, (p < 0.01), and the P-T, A-C, A-T haplotypes were associated with higher TG levels (p < 0.01). CONCLUSIONS: PPAR α and PPAR γ polymorphisms and haplotypes may be the genetic risk factors for dyslipidemia.

Head-to-head comparison of cone-beam breast computed tomography and mammography in the diagnosis of primary breast cancer: A systematic review and meta-analysis.

INTRODUCTION: To compare the diagnostic performance of cone-beam breast computed tomography (CBBCT) and mammography (MG) in primary breast cancer. METHODS: PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang DATA, and China Science and Technology Journal databases were searched comprehensively from inception to March 2023. Sensitivity and specificity were calculated using bivariate random-effects models, and a summary receiver operating characteristic (SROC) curve was constructed. Bivariate I2 statistics and meta-regression analyses were also performed. The differences in diagnostic performance between CBBCT and MG were analysed using Z-test statistics. Clinical utility was explored using Fagan's nomogram, and quality assessment was conducted utilising the Quality Assessment of Diagnostic Accuracy Studies-2 checklist. RESULTS: The summary sensitivity and specificity for CBBCT in diagnosing primary breast cancer were 0.92 (95 % CI: 0.87-0.94) and 0.79 (95 % CI: 0.71-0.85), respectively, and the area under the curve (AUC) of the SROC was 0.93 (95 % CI: 0.90-0.95). For MG, the summary sensitivity and specificity were 0.77 (95 % CI: 0.69-0.83) and 0.75 (95 % CI: 0.66-0.82), respectively, with an AUC of 0.83 (95 % CI: 0.80-0.86). The Z-test revealed that the summary sensitivity of CBBCT was significantly higher than that of MG (P < 0.001). Additionally, the summary AUC of CBBCT was significantly higher than that of MG (P < 0.001). CONCLUSION: The diagnostic performance of CBBCT for primary breast cancer was better than that of MG. However, the results of both the CBBCT and MG are based on studies with small sample sizes. Further studies with larger sample sizes and more comprehensive designs are required to address this issue.