New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol.

BACKGROUND: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. METHODS: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. RESULTS: We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum. CONCLUSIONS: Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.

Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis.

BACKGROUND: High blood cholesterol accelerates the progression of atherosclerosis, which is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis, which results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease. METHODS: Low-density lipoprotein (LDL) receptor (LDLR) was used as bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK; encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han people was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice and knocked down Klkb1 using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and proprotein convertase subtilisin/kexin 9 inhibition also was evaluated. In addition, we applied the anti-PK neutralizing antibody that blocked the PK and LDLR interaction in mice. Mice lacking both PK and apolipoprotein e (Klkb1-/-Apoe-/-) were generated to assess the role of PK in atherosclerosis. RESULTS: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of proprotein convertase subtilisin/kexin 9 with evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed the progression of atherosclerosis in mice on Apoe-deficient background. CONCLUSIONS: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol, and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat atherosclerotic cardiovascular disease.

A prediction model based on platelet parameters, lipid levels, and angiographic characteristics to predict in-stent restenosis in coronary artery disease patients implanted with drug-eluting stents.

BACKGROUND: The present study was aimed to establish a prediction model for in-stent restenosis (ISR) in subjects who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). MATERIALS AND METHODS: A retrospective cohort study was conducted. From September 2010 to September 2013, we included 968 subjects who had received coronary follow-up angiography after primary PCI. The logistic regression analysis, receiver operator characteristic (ROC) analysis, nomogram analysis, Hosmer-Lemeshow χ2 statistic, and calibration curve were applied to build and evaluate the prediction model. RESULTS: Fifty-six patients (5.79%) occurred ISR. The platelet distribution width (PDW), total cholesterol (TC), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and lesion vessels had significant differences between ISR and non-ISR groups (all P < 0.05). And these variables were independently associated with ISR (all P < 0.05). Furthermore, they were identified as predictors (all AUC > 0.5 and P < 0.05) to establish a prediction model. The prediction model showed a good value of area under curve (AUC) (95%CI): 0.72 (0.64-0.80), and its optimized cut-off was 6.39 with 71% sensitivity and 65% specificity to predict ISR. CONCLUSION: The incidence of ISR is 5.79% in CAD patients with DES implantation in the Xinjiang population, China. The prediction model based on PDW, SBP, TC, LDL-C, and lesion vessels was an effective model to predict ISR in CAD patients with DESs implantation.

Genetic polymorphism of IDOL gene was associated with the susceptibility of coronary artery disease in Han population in Xinjiang, China.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide. In this study, we aimed to explore whether some genetic variants of the human IDOL gene were associated with CAD among Chinese population in Xinjiang. METHODS: We designed two independent case-control studies. The first one included in the Han population (448 CAD patients and 343 controls), and the second one is the Uygur population (304 CAD patients and 318 controls). We genotyped three SNPs (rs2072783, rs2205796, and rs909562) of the IDOL gene. RESULTS: Our results revealed that, in the Han female subjects, for rs2205796, the distribution of alleles, dominant model (TT vs. GG + GT) and the additive model (GG + TT vs. GT) showed significant differences between CAD patients and the control subjects (P = 0.048, P = 0.014, and P = 0.032, respectively). CONCLUSIONS: The rs2205796 polymorphism of the IDOL gene is associated with CAD in the Chinese Han female population in Xinjiang, China.

FBXW7 gene polymorphism is associated with type 2 diabetes in the Uygur population in Xinjiang, China.

BACKGROUND: FBXW7 gene expression is positively correlated with glycolipid metabolism and is associated with diabetes in animal models. In the current study, we focused on exploring whether genetic variants of the FBXW7 gene were associated with type 2 diabetes (T2DM) and the risk factors for T2DM in Uygur people in Xinjiang, China. METHODS: A total of 2164 Chinese Uygur subjects (673 T2DM patients and 1491 controls) were recruited for our case-control study, and four SNPs (rs10033601, rs2255137, rs2292743 and rs35311955) of the FBXW7 gene were genotyped using the improved multiplex ligation detection reaction (iMLDR) technique. RESULTS: Our study showed that the genotypes using the overdominant model (GA vs AA + GG) of rs10033601 and using the overdominant model (TA vs TT + AA) of rs2292743 were significantly different between T2DM patients and the controls (P = 0.005 and P = 0.012, respectively). After multivariate adjustments for confounders, the rs10033601 and rs2292743 SNPs were still independent risk factors for T2DM [GA vs AA + GG: odds ratio = 1.35, 95% confidence interval (CI) = 1.12-1.64, P = 0.002; TA vs TT + AA: OR = 1.28, 95% CI = 1.06-1.55, P = 0.011]. Participants within the Chinese Uygur populations and who with the GA genotype of rs10033601 and the TA genotype of rs2292743 were associated with significantly elevated glucose levels. CONCLUSIONS: Our study revealed that both rs10033601 and rs2292743 of the FBXW7 gene were associated with T2DM in the Uygur populations in Xinjiang.

IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation.

OBJECTIVE: A high level of LDL-C (low-density lipoprotein cholesterol) is a major risk factor for cardiovascular disease. The E3 ubiquitin ligase named IDOL (inducible degrader of the LDLR [LDL receptor]; also known as MYLIP [myosin regulatory light chain interacting protein]) mediates degradation of LDLR through ubiquitinating its C-terminal tail. But the expression profile of IDOL differs greatly in the livers of mice and humans. Whether IDOL is able to regulate LDL-C levels in humans remains to be determined. Approach and Results: By using whole-exome sequencing, we identified a nonsynonymous variant rs149696224 in the IDOL gene that causes a G51S (Gly-to-Ser substitution at the amino acid site 51) from a Chinese Uygur family. Large cohort analysis revealed IDOL G51S carriers (+/G51S) displayed significantly higher LDL-C levels. Mechanistically, the G51S mutation stabilized IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL(G51S) exhibited a stronger ability to promote ubiquitination and degradation of LDLR. Adeno-associated virus-mediated expression of IDOL(G51S) in mouse liver decreased hepatic LDLR and increased serum levels of LDL-C, total cholesterol, and triglyceride. CONCLUSIONS: Our study demonstrates that IDOL(G51S) is a gain-of-function variant responsible for high LDL-C in both humans and mice. These results suggest that IDOL is a key player regulating cholesterol level in humans.

TBL2 methylation is associated with hyper-low-density lipoprotein cholesterolemia: a case-control study.

BACKGROUND: HMGCR, SCAP, SREBF1, SREBF2 and TBL2 are well-known genes that are involved in the process of lipid metabolism. However, it is not known whether epigenetic changes of these genes are associated with lipid metabolism. In this study, the methylation levels of the HMGCR, SCAP, SREBF1, SREBF2 and TBL2 genes were analyzed between samples from a hyper-low-density lipoprotein cholesterolemia (hyper-LDL) group and a control group to examine the association between the methylation levels of these genes and the risk of hyper-LDL. METHODS: In this study, a case-control approach was used to explore the association between DNA methylation and hyper-LDL. The DNA methylation levels of HMGCR, SCAP, SREBF1, SREBF2 and TBL2 genes and 231 CpG sites in the promoter regions of these genes were measured in 98 hyper-LDL participants and 89 participants without hypo-LDL. RESULTS: Compared with participants without hyper-LDL, patients with hyper-LDL TBL2 gene had lower methylation levels (11.93 vs. 12.02, P = 0.004). The methylation haplotypes with significant abundance in the TBL2 gene are tcttttttttt (P = 0.034), ctttttttcct (P = 0.025), ctctttctttt (P = 0.040), ccttttttttt (P = 0.028), and tctttttttttttttt. CONCLUSION: The study demonstrates that participants with hyper-LDL have lower methylation of TBL2. The results suggest that DNA methylation of TBL2 can decrease the risk for hyper-LDL in humans.

SOAT1 methylation is associated with coronary heart disease.

BACKGROUND: This study was designed to investigate whether differential DNA methylationin of cholesterol absorption candidate genes can function as a biomarker for patients with coronary heart disease (CHD). METHODS: DNA methylation levels of the candidate genes FLOT1, FLOT2 and SOAT1 were measured in peripheral blood leukocytes (PBLs) from 99 patients diagnosed with CHD and 89 control subjects without CHD. A total of 110 CPG sites around promoter regions of them were examined. RESULTS: Compared with groups without CHD, patients with CHD had lower methylation levels of SOAT1 (P<0.001). When each candidate genes were divided into different target segments, patients with CHD also had lower methylation levels of SOAT1 than patients without (P = 0.005). After adjustment of other confounders, methylation levels of SOAT1 were still associated with CHD (P = 0.001, OR = 0.290, 95% CI: 0.150-0.561). CONCLUSIONS: SOAT1 methylation may be associated with development of CHD. Patients with lower methylation levels in SOAT1 may have increased risks for CHD. Further studies on the specific mechanisms of this relationship are necessary.

The clathrin adaptor proteins ARH, Dab2, and numb play distinct roles in Niemann-Pick C1-Like 1 versus low density lipoprotein receptor-mediated cholesterol uptake.

The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake.

The association of cholesterol absorption gene Numb polymorphism with Coronary Artery Disease among Han Chinese and Uighur Chinese in Xinjiang, China.

BACKGROUND: Hypercholesterolemia is a major risk factor for coronary artery disease (CAD). As Numb is an important regulating factor for intestinal cholesterol absorption and plasma cholesterol level, the aim of the present study is to assess the association between human Numb gene polymorphism and CAD among Han and Uighur Chinese. METHODS: We have conducted two independent case-control studies in Han Chinese (384 CAD patients and 433 controls) and Uighur Chinese (506 CAD patients and 351 controls) subjects. All subjects were genotyped for four kinds of SNPs (rs12435797, rs2108552, rs1019075 and rs17781919) and SNP is used as a genetic marker for human Numb gene. Genotyping was undertaken using TaqMan SNP genotyping assay, and the subjects' ethnicity and gender were considered in the analysis. RESULTS: We found that rs2108552 was associated with CAD in the dominant model (CC vs CG + GG) for the total Han Chinese population (n = 200) and Han Chinese males (n = 115) (P = 0.004 and P = 0.001, respectively). The difference remained statistically significant after multivariate adjustment (total: OR = 1.687, P = 0.004; male: OR = 1.498, P = 0.006). Further, for the total (n = 817) and male (n = 490) Han Chinese, the frequency of the haplotype (T-C-T-C) was significantly higher in the CAD patients than in the controls (P = 0.004 and P = 0.002), and the frequency of the haplotype (G-G-T-C) was significantly lower in the CAD patients than in the control subjects (P = 0.013, P = 0.007). In addition, for the total (n = 857) and male (n = 582) Uighur Chinese, we observed that rs12435797 was associated with CAD in an additive and recessive model (P = 0.021 and P = 0.009; P = 0.048 and P = 0.034). However, the difference did not remain statistically significant after multivariate adjustment. The overall distribution of rs2108552, rs1019075 and rs17781919 genotypes, alleles and the frequency of the haplotype established by four SNPs showed no significant difference between CAD patients and control subjects in the total, male and female Uighur Chinese. CONCLUSIONS: The results of this study indicate that CC genotype of rs2108552 and T-C-T-C haplotypes in Numb gene is a possible risk genetic marker and G allele and G-G-T-C haplotypes is a possible protective genetic marker for CAD in male Han Chinese.

Relationship between CYP17A1 genetic polymorphism and coronary artery disease in a Chinese Han population.

BACKGROUND: CYP17A1 gene encodes P450c17 proteins, which is a key enzyme that catalyzes the formation of sex hormones. Many clinical studies showed that sex hormones levels play an important role in the pathogenesis of coronary artery disease (CAD). However, the relationship between CYP17A1 genetic polymorphisms and CAD remains unclear. The aim of this study was to investigate the association of CYP17A1 genetic polymorphisms with CAD in a Han population of China. METHODS: A total of 997 people include 490 patients and 507 controls were selected for the present study. Five single-nucleotide polymorphisms (SNPs) (rs4919686, rs1004467, rs4919687, rs10786712, and rs2486758) were genotyped by using the real-time PCR (TaqMan) method. RESULTS: For men, the rs10786712 was found to be associated with CAD in a recessive model (P=0.016), after adjustment of the major confounding factors, the significant difference was retained (OR=1.644, 95% confidence interval [CI]: 1.087-2.488, P=0.019). For women, the rs1004467 was also found to be associated with CAD in a dominant model (P=0.038), the difference remained statistically significant after multivariate adjustment (OR=1.623, 95% CI: 1.023-2.576, P=0.040). The distribution of rs4919687 genotypes showed a significant difference between CAD and control participants in a recessive model (P=0.019), the significant difference was retained after adjustment for covariates (OR=0.417, 95% CI: 0.188-0.926, P=0.032). CONCLUSION: Rs1004467, rs4919687, rs10786712 of CYP17A1 gene are associated with CAD in Han population of China. The TT genotype of rs10786712 could be a protective genetic marker of CAD in men. The CC genotype of rs1004467 and the AA genotype of rs4919687 could be risk genetic markers of CAD in women. However, large sample size study including other SNPs of CYP17A1 should be performed in future studies.

Optimal cutoff of the waist-to-hip ratio for detecting cardiovascular risk factors among Han adults in Xinjiang.

BACKGROUND: The optimal cutoff of the waist-to-hip ratio (WHR) among Han adults in Xinjiang, which is located in the center of Asia, is unknown. We aimed to examine the relationship between different WHRs and cardiovascular risk factors among Han adults in Xinjiang, and determine the optimal cutoff of the WHR. METHODS: The Cardiovascular Risk Survey was conducted from October 2007 to March 2010. A total of 14618 representative participants were selected using a four-stage stratified sampling method. A total of 5757 Han participants were included in the study. The present statistical analysis was restricted to the 5595 Han subjects who had complete anthropometric data. The sensitivity, specificity, and distance on the receiver operating characteristic (ROC) curve in each WHR level were calculated. The shortest distance in the ROC curves was used to determine the optimal cutoff of the WHR for detecting cardiovascular risk factors. RESULTS: In women, the WHR was positively associated with systolic blood pressure, diastolic blood pressure, and serum concentrations of serum total cholesterol. The prevalence of hypertension and hypertriglyceridemia increased as the WHR increased. The same results were not observed among men. The optimal WHR cutoffs for predicting hypertension, diabetes, dyslipidemia and ≥ two of these risk factors for Han adults in Xinjiang were 0.92, 0.92, 0.91, 0.92 in men and 0.88, 0.89, 0.88, 0.89 in women, respectively. CONCLUSIONS: Higher cutoffs for the WHR are required in the identification of Han adults aged ≥ 35 years with a high risk of cardiovascular diseases in Xinjiang.

A novel polymorphism of the GP78 gene is associated with coronary artery disease in Han population in China.

BACKGROUND: GP78 is a membrane-anchored ubiquitin ligase mediating the degradation of 3-hydroxy-3-methyl-glutaryl-CoA coenzyme A reductase (HMGCR) and Insig-1, which was very essential for the synthesis of cholesterol process. Cholesterol levels have a causal role in the development of cardiovascular disease. The aim of the present study was to assess the association between the human gp78 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China. METHODS: We used two independent case-control studies: a Han population (602 CAD patients and 572 control subjects) and a Uygur population (374 CAD patients and 376 control subjects). All CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (SNPs) (rs731119, rs2617849 and rs2440472) of gp78 gene by a Real-time PCR instrument. RESULTS: In the Han population, for total and men, the distribution of SNP3 (rs2440472) alleles and the dominant model (AA vs AG + GG) and recessive model (GG vs AG + AA) showed a significant difference between CAD and control participants (for allele: P = 0.003 and P = 0.002, respectively; for dominant model: P = 0.041 and P = 0.026, respectively; for recessive model: p = 0.004 and p = 0.004, respectively).The significant difference in both the two models was retained after adjustment for covariates (for dominant model OR:0.760, 95% confidence interval [CI]:0.584-0.99, P = 0.042; OR:0.686, 95% CI: 0.498-0.946, P = 0.022, respectively; for recessive model OR: 1.451, 95% CI: 1.067-1.974, P = 0.018; OR: 1.789, 95% CI: 1.219-2.627, P = 0.000). Our data was also assessed via haplotype-based case-control studies. For the Han population, for total, The G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.02), and the G-C-A haplotype in CAD was significantly lower than that in the control group (P = 0.0443), And for man, the G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.0048). CONCLUSIONS: The GG genotype and G allele of rs2440472 in gp78 gene could be a risk genetic marker of CAD in Han population in China.

Best anthropometric and atherogenic predictors of metabolic syndrome in the Chinese Han population in Xinjiang: the Cardiovascular Risk Survey.

OBJECTIVE: This study aimed to identify the best predictor of metabolic syndrome (MetS) by comparing the predicting ability of various anthropometric and atherogenic parameters in the Chinese Han population in Xinjiang. METHODS: A representative, cross-sectional sample of 5,757 Chinese Han adults were selected from the Cardiovascular Risk Survey conducted from October 2007 to March 2010. MetS prevalence, area under the curve (AUC), distance on the receiver operating characteristic curve and the cut-offs of each variable were compared for the presence of MetS. RESULTS: According to the criteria of the International Diabetes Federation (IDF), the Joint Interim Statement (JIS) and the Third Adult Treatment Panel (ATPIII), 32.1, 48.5, 39.3% of men and 38.0, 45.1, 44.9% of women had MetS in Xinjiang. According to the IDF criteria, the waist-to-height ratio (WHtR) had the highest AUC value in men (0.836) and women (0.837), with the optimal cut-off of 0.54 in men and 0.53 in women. According to both the JIS and ATPIII criteria, triglycerides/high-density lipoprotein cholesterol TG/HDL-C had the highest AUC value in men (0.830 and 0.833, respectively) and women (0.832 and 0.827, respectively), with the optimal cut-offs being 1.6 and 1.2 in men and 1.1 and 1.1 in women, respectively. CONCLUSION: WHtR was the best predictor of MetS according to the IDF criteria while TG/HDL-C was the best predictor of MetS according to the JIS and ATPIII criteria.

SAA1 genetic polymorphisms are associated with plasma glucose concentration in non-diabetic subjects.

BACKGROUND: Serum amyloid A (SAA) was reported to be associated with insulin resistance and type-2 diabetes. The present study aimed to investigate the association of SAA genetic polymorphisms with plasma glucose levels in non-diabetic subjects. METHODS: All participants (n=1220) were selected from subjects participating in the Cardiovascular Risk Survey (CRS) study. Five single-nucleotide polymorphisms (SNPs) (rs2229338, rs12218, rs4638289, rs7131332 and rs11603089) of SAA gene were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. RESULTS: In the present study, we found rs2229338, rs4638289 and rs12218 were significantly associated with plasma glucose levels in a dominate model, recessive model or additive model before and after multivariate adjustment (all p<0.05). These associations were not found in rs7131332 and rs11603089 before and after adjustment of key co-variants. CONCLUSIONS: The genetic polymorphisms of SAA1 were associated with plasma glucose levels in non-diabetic subjects.

A novel polymorphism (901G > a) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population.

BACKGROUND: C5L2, a G protein-coupled receptor (GPCR), has been demonstrated to be a ligand for acylation-stimulating protein (ASP). The aim of the present study is to evaluate the association of a novel variation (901A > G) of C5L2 gene with coronary artery disease (CAD). METHODS: We identified a novel single nucleotide polymorphism (SNP), (901G > A), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from Arginine to glutaminate at codon 300. We analyzed the relationship between this SNP and CAD in two independent case-control studies: one was in a Han population (492 CAD patients and 577 control subjects) and the other was in a Uygur population (319 CAD patients and 554 control subjects). RESULTS: The frequency of AG genotype in CAD subjects was less than that in the control subjects not only in Han (1.8% vs 8.6%, P < 0.001, OR = 0.143, 95% CI: 0.068 ~ 0.302) but also in Uygur population (0.9% vs 5.2%, P = 0.001, OR = 0.246, 95% CI: 0.072 ~ 0.837). After adjustment for known CAD risk factors such as hypertension, diabetes, smoking, age and gender, the difference remained significant. CONCLUSION: The 901G > A polymorphism of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.

Association of COL4A1 genetic polymorphisms with coronary artery disease in Uygur population in Xinjiang, China.

BACKGROUND: Type IV collagen is important for the structural integrity and function of basement membranes. Basement membranes surround vascular smooth muscle cells in the media, COL4A1 is the most abundant component of type IV collagen in all Basement membranes. However, the relationship between COL4A1 genetic polymorphisms and coronary artery disease (CAD) remains unclear. We performed a case-control study to explore the association of COL4A1 genetic polymorphisms with CAD in Uygur population of China. METHODS: 1095 Uygur people (727 men, 368 women) including 471 CAD patients and 624 controls were selected for the present study. Two SNPs (rs605143 and rs565470) were genotyped by using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method. RESULTS: For total and men, the rs605143 was found to be associated with CAD by in a dominate model (p = 0.014, p = 0.013, respectively). The difference remained statistically significant after multivariate adjustment (p = 0.036, p = 0.014, respectively). The rs565470 was also found to be associated with CAD in a recessive model for total and men (both p < 0.001), and the difference remained statistically significant after multivariate adjustment (P = 0.002, P = 0.001, respectively). CONCLUSION: Both rs605143 and rs565470 of COL4A1gene are associated with CAD in Uygur population of China.

Genetic variation in Tanis was associated with elevating plasma triglyceride level in Chinese nondiabetic subjects.

BACKGROUND: The association of genetic polymorphisms of Tanis with triglyceride concentration in human has not been thoroughly examined. We aimed to investigate the relationship between triglyceride concentrations and Tanis genetic polymorphisms. METHODS: All participants (n=1497) selected from subjects participating in the Cardiovascular Risk Survey (CRS) study were divided into two groups according to ethnicity (Han: n=1059; Uygur: n= 438). Four tagging SNPs (rs12910524, rs1384565, rs2101171, rs4965814) of Tanis gene were genotyped using TaqMan® assays from Applied Biosystems following the manufacturer's suggestions and analyzed in an ABI 7900HT Fast Real-Time PCR System. RESULTS: We found that the SNP rs12910524 was associated with triglyceride levels by analyses of a dominant model (P<0.001), recessive model (P <0.001) and additive model (P < 0.001) not only in Han ethnic but also in Uygur ethnic group, and the difference remained significant after the adjustment of sex, age, alcohol intake, smoking, BMI and plasma glucose (GLU) level (All P < 0.001). However, this relationship was not observed in rs1384565, rs2101171, and rs4965814 before and after multivariate adjustment (All P > 0.05). Furthermore, there were significant interactions between rs12910524 and GLU on TG both in Han (P=0.001) and Uygur population (P=2.60×10(-4)). CONCLUSION: Our results indicated that the rs12910524 in the Tanis gene was associated with triglyceride concentrations in subjects without diabetes in China.

Prevalence of major cardiovascular risk factors and adverse risk profiles among three ethnic groups in the Xinjiang Uygur Autonomous Region, China.

BACKGROUND: Prevalence of cardiovascular disease (CVD) risk factors have been scarcely studied in Xinjiang, a multi-ethnic region. METHODS: Multi-ethnic, cross-sectional cardiovascular risk survey study in Xinjiang, including individuals of Uygur (n = 4695), Han (n = 3717) and Kazakh (n = 3196) ethnicities, aged 35-74 years. Analyses involved 11,608 participants with complete data enrolled between October 2007 and March 2010. RESULTS: There were differences in age-standardized prevalence of CVD risk factors between the three groups (all P < 0.001). Hypertension, obesity and smoking rates were higher among Kazakh (54.6%, 24.5%, and 35.8%, respectively). Dyslipidemia prevalence was higher among Uygur (54.3%), and diabetes prevalence was higher among Hans (7.1%). Age-standardized prevalence of adverse CVD risk profiles was different across different ethnicities. Compared with the Han participants, the Uygur and Kazakh had more CVD risk factors (P < 0.001). Compared with the Han participants, the adjusted odds ratios of 1, 2, and ≥3 risk factors profiles for Kazakh and Uygur participants were higher (all P < 0.001). CONCLUSIONS: The present study showed the pervasive burden of CVD risk factors in all participant groups in the Xinjiang region. Three major ethnic groups living in Xinjiang had striking differences in the prevalence of major CVD risk factors and adverse risk profiles. Ethnic-specific strategies should be developed to prevent CVD in different ethnic groups, as well as to develop strategies to prevent future development of adverse CVD risk factors at a younger age.