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.

[Epidemiological survey of carotid artery intima-media thickness in Han, Uygur and Hazakh population of Xinjiang Uygur autonomous region].

OBJECTIVE: To investigate carotid artery intima-media thickness (IMT) and the correlated risk factors in Han, Uygur, Hazakh residents over 35 years old of Xinjiang Uygur autonomous region. METHOD: Cross-sectional and cluster sampling random selected method was carried out for residents over 35 years old in Han, Uygur, Hazakh population of Xinjiang to investigate IMT and correlated risk factors. RESULTS: IMT of Han, Uygur, Hazakh residents over 35 years old of Xinjiang Uygur autonomous region was (0.0761 ± 0.0283) cm, (0.0663 ± 0.0262) cm, and (0.0781 ± 0.0274) cm, respectively. There were significantly difference between various nationality (all P < 0.05). IMT was thicker in male Han people than in female Han people [(0.0807 ± 0.0288) cm vs. (0.0717 ± 0.0270) cm, P < 0.01] and in male Uygur than in female Uygur residents [(0.0706 ± 0.0270) cm vs. (0.0633 ± 0.0252) cm, P < 0.01] and in male Hazakh and female Hazakh residents [(0.0794 ± 0.0280) cm vs. (0.0768 ± 0.0268) cm, P < 0.01]. Linear correlation analysis showed that age (r = 0.176, P < 0.05), systolic blood pressure (r = 0.168, P < 0.05), diastolic blood pressure (r = 0.167, P < 0.05), fasting blood glucose (r = 0.053, P < 0.05), total cholesterol (r = 0.097, P < 0.05) and ankle brachial index (r = 0.067, P < 0.05) were significantly correlated with IMT. CONCLUSIONS: Our results showed that IMT was thicker in Hazakh residents than in Han and Uygur residents. IMT was closely related to known cardiovascular risk factors including age, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol and ankle brachial index level.

IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China.

Hyperlipidemia is one of the main risk factors that contributed to atherosclerosis and coronary artery disease (CAD). In the present study, our objective was to explore whether some genetic variants of human IDOL gene were associated with hyperlipidemia among Han population in Xinjiang, China. We designed a case-control study. A total of 1,172 subjects (588 diagnosed hyperlipidemia cases and 584 healthy controls) of Chinese Han were recruited. We genotyped three SNPs (rs9370867, rs909562, and rs2072783) of IDOL gene in all subjects by using the improved multiplex ligation detection reaction (iMLDR) method. Our study demonstrated that the distribution of the genotypes, the dominant model (AA vs GG + GA), and the overdominant model (AA + GG vs GA) of the rs9370867 SNP had significant differences between the case group and controls (all P < 0.001). For rs909562 and rs2072783, the distribution of the genotypes, the recessive model (AA + GA vs GG) showed significant differences between the case subjects and controls (P = 0.002, P = 0.007 and P = 0.045, P = 0.02, respectively). After multivariate adjustment for several confounders, the rs9370867 SNP is still an independent risk factor for hyperlipidemia [odds ratio (OR) = 1.380, 95% confidence interval (CI) = 1.201-1.586, P < 0.001]. The rs9370867 of human IDOL gene was associated with hyperlipidemia in Han population.

An elevated monocyte-to-high-density lipoprotein-cholesterol ratio is associated with mortality in patients with coronary artery disease who have undergone PCI.

BACKGROUND: The aim of the present study was to investigate the association between the monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) and the outcomes of patients with coronary artery disease (CAD) who were treated with percutaneous coronary intervention (PCI). METHODS: A total of 5679 CAD patients from CORFCHD-PCI, a retrospective cohort study (identifier: ChiCTR-ORC-16010153), who underwent PCI were included in the study and divided into three tertiles according to their MHR values. The primary outcome was long-term mortality after PCI. The main secondary endpoints were stroke, readmission, and major adverse cardiovascular events (MACEs), defined as the combination of cardiac death, recurrent myocardial infarction, and target vessel reconstruction. The average follow-up time was 35.9 ± 22.6 months. RESULTS: Patients were divided into three groups according to MHR tertiles: the first tertile (MHR < 0.4; n=1290), second tertile (MHR ≥ 0.4-0.61; n=1878) and third tertile (MHR > 0.61; n=1870). The all-cause mortality (ACM) incidence was significantly lower in the first and second tertiles than in the third tertile (adjusted HR = 0.658, [95% CI: 0.408-0.903], P=0.009 and HR = 0.712, [95% CI: 0.538-0.941], P=0.017, respectively). Cardiac mortality (CM) occurred in 235 patients: 60 (3.1%) in the first tertile group, 74 (3.9%) in the second tertile group and 101 (5.4%) in the third tertile group. There was a significant difference in the CM incidence between the first tertile group and the third tertile group (HR = 0.581, [95% CI: 0.406-0.832], P=0.003), and there was also a difference in the CM incidence between the second tertile group and the third tertile group (HR = 0.690, [95% CI: 0.506-0.940], P=0.019). CONCLUSION: The present study indicated that an increased MHR was independently associated with long-term mortality in CAD patients who have undergone PCI.

A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption.

A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1-deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.

Personalized antiplatelet therapy according to CYP2C19 genotype after percutaneous coronary intervention: a randomized control trial.

OBJECTIVE: The objective of this study is to compare personalized antiplatelet therapy according to CYP2C19 phenotype with conventional antiplatelet therapy in patients after percutaneous coronary intervention (PCI). METHODS: A total of 600 patients with coronary artery disease (CAD) undergoing PCI randomly received a personalized antiplatelet therapy (group A; n=301) or conventional antiplatelet treatment (group B; n=299). For group A, antiplatelet therapy was performed according to CYP2C19 phenotype. For group B, the patients received conventional antiplatelet treatment without detected CYP2C19 genotype. The primary end point was compared between these two groups. This study is registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-11001807). RESULTS: The primary end point occurred in 27 patients assigned to conventional treatment as compared with 8 patients assigned to personalized therapy (cumulative event rate, 9.03% vs. 2.66%; P<0.01). The composite rate of death, myocardial infarction, or stroke at 180 days occurred in 3 and 18 patients in the two groups, respectively (cumulative event rate, 1.0% and 6.2%, P<0.01). The cumulative 180-day incidence of ST was significantly lower in group A than in group B (0.66% vs. 3.01%, P=0.032). The 180-day incidence of MI (0.33% vs. 3.01%, P=0.011) and death (0.33% vs. 2.34%, P=0.011) was fewer than that in control, respectively. We did not find the significant difference in bleeding events between the 2 groups. CONCLUSION: Personalized antiplatelet therapy according to CYP2C19 genotype after PCI can significantly decrease the incidence of major adverse cardiovascular events and the risk of 180-day ST in Chinese population.

Type 2 diabetes in Xinjiang Uygur autonomous region, China.

BACKGROUND: The aim of this study was to estimate the prevalence and distribution of type 2 diabetes and to determine the status of type 2 diabetes awareness, treatment, and control in Xinjiang, China. Our data came from the Cardiovascular Risk Survey (CRS) study designed to investigate the prevalence and risk factors for cardiovascular diseases in Xinjiang from October 2007 to March 2010. A total of 14 122 persons (5583 Hans, 4620 Uygurs, and 3919 Kazaks) completed the survey and examination. Diabetes was defined by the American Diabetes Association 2009 criteria. METHODOLOGY/PRINCIPAL FINDINGS: Overall, 9.26% of the Han, 6.23% of the Uygur, and 3.65% of the Kazak adults aged ≥35 years had diabetes. Among diabetes patients, only 53.0% were aware of their blood glucose level, 26.7% were taking hypoglycemic agents, and 10.4% achieved blood glucose control in Han, 35.8% were aware of their blood glucose level, 7.3% were taking hypoglycemic agents, and 3.13% achieved blood glucose control in Uygur, and 23.8% were aware of their blood glucose level, 6.3% were taking hypoglycemic agents, and 1.4% achieved blood glucose control in Kazak, respectively. CONCLUSIONS/SIGNIFICANCE: Our results indicate that diabetes is highly prevalent in Xinjiang. The percentages of those with diabetes who are aware, treated, and controlled are unacceptably low. These results underscore the urgent need to develop national strategies to improve prevention, detection, and treatment of diabetes in Xinjiang, the west China.

Alcohol consumption and carotid atherosclerosis in China: the Cardiovascular Risk Survey.

AIM: The relationship between alcohol consumption and carotid atherosclerosis has been reported in some epidemiological studies, but the results were conflicting. We investigated the association between alcohol intake and carotid atherosclerosis in the Han, Uygur, and Kazakh populations in Xinjiang in western China. METHODS AND RESULTS: The study population sample comprised 13,037 Chinese people (5277 Han, 4572 Uygur, and 3188 Kazakh) aged ≥35 years who participated in a cardiovascular risk survey between June 2007 and March 2010. Daily consumption of alcohol was determined by the number and frequency of alcoholic beverages consumed. Carotid-artery parameters, including common carotid artery intima-media thickness (CCA-IMT) and carotid plaques were measured using high-resolution B-mode ultrasonography. In the Han and Kazakh populations, CCA-IMT as a function of alcohol consumption was depicted as a J-shaped curve with a nadir for the alcohol-intake category of 20-29.9 g/day; In the Uygur population, a similar curve with a nadir of 30-49.9 g/day was observed. With respect to the prevalence of carotid plaques, we also observed similar curves in the Han and Kazakh populations, but not in the Uygur population. After adjustment for age, sex, blood pressure, body mass index, and smoking status, as well as levels of glucose, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol, the J-shaped curves remained. CONCLUSIONS: Our results indicated that alcohol consumption was associated with carotid atherosclerosis and that moderate drinking had an inverse association with carotid atherosclerosis. However, the definition of moderate drinking could be different in Han, Uygur, and Kazakh populations.