[Show abstract][Hide abstract] ABSTRACT: The molecular mechanisms that drive the development of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) remain elusive. Accumulated evidence suggests that microRNAs are essential regulators of cardiac remodelling. We have been suggested that microRNAs could play a role in the process of HCM. To uncover which microRNAs were changed in their expression, microRNA microarrays were performed on heart tissue from HCM patients (n = 7) and from healthy donors (n = 5). Among the 13 microRNAs that were differentially expressed in HCM, miR-451 was the most down-regulated. Ectopic overexpression of miR-451 in neonatal rat cardiomyocytes (NRCM) decreased the cell size, whereas knockdown of endogenous miR-451 increased the cell surface area. Luciferase reporter assay analyses demonstrated that tuberous sclerosis complex 1 (TSC1) was a direct target of miR-451. Overexpression of miR-451 in both HeLa cells and NRCM suppressed the expression of TSC1. Furthermore, TSC1 was significantly up-regulated in HCM myocardia, which correlated with the decreased levels of miR-451. As TSC1 is a known positive regulator of autophagy, we examined the role of miR-451 in the regulation of autophagy. Overexpression of miR-451 in vitro inhibited the formation of the autophagosome. Conversely, miR-451 knockdown accelerated autophagosome formation. Consistently, an increased number of autophagosomes was observed in HCM myocardia, accompanied by up-regulated autophagy markers, and the lipidated form of LC3 and Beclin-1. Taken together, our findings indicate that miR-451 regulates cardiac hypertrophy and cardiac autophagy by targeting TSC1. The down-regulation of miR-451 may contribute to the development of HCM and may be a potential therapeutic target for this disease.
Journal of Cellular and Molecular Medicine 09/2014; · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimsAlthough genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long-term outcomes of HCM.Methods and resultsA total of 529 unrelated HCM patients were prospectively recruited and followed for 4.7 ± 3.2 years. Eight sarcomere genes were screened with targeted resequencing and identified variants were validated through Sanger sequencing. After polymorphisms and likely neutral rare variants were excluded, the patients were segregated into three groups based on the dosage of rare variants: no rare variant, a single rare variant, and multiple rare variants. Multiple rare variants were identified in 7.2% (38/529) of the study patients. Patients with multiple rare variants were younger at diagnosis, and had greater maximum LV wall thicknesses and larger left atria. The risk for cardiovascular death in patients with multiple rare variants was higher than in those without rare variants (P = 10−5) or in those with a single rare variant (P = 2 × 10−5). Multivariable analysis revealed that multiple rare variants were a risk factor for cardiovascular death [hazard ratio (HR) 3.74, 95% confidence interval (CI) 1.84–7.58, P = 0.0003], as well as sudden cardiac death (HR 3.57, 95% CI 1.23–10.35, P = 0.019) and heart failure-related death (HR 4.62, 95% CI 1.67–12.76, P = 0.003).Conclusions
The presence of multiple rare variants in sarcomere genes is a risk factor for malignant outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients.
European Journal of Heart Failure 07/2014; · 5.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Left ventricular non-compaction (LVNC) is genetically heterogeneous. It has been previously shown that LVNC is associated with defects in TAZ, DNTA, LDB3, YWHAE, MIB1, PRDM16, and sarcomeric genes. This study was aimed to investigate sarcomeric gene mutations in a Chinese population with LVNC. From 2004 to 2010, 57 unrelated Chinese patients with LVNC were recruited at Fuwai Hospital, Beijing, China. Detailed clinical evaluation was performed on the probands and available family members. DNA samples isolated from the peripheral blood of the index cases were screened for 10 sarcomeric genes, including MYH7, MYBPC3, MYL2, MYL3, MYH6, TNNC1, TNNT2, TNNI3, TPM1, and ACTC1. Seven heterozygous mutations (6 missense and 1 deletion) were identified in 7 (12 %) of the patients. These mutations were distributed among 4 genes, 4 in MYH7, and 1 each in ACTC1, TNNT2, and TPM1. Six of the mutations were novel and another one was reported previously. All mutations affected conserved amino acid residues and were predicted to alter the structure of the proteins by in silico analysis. No significant difference was observed between mutation-positive and mutation-negative patients with respect to clinical characteristics at baseline and mortality during follow-up. In conclusion, our study indicates that sarcomeric gene mutations are uncommon causes of LVNC in Chinese patients and genetic background of the disease may be divergent among the different races.
[Show abstract][Hide abstract] ABSTRACT: Sex plays an important role in the clinical expression and prognosis of various cardiovascular diseases. This study was designed to observe the effects of sex on hypertrophic cardiomyopathy (HCM).
PLoS ONE 01/2014; 9(7):e102969. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger (MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
International Journal of Molecular Sciences 01/2014; 15(6):9302-13. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Although mutations of several genes are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the exact correlation between genotype and ventricular arrhythmia features remain unclear. This study was aimed to examine the possible association of the 9 known genes of ARVC with clinical and electrophysiological characteristics.
-Ninety subjects diagnosed with ARVC who underwent electrophysiological study were recruited for screening the 9 known ARVC-causing genes. A total of 53 mutations were identified in 57 (63%) subjects. Mutation carriers had more frequent clinical ventricular tachycardia (VT) (89% vs. 55%; P < 0.001) and negative T waves in V1 to V3 (61% vs. 33%; P = 0.016). Subjects with plakophilin-2 (PKP2) mutations also had more frequent VT than those without mutation in PKP2. Comparison between subjects with multiple and single mutation showed that syncope occurred more often in the former group (58% vs. 24%; P = 0.018). VT was significantly more often induced in mutation carriers compared with non-carriers (75% vs. 39%; P = 0.001), as well as in PKP2 mutation carriers compared with subjects without PKP2 mutations (80% vs. 48%; P = 0.002). Induced VT with a rate ≥ 200bpm was more often documented in mutation carriers (88% vs. 54%; P = 0.013), as well as PKP2 mutation carriers (91% vs. 67%; P = 0.041).
-Pathogenic gene mutations were found in nearly 2/3 of subjects diagnosed with ARVC. Mutations carriers, especially PKP2, had a higher proportion of a history of VT and more inducible fast VT.
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to evaluate the clinical course of isolated left ventricular noncompaction (ILVNC) and to identify the predictors for adverse outcomes in an adult cohort with ILVNC. Between March 2003 and April 2012, 106 adult patients diagnosed with ILVNC at Fuwai Hospital were included in this study. The medical history, electrocardiograms, and echocardiograms of these patients were retrospectively analyzed by chart review. Of these patients, 64 (60 %) were in New York Heart Association (NYHA) functional class III/IV and 84 (79 %) had systolic dysfunction (left ventricular ejection fraction (LVEF) <50 %). During a follow-up of 2.9 ± 2.1 years, 28 (26 %) patients died or underwent heart transplantation. The annual incidence of death or transplantation was 9.1 %. The determinants of death or heart transplantation included NYHA functional class III/IV (hazard ratio (HR) 4.52; 95 % confidence interval (CI) 1.57-13.04; P = 0.005), decreased left ventricular ejection fraction (HR 0.94; 95 % CI 0.90-0.97; P = 0.001), dilated left ventricular end-diastolic diameter (HR, 1.06; 95 % CI, 1.02-1.09; P = 0.001), increased left atrial diameter (HR 1.08; 95 % CI 1.03-1.14; P = 0.001), reduced systolic blood pressure (HR 0.96; 95 % CI 0.94-0.99; P = 0.003), the presence of pulmonary hypertension (HR 3.50; 95 % CI 1.63-7.51; P = 0.001), and right bundle branch block (HR 7.79; 95 % CI 2.56-23.76; P < 0.001). In conclusion, this study demonstrates that ILVNC is related to a high incidence of death or heart transplantation. Advanced heart failure, a dilated left heart with systolic dysfunction, reduced systolic blood pressure, pulmonary hypertension, and right bundle branch block predict adverse outcomes of ILVNC.
[Show abstract][Hide abstract] ABSTRACT: Genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM) has been challenging because of the genetic and clinical heterogeneity. To determine the mutation profile of Chinese patients with HCM and to correlate genotypes with phenotypes, we performed a systematic mutation screening of the eight most commonly mutated genes encoding sarcomere proteins in 200 unrelated Chinese adult patients using direct DNA sequencing. A total of 98 mutations were identified in 102 mutation carriers. The frequency of mutations in MYH7, MYBPC3, TNNT2 and TNNI3 was 26.0, 18.0, 4.0 and 3.5 % respectively. Among the 200 genotyped HCM patients, 83 harbored a single mutation, and 19 (9.5 %) harbored multiple mutations. The number of mutations was positively correlated with the maximum wall thickness. We found that neither particular gene nor specific mutation was correlated to clinical phenotype. In summary, the frequency of multiple mutations was greater in Chinese HCM patients than in the Caucasian population. Multiple mutations in sarcomere protein may be a risk factor for left ventricular wall thickness.
[Show abstract][Hide abstract] ABSTRACT: Protein kinase plays an essential role in controlling cardiac growth and hypertrophic remodeling. The cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific kinase, is associated with cardiomyocyte hypertrophy. However, the precise function of TNNI3K in regulating cardiac remodeling has remained controversial.
In a rat model of cardiac hypertrophy generated by transverse aortic constriction, myocardial TNNI3K expression was significantly increased by 1.62 folds (P<0.05) after constriction for 15 days. To investigate the role of TNNI3K in cardiac hypertrophy, we generated transgenic mouse lines with overexpression of human TNNI3K specifically in the heart. At the age of 3 months, the high-copy-number TNNI3K transgenic mice demonstrated a phenotype of concentric hypertrophy with increased heart weight normalized to body weight (1.31 fold, P<0.01). Echocardiography and non-invasive hemodynamic assessments showed enhanced cardiac function. No necrosis or myocyte disarray was observed in the heart of TNNI3K transgenic mice. This concentric hypertrophy maintained up to 12 months of age without cardiac dysfunction. The phospho amino acid analysis revealed that TNNI3K is a protein-tyrosine kinase. The yeast two-hybrid screen and co-immunoprecipitation assay identified cTnI as a target for TNNI3K. Moreover, TNNI3K overexpression induced cTnI phosphorylation at Ser22/Ser23 and , suggesting that TNNI3K is a novel upstream regulator for cTnI phosphorylation.
TNNI3K promotes a concentric hypertrophy with enhancement of cardiac function via regulating the phosphorylation of cTnI. TNNI3K could be a potential therapeutic target for preventing from heart failure.
PLoS ONE 01/2013; 8(3):e58570. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.
A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.
A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.
Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.
PLoS ONE 01/2013; 8(6):e67087. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac hypertrophy has been known as an independent predictor for cardiovascular morbidity and mortality. Molecular mechanisms underlying the development of heart failure remain elusive. Recently, microRNAs (miRs) have been established as important regulators in cardiac hypertrophy. Here, we reported miR-221 was up-regulated in both transverse aortic constricted mice and patients with hypertrophic cardiomyopathy (HCM). Forced expression of miR-221 by transfection of miR-221 mimics increased myocyte cell size and induced the re-expression of fetal genes, which were inhibited by the knockdown of endogenous miR-221 in cardiomyocytes. The TargetScan algorithm-based prediction identified that p27, a cardiac hypertrophic suppressor, is the putative target of miR-221, which was confirmed by luciferase assay and Western blotting. In conclusion, our results demonstrated that miR-221 regulated cardiomyocyte hypertrophy probably through down-regulation of p27, suggesting that miR-221 may be a new intervention target for cardiac hypertrophy.
Journal of Cellular Biochemistry 01/2012; 113(6):2040-6. · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of peripheral arterial disease (PAD) is heterogeneous even in the presence of similar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibility of PAD.
A total of 485 patients with PAD (defined by the ankle-brachial index) and 970 age- and gender-matched controls were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determined by a quantitative PCR-based method. Two common promoter variants of the hTERT gene were genotyped to assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptional activity.
After adjustment for vascular risk factors and genetic variants in the hTERT gene, individuals in the lowest and middle tertiles of telomere length had a significantly higher risk of PAD than did those in the highest tertile (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.29-2.49 in the middle tertile; 3.15, 95%CI 2.31-4.29 in the lowest tertile). Haplotype analysis using the 2 variants (rs2735940 and rs2853669) showed that subjects with the at-risk C-C haplotype had shorter telomere length than those individuals with the T-T haplotype and consistently had 1.30-fold (OR 1.30, 95%CI 1.06-1.58; P = 0.005) increased risk for PAD. The C-C haplotype had 43% lowered transcription activity of hTERT promoter (P<0.001).
The associations between the functional haplotype of hTERT gene and telomere length and the risk of atherosclerotic PAD suggested that mean leukocyte telomere length may independently serve as a potential predictor of PAD.
PLoS ONE 01/2012; 7(10):e47029. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate whether plasma levels of HDL cholesterol (HDL-C) were associated with the risk of intracerebral hemorrhage (ICH). Plasma HDL-C was determined via enzymatic methods, and ICH was ascertained via medical history, physical examination, and brain imaging (computed tomography or magnetic resonance imaging). The multivariable logistic regression model was used to calculate the odds ratios (OR) and 95% confidence intervals (CI) of ICH according to levels of plasma cholesterol. A total of 170 patients with ICH were identified from 6,046 participants. After adjustment for conventional cardiovascular risk factors, the OR was 2.06 (95% CI, 1.25-3.12; P < 0.01) for participants in the first tertile of HDL-C levels (<1.38 mmol/l) and 1.13 (95% CI, 0.72-1.78; P = 0.59) for participants in the second tertile (1.38-1.64 mmol/l), compared with participants in the third tertile (∩≥1.65 mmol/l). Subgroup analysis indicated that the detrimental effects of HDL-C were more significant in men and lean participants than in their corresponding controls, independent of hypertension. The results presented herein indicate that low plasma HDL-C (<1.38 mmol/l) may be associated with risk of ICH.
The Journal of Lipid Research 06/2011; 52(9):1747-54. · 4.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: uPA (urokinase-plasminogen activator) and its receptor (uPAR) have been implicated in a broad spectrum of pathophysiological processes, including fibrinolysis, proteolysis, inflammation, atherogenesis and plaque destabilization, all of which are involved in the pathogenesis of MI (myocardial infarction). We hypothesized that putative functional genetic variation in the two genes encoding uPA and uPAR (PLAU and PLAUR respectively) might influence the susceptibility to MI. We genotyped rs4065 [3'-UTR (untranslated region) *141C>T) and rs2227564 (Pro141Leu) in the PLAU gene as well as rs344781 (-516T>C) in the PLAUR gene in 633 MI patients and 1237 gender- and age-matched control subjects. Our results showed that the T allele of rs4065 was significantly associated with an increased risk of MI, with an adjusted OR (odds ratio) of 1.38 [95% CI (confidence interval), 1.07-1.78; P=0.012) under the dominant model, 1.4 (95% CI, 1.12-1.75; P=0.003) under the additive model and 2.5 (95% CI, 1.15-5.41; P=0.02) under the recessive model. The findings were then replicated in another independent case-control study including 545 MI patients and 597 control subjects. In conclusion, our results suggest that rs4065 might be a previously unknown genetic risk factor for MI in the Chinese Han population.
[Show abstract][Hide abstract] ABSTRACT: Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is characterized by increased ventricular wall thickness that cannot be explained by underlying conditions, cadiomyocyte hypertrophy and disarray, and increased myocardial fibrosis. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that more genes may be involved. Nexilin, encoded by NEXN, is a cardiac Z-disc protein recently identified as a crucial protein that functions to protect cardiac Z-discs from forces generated within the sarcomere. We screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease. Two missense mutations, c.391C>G (p.Q131E) and c.835C>T (p.R279C), were identified in exons 5 and 8 of NEXN, respectively, in two probands. Each of the two mutations segregated with the HCM phenotype in the family and was absent in 384 control chromosomes. In silico analysis revealed that both of the mutations affect highly conserved amino acid residues, which are predicted to be functionally deleterious. Cellular transfection studies showed that the two mutations resulted in local accumulations of nexilin and that the expressed fragment of actin-binding domain containing p.Q131E completely lost the ability to bind F-actin in C2C12 cells. Coimmunoprecipitation assay indicated that the p.Q131E mutation decreased the binding of full-length NEXN to α-actin and abolished the interaction between the fragment of actin-binding domain and α-actin. Therefore, the mutations in NEXN that we describe here may further expand the knowledge of Z-disc genes in the pathogenesis of HCM.
The American Journal of Human Genetics 10/2010; 87(5):687-93. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mitogen-activated protein kinase kinase 7 (MKK7) induces cardiac hypertrophy by activating the c-Juns NH2-terminal kinases (JNK). It has been reported that growth arrest and DNA-damage-inducible beta (GADD45Beta) binds to MKK7 directly and blocks its catalytic activity, mediates the inhibition of JNK signaling. However, the potential role of GADD45Beta on cardiac hypertrophy has not been investigated. In this study, we found co-infection of cardiomyocytes with adenoviral vectors expressing MKK7 and GADD45B could counteract the characteristic hypertropic responses, including an increase in cell size and elevated atrial natriuretic factor (ANP) expression which induced by overexpression of MKK7. Furthermore, siRNA-mediated knockdown of GADD45B could also cause cardiomyocytes hypertrophy. GeneChip data showed that GADD45B mRNA decreased significantly in patients with hypertrophy cardiomyopathy (HCM) compared with healthy subjects. Association study indicated that haplotype (rs2024144-rs3783501) of GADD45B affected the thickness of inter-ventricular septum in patients with HCM. Dual-luciferase assay showed that C-A haplotype displayed significantly increased transcription activity compared to T-G haplotype.
Biochemical and Biophysical Research Communications 09/2008; 372(4):623-8. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No data are available on survival analysis and longitudinal evolution of patients with gene mutations of beta-myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3) in Chinese.
To prospectively investigate whether different gene mutations confer distinct prognosis.
We performed a prospective study in 70 HCM patients and 46 genetically affected family members without HCM-phenotype with direct DNA sequencing of MYH7 and MYBPC3, clinical assessments, and 5.8 +/- 1.8 years follow-up.
After follow-up, more surgical intervention (8/52 versus 0/18, p < 0.001), higher sudden death risk (7/52 versus 0/18, p < 0.001) and shorter life span were found in patients with MYH7 mutations than in patients with MYBPC3 mutations (45.1 +/- 14.0 versus 73.5 +/- 7.5 years, p = 0.03). Seven of the 27 mutation carriers of MYH7 had clinical presentations of HCM, but no carriers of MYBPC3 mutations developed to HCM during follow-up. Maximal wall thickness was thicker in the patients carrying mutations in the global region of MYH7 than in those carrying mutations in the rod region of MYH7 (21.5 +/- 6.6 versus 15 +/- 6.1 mm, p < 0.05) at baseline. More sudden death (7/41 versus 0/11) and left ventricular dysfunction (NYHA Class III approximately IV, 17/32 versus 1/10) were identified in patients with mutations in the global region of MYH7 than in patients with other mutations.
MYH7 mutations, especially in the global region, cause malignant clinical phenotypes.
[Show abstract][Hide abstract] ABSTRACT: Homocysteine thiolactone adducts have been proposed as the culprit of homocysteine related cardiovascular diseases. We studied the association of these adducts in plasma, and the gene polymorphism of paraoxonase-2 with coronary heart disease.
254 patients and 308 controls were recruited for the study. Homocysteine thiolactone adducts were determined with ELISA. The codon 311 polymorphism of paraoxonase-2 gene was genotyped by using polymerase chain reaction and restrictive digestion.
The plasma level of homocysteine thiolactone adducts were significantly higher in patients than in controls (40.65 +/- 10.87 u/ml vs. 30.58 +/- 10.20 u/ml, P <0.01), with odds ratio of 7.34 (95% confidence interval 4.020-13.406, P <0.01), and increased according to the number of atherosclerotic coronary arteries: 35.59 +/- 10.34 units/ml (n = 76); 41.88 +/- 8.83 (n = 70) and 43.13 +/- 11.47 (n = 108) in subjects with 1, 2 and 3 affected arteries, respectively (r =0.174, P < 0.01). The frequency of CC genotype was significantly higher in patients with coronary heart disease (7.48%) than in controls (1.62%, P < 0.01), with adjusted odds ratio of 4.367 (95% confidence interval: 1.178 to 16.191, P < 0.01), so was the C allele (23.2% vs. 14.9%, P < 0.05).
High plasma homocysteine thiolactone adducts and the CC 311 genotype of paraoxonase-2 gene may be the emerging risk factor for coronary heart disease.