陈金星
中国医学科学院阜外医院 中德
The fibrillin-1 (FBN1) gene mutations result in Marfan syndrome (MFS) and have a variety of phenotypic variations. This disease is involved in the skeletal, ocular and cardiovascular system. Here we analyzed genotype-phenotype correlation in two Chinese families with MFS. Two patients with thoracic aortic aneurysms and dissections were diagnosed as MFS according to the revised Ghent criteria. Peripheral blood samples were collected and genomic DNAs were isolated from available cases, namely, patient-1 and his daughter and son, and patient-2 and his parents. According to the next-generation sequencing results, the mutations in FBN1 were confirmed by direct sequencing. A heterozygous frameshift mutation in exon 12 of FBN1 was found in the proband-1 and his daughter. They showed cardiovascular phenotype thoracic aortic aneurysms and dissections, a life-threatening vascular disease, and atrial septal defect respectively. One de novo missense mutation in exon 50 of FBN1 was identified only in the patient-2, showing aortic root aneurysm and aortic root dilatation. Intriguingly, two novel mutations mainly caused the cardiovascular complications in affected family members. No meaningful mutations were found in these two patients by screening all exons of 428 genes related with cardiovascular disease. The high incidence of cardiovascular manifestations might be associated with the two novel mutations in exon 12 and 50 of FBN1.
Molecular biology reports 2016
Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.
PloS one 2014
Variants at the 9p21 locus have been associated with coronary artery disease (CAD); coronary artery calcification (CAC) is related to CAD and other cardiovascular events. To determine the association of the 9p21 locus with CAD in the presence and absence of CAC, 4 groups were enrolled in a case-control study, including 527 CAD patients without CAC, 692 CAD patients with CAC, 585 individuals with simple CAC but no CAD, and 725 healthy controls. The rs1333049 representing the locus was associated with CAD in the presence of CAC (odds ratio = 1.38 in allelic analysis, 95%CI, 1.19-1.60, P<0.001), but not in the absence of CAC. Additionally, rs1333049 was not associated with simple CAC or CAC severity/extent in CAD patients with CAC. 849 CAD patients undergoing revascularization (660 with CAC and 189 without CAC) were enrolled in a cohort study to test its association with cardiovascular events in CAD patients with and without CAC in a 3-year follow-up. rs1333049 was significantly associated with the incidence of cardiovascular events in non-target vessels in patients with CAC (hazard ratio = 1.44, 95%CI, 1.08-1.91, P = 0.012), but not in those without CAC. The variants at the 9p21 locus were related to CAD and post-revascularization events only in the presence of CAC, suggesting that they may confer risk of calcification-related coronary atherosclerosis.
PloS one 2014
BACKGROUND:Two endophenotypes of arterial calcification, calcification on arterial wall and calcification in atherosclerotic plaques, are associated with different types of cardiovascular events. Mgp-deficient mice showed matrix Gla protein (MGP) is strongly associated with calcification on arterial wall without atherosclerotic plaques, and MGP variants were not significantly associated with myocardial infarction. MGP may play different roles in the 2 endophenotypes.METHODS AND RESULTS:We analyzed the associations of MGP variants rs4236, rs1800801, and rs1800802 with the 2 endophenotypes determined by multidetector computed tomography angiography. A total of 585 with calcification on coronary artery wall, 675 with calcification in coronary atherosclerotic plaques, 454 with calcification on aortic wall, and 725 controls were enrolled. After Bonferroni correction, rs4236 and rs1800801 were still associated with calcification on arterial wall, the odds ratios were 0.708 (95% confidence interval, 0.540-0.928) for rs4236 and 0.652 (95% confidence interval, 0.479-0.888) for rs1800801 in coronary artery wall calcification, and 0.699 (95% confidence interval, 0.525-0.931) for rs4236 and 0.650 (95% confidence interval, 0.467-0.905) for rs1800801 in aortic wall calcification, respectively. The variants were correlated with calcification severity by ln(CAC Agatston score+1) in coronary artery wall calcification but not in atherosclerotic plaque calcification. In accordance with their associations with calcification on arterial wall, rs4236C and rs1800801A were associated with higher MGP plasma levels, whereas rs1800802C was associated with lower MGP levels in normal controls. Because of the role of calcification in plaque vulnerability, their associations with acute myocardial infarction were also determined in 771 controls and 752 patients, no association was found.CONCLUSIONS:MGP genetic variants showed association with calcification on arterial wall but not with calcification in atherosclerotic plaques.
Circulation. Cardiovascular genetics 2013
VKORC1 genetic polymorphisms affect warfarin dose response, aortic calcification, and the susceptibility of coronary artery disease as shown in our previous study. Little is known regarding the association of VKORC1 polymorphisms with coronary artery calcification (CAC) and the role of CAC in the association with coronary artery disease (CAD). Due to a natural haplotype block in the VKORC1 gene in Chinese, polymorphism rs2359612 was analyzed in a case-control study and a prospective study. The case-control study included 464 CAD patients with non-calcified plaque (NCP), 562 CAD patients with mixed calcified plaque (MCP), 492 subjects with calcified plaque (CP), and 521 controls. The rs2359612C was only associated with increased risk of MCP, the CAD in the presence of CAC; the odds ratio was 1.397 (95 % CI 1.008-1.937, P < 0.05), which was replicated in the second independent population. On the contrary, a negative correlation was observed between rs2359612 and log-transformed Agatston score, and rs2359612 was negatively associated with the number of calcified vessels. Moreover, in a prospective study including 849 CAD patients undergoing revascularization, rs2359612C predicted a higher incidence of cardiovascular events in MCP subgroup; the relative risk was 1.435 (95 % CI 1.008-2.041, P = 0.045), which was not observed in the NCP subgroup. We conclude that the rs2359612C was associated with a higher risk of CAD in the presence of CAC and a higher incidence of cardiovascular events in CAD patients with CAC, but a lower coronary calcification. VKORC1 polymorphisms may be associated with the endophenotype of CAD, calcification-related atherosclerosis.
Human genetics 2013
BACKGROUND:Vitronectin is involved in the whole process of atherosclerosis. Our aim is to determine the association of VTN functional promoter variants with different types of vascular disease, and conclude the roles of vitronectin involved in vascular disease.METHODS:Gel shift assays and luciferase reporter assays were used to determine the impact of variants on promoter activity. The correlation of plasma vitronectin levels with the variant was assessed in normal controls. The association of the variant with vascular disease was determined in 3 case-control studies.RESULTS:A strong linkage disequilibrium was found between rs2227721 and rs2227720 in VTN promoter in Chinese (r(2)=1.0). Both variants resulted in a decreased transcription activity, and rs2227721 decreased the binding efficiency of transcription factor YY1 to the region. The rs2227721 was correlated with plasma vitronectin levels in normal controls (r=-0.207, P=0.028). The rs2227721 was associated with susceptibility of vascular disease; the odds ratios among subjects carrying rs2227721-T allele were 1.298 (95% Confidence Interval-CI, 1.033-1.631) for non-MI CAD (P<0.05), 1.346 (95% CI, 1.068-1.695) for chronic MI (P<0.05), 1.486 (95% CI, 1.145-1.928) for acute MI (P<0.001), and 1.619 (95% CI, 1.108-2.366) for deep venous thrombosis (P<0.05).CONCLUSION:VTN promoter haplotype would be a novel genetic marker for vascular disease.
International journal of cardiology 2013
OBJECTIVE:The clinical significance of an intramural course (or bridging) of the coronary artery remains controversial. We investigated the relationship between intramural coronary arteries (ICAs) and coronary stenosis and prognosis of subjects with ICA.METHODS AND RESULTS:ICA and coronary stenosis were assessed by multidetector computed tomography coronary angiography. ICAs in the left anterior descending artery were studied, which were further classified as superficial (≤2 mm) or deep type (>2 mm). Coronary stenosis was classified as nonstenosis, insignificant stenosis (<50%), and significant stenosis (≥50%). A total of 261 subjects with ICA in left anterior descending artery were identified from 2318 enrolled subjects. Most of the ICAs (66.3%) were superficial. ICA was positively associated with insignificant stenosis, and the odds ratios were 2.055 (95% confidence interval, 1.405-3.007), 3.314 (1.818-6.039), and 1.640 (1.036-2.597) for overall, deep, and superficial ICA (all P<0.05), respectively. In the case of significant stenosis, ICA was negatively associated, and the odds ratios were 0.555 (0.416-0.739) and 0.413 (0.288-0.590) for overall and superficial ICA (both P<0.05), respectively, and 0.985 (0.611-1.588; P>0.05) for deep ICA type. The depth and location of ICA correlated with stenosis. The major cardiac events, including cardiovascular death, myocardial infarction, and revascularization, were recorded during 3-year follow-up. ICA predicted a lower incidence of major cardiac events, especially superficial type; the adjusted hazard ratios were 0.585 (0.375-0.911; P=0.018) and 0.535 (0.300-0.954; P=0.034) for total and superficial type, respectively.CONCLUSIONS:ICA, especially deep type, is positively associated with insignificant stenosis proximal to ICA. Meanwhile, ICA, especially superficial type, is negatively associated with significant stenosis proximal to ICA and predicts a better prognosis not only in normal subjects but also in patients with coronary artery disease.
Arteriosclerosis, thrombosis, and vascular biology 2013
BACKGROUND:PIVKAII (protein induced by vitamin K absence), used for screening for hepatocellular carcinoma (HCC), is influenced by vitamin K epoxide reductase complex subunit 1 (VKORC1). VKORC1 haplotype frequency is significantly different in ethnic groups. We evaluated whether VKORC1 haplotypes could influence the performance characteristics of PIVKAII in screening for HCC.METHODS:A total 228 HCC patients and 258 patients with hepatitis B were recruited. Tumor size was measured in 76 patients with HCC. Serum PIVKAII concentrations and VKORC1 haplotype were determined in the cohort. Youden's index and ROC curves were used to compare the performance characteristics of PIVKAII in screening for HCC.RESULTS:In the HCC group and in patients with hepatitis B, serum PIVKAII concentrations were higher in VKORC1 rs2395612 TT carriers than in CC/CT carriers (50.34±72.18 vs. 11.98±27.45, p<0.05 in HCC group and 1.92±0.52 vs. 1.48±0.36, p<0.01). The estimated optimal cut-off value of PIVKAII for screening HCC was 2.0 and 3.0 ng/mL in CC/CT carriers and TT carriers, respectively. Furthermore, VKORC1 haplotypes also influenced the association of serum PIVKAII concentrations with HCC tumor size in patients with HCC.CONCLUSIONS:VKORC1 haplotypes influence the performance characteristics of PIVKAII for screening of HCC. Thus, measurement could be complementary for PIVKAII in HCC screening.
Clinical chemistry and laboratory medicine 2010
A novel gene (GenBank accession No. AF113208) named KCTD10 (potassium channel tetramerisation domain-containing 10) was cloned from our 5300 EST database of human aorta cDNA library. Computational analysis showed that KCTD10 cDNA is 2,638 bp long, encoding 313 amino acids with a proliferating cell nuclear antigen binding motif, mapped to chromosome 12q24.11 with 7 exons, ubiquitously expressed in all 12 tested normal tissues and 7 of 8 tested tumor cell lines from MTN membranes by Northern blot. Nuclear localization of KCTD10 was observed in A549 cells. Yeast two-hybrid analysis and immunoprecipitation assay showed that KCTD10 can interact with PCNA. In A549 cells, KCTD10 down-regulation could inhibit cell proliferation, but its over-expression could not influence cell proliferation. The results suggest that KCTD10 may be associated with DNA synthesis and cell proliferation.
Journal of cellular biochemistry 2009
Plasma homocysteine concentrations have been associated with the risk of stroke, but its relevance to secondary vascular events and mortality after stroke remains unclear because of inconsistent results from clinical trials. The aim of the present study was to investigate whether plasma homocysteine levels and the MTHFR (methylenetetrahydrofolate reductase) variant C677T contributed to the risk of stroke recurrence and all-cause mortality in a large prospective cohort of stroke patients in a Chinese population. A total of 1823 stroke patients (age, 35-74 years) were recruited during 2000-2001 and prospectively followed-up for a median of 4.5 years. During the follow-up, 347 recurrent strokes and 323 deaths from all-causes were documented. After adjustment for age, gender and other cardiovascular risk factors, a high homocysteine concentration was associated with an increased risk of 1.74-fold for stroke recurrence {RR (relative risk), 1.74 [95% CI (confidence interval), 1.3-2.3]; P<0.0001} and 1.75-fold for all-cause mortality [RR, 1.75 (95% CI, 1.3-2.4); P<0.0001] when highest and lowest categories were compared. Spline regression analyses revealed a threshold level of homocysteine for stroke recurrence. By dichotomizing homocysteine concentrations, the RRs were 1.31 (95% CI, 1.10-1.61; P=0.016) for stroke recurrence and 1.47 (95% CI, 1.15-1.88; P<0.0001) for all-cause mortality in patients with homocysteine levels > or =16 micromol/l relative to those with levels <16 micromol/l. The association of elevated plasma homocysteine concentrations with all-cause mortality was mainly due to an increased risk of cardiovascular deaths. No significant association was found between MTHFR C677T and stroke recurrence or mortality. In conclusion, our findings suggest that elevated homocysteine concentrations can predict the risk of stroke recurrence and mortality in patients with stroke.
Clinical science (London, England : 1979) 2009
