ITPKC polymorphism (rs7251246 T > C), coronary artery aneurysms, and thrombosis in patients with Kawasaki disease in a Southern Han Chinese population.

Objectives: Kawasaki disease (KD) is a commonly acquired pediatric systemic vasculitis disease resulting in coronary artery aneurysm (CAA). The relationship between the ITPKC polymorphism (rs7251246) and the severity and susceptibility to KD in the Han Chinese population in Southern China remains unclear. Methods: We enrolled 262 children as controls and 221 children with KD (46 [20.8%] with intravenous immunoglobulin resistance and 82 [37.1%] with CAA). The relationship between the ITPKC rs7251246 polymorphism, KD susceptibility, and CAA formation was investigated. Results: While the ITPKC rs7251246 T>C polymorphism was not significantly associated with KD susceptibility, it was significantly related to the CAA risk in children with KD [CC/CT vs. TT: adjusted odds ratio [OR] 2.089, 95% confidence interval [CI] 1.085-4.020]. Male children with the rs7251246 CT/TT genotype had a significantly lower risk of thrombosis [CT/TT vs. CC: adjusted OR 0.251, 95% CI 0.068-0.923]. Children with KD, especially those with CAA, had significantly downregulated ITPKC mRNA compared to healthy children. ITPKC mRNA levels were lower in children with CAA who developed thrombosis (P=0.039). In children with KD, the CC genotype showed lower mRNA levels of ITPKC (P=0.035). Conclusion: The ITPKC rs7251246 T>C polymorphism may be a risk factor for CAA and thrombosis in children with KD in the Han Chinese population, likely due to differences in mature mRNA levels caused by interference of RNA splicing. Dual antiplatelet therapy for thrombosis is recommended for male children with the rs7251246 CC genotype.

Association study of miR-149, miR-196a2, and miR-499a polymorphisms with coronary artery aneurysm of Kawasaki disease in southern Chinese population.

BACKGROUND: Accumulating evidence suggests that several microRNA (miRNA) polymorphisms are closely associated with disease susceptibility or progression, such as in Kawasaki disease (KD). Our previous studies revealed the association of miR-149 rs2292832 T>C and miR-196a2 rs11614913 C>T polymorphisms with KD susceptibility. The present study further focused on the relationship between three miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and the risk of coronary artery aneurysm (CAA) in southern Chinese KD patients. METHODS: We evaluated 318 KD patients with CAAs and 784 patients without CAAs. TaqMan assays were used to estimate genotyping and analyze the relationship between miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and risk associations of CAA by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found that the miR-149 rs2292832 TC/CC genotype increased the CAA risk (adjusted OR = 1.53, 95% CI = 1.15-2.03, p = 0.003 for TC, adjusted OR = 1.63, 95% CI = 1.08-2.47, p = 0.021 for CC), whereas the miR-499a rs3746444 AG genotype decreased the CAA risk in KD patients (adjusted OR = 0.33, 95% CI = 0.25-0.45 p ≤ 0.001). Moreover, patients carrying two or three of these single nucleotide polymorphism (SNP) genotypes (rs2292832 TC/CC and rs11614913 TT and rs3746444 AA) had a higher risk for CAA than those who harbored only zero or one of these SNP genotypes. CONCLUSIONS: Our results demonstrated that the miR-149 rs2292832 T>C polymorphism increased the risk of CAA in KD patients and that the miR-499a rs3746444 A>G polymorphism decreased the risk of CAA in KD patients. Further studies with larger sample sizes and different centers are needed to confirm the findings of the present study.

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Three novel ATG16L1 mutations in a patient with acute myocardial infarction and coronary artery ectasia: A case report.

INTRODUCTION: Acute myocardial infarction (AMI) is a specific type of coronary artery disease (CAD) caused by the rupture of coronary atherosclerotic plaques. Coronary artery ectasia (CAE) is a rare phenotype of cardiovascular disease that may promote thrombosis and inflammatory responses leading to myocardial infarction due to abnormal dilatation of blood vessels and coronary blood flow disorders. It is a complicated disease and shows interaction between genetic and environmental factors. PATIENT CONCERNS: A 34-year-old male patient was admitted to our hospital on May 12, 2016, with complaints of chest pain for 1 hour duration. DIAGNOSIS: Coronary angiography through the emergency medical service (EMS) system showed 100% occlusion at the first turning point of the right coronary artery (RCA), along with tumor-like expansion of the proximal segment of the RCA and the end of the left main (LM) artery. The patient was diagnosed with AMI and CAE. Three-point mutations in the ATG16L1 gene were identified by direct sequencing. INTERVENTIONS: After admission, the patient underwent emergency green channel coronary angiography and percutaneous coronary intervention (PCI) to assess and unblock the stenosis and occlusion of the RCA lumen, but no stenting was performed because the catheter could not pass the second inflection point of the RCA. Aspirin enteric-coated tablets, clopidogrel sulfate tablets, tirofiban hydrochloride, and low molecular weight heparin calcium were given as anticoagulant and antiplatelet therapy. Atorvastatin calcium tablets were used to regulate blood lipid levels. Perindopril and spironolactone were used to inhibit the renin-angiotensin-aldosterone system (RAAS) to reverse myocardial remodeling. Acetylcholinesterase inhibitors (ACEI) and beta blockers were administered to resist ventricular remodeling and improve cardiac function and prognosis after the patient's blood pressure and heart rhythm were stabilized. OUTCOMES: After active rescue treatment, the patient recovered and was discharged. A coronary angiogram performed 2 years later showed that the RCA blood flow was restored, and the patient had recovered well. CONCLUSION: Three-point mutations in the ATG16L1 gene were identified in a patient with AMI and CAE, which extended the mutation spectrum of the ATG16L1 gene. Hence, the etiology of coronary artery aneurysmal dilatation is worthy of further investigation.

Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome.

Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet-derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular-type Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow-up examinations.

Is KCNH1 mutation related to coronary artery ectasia.

BACKGROUND: Coronary artery ectasia (CAE) is an uncommon finding in patients undergoing coronary angiography and acute myocardial infarction is an extremely uncommon condition in the presence of coronary artery ectasia. To date, 50 gene variants associated with coronary artery disease have been identified, but none appear to be related to coronary artery ectasia. CASE PRESENTATION: This is a rare case of Coronary artery ectasia which is considered to be related to Gene variations in potassium voltage-gated channel subfamily H member 1, KCNH1 (encoding a protein designated ether à go-go, EAG1 or KV10.1). CONCLUSION: Occurrence of Acute myocardial infarction in patient with coronary artery ectasia after diarrhea is a very rare condition and involvement of KCNH1 gene mutation which is described in this case report.

Diagnostic Significance of miR-937 in Peripheral Blood Mononuclear Cells of Kawasaki Disease.

Beckground: The current study aims to investigate whether miR-937 can be used as a diagnostic biomarker in peripheral blood mononuclear cells (PBMCs) for children with Kawasaki disease (KD) with or without coronary artery dilation (CAD). METHODS: Gene chip technology was used to screen miRNAs differentially expressed between KD children and normal healthy children. Furthermore, real time PCR was carried out to validate the expression of miR-937 in 50 children with KD (25 cases with and 25 cases without CAD) and 25 healthy children. Meanwhile, target genes of miR-937 were analyzed using TargetScan and dual luciferase reporter assay. RESULTS: First, 20 miRs with significantly differentially expressed mononuclear cell (PBMCs) in peripheral blood between children with KD and normal healthy children were identified by gene chip technology. Real time PCR analysis validated that the expression of miR-937 decreased most significantly among all differentially expressed miRNAs. Secondly, miR-937 was down-regulated significantly before treatment with gamma globulin (IVIG), while its expression was significantly up-regulated after IVIG treatment. In addition, the expression of miR-937 in KD children with CAD was significantly lower than that of KD children without CAD. Person's correlation assay showed that miR-937 negatively correlated with CAD. Dual luciferase reporter assay indicated that IL-1ß was a target gene of miR-937. CONCLUSIONS: In summary, miR-937 in PBMCs was involved in the occurrence and development of KD, which provides new ideas for the prevention and treatment of KD coronary artery dilation.

An Angiotensinogen Gene Polymorphism (rs5050) Is Associated with the Risk of Coronary Artery Aneurysm in Southern Chinese Children with Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute vasculitis disease that commonly causes acquired heart disease in children. Coronary artery aneurysm (CAA) is a major complication of KD. However, the pathogenesis of KD remains unclear. The results of a genome-wide association study (GWAS) showed that two functional single-nucleotide polymorphisms (SNPs; rs699A>G and rs5050T>G) in the angiotensinogen (AGT) gene were related to cardiovascular disease susceptibility. The purpose of our study was to estimate the relationship between the two GWAS-identified AGT gene polymorphisms and the risk of CAA in Southern Chinese children with KD. METHODS: We genotyped the two AGT gene polymorphisms (rs699A>G and rs5050T>G) in 760 KD cases and 972 healthy controls. We used the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the degree of the associations. RESULTS: These two AGT gene polymorphisms were not associated with a risk of KD relative to the controls, but after adjusting for sex and age, the carriers of the rs5050G allele with TG/GG vs TT had an adjusted OR = 1.56, 95% CI = 1.01-2.41, and P = 0.044 relative to the carriers of the rs5050TT genotype. The susceptibility to CAA was more predominant in KD patients younger than 12 months old. CONCLUSIONS: Our results indicate that the AGT gene polymorphism rs5050T>G may increase the risk of CAA in children with KD, especially those who are younger than 12 months. These results need to be verified by a validation study with a larger sample size.

Atypical coronary artery aneurysms due to Kawasaki disease in Noonan syndrome with a novel PTPN11 mutation.

We report a 3-year-old boy with giant and atypical coronary artery aneurysms in the acute phase of Kawasaki disease, despite appropriate therapeutic intervention, in Noonan syndrome with a novel heterozygous PTPN11 mutation, c. 907 G>A (p.Asp303Asn). We hypothesised that this PTPN11 mutation might affect both hyperinflammation caused by Kawasaki disease and vascular fragility in the coronary artery, resulting in coronary artery aneurysms.

Identification of the TIFAB Gene as a Susceptibility Locus for Coronary Artery Aneurysm in Patients with Kawasaki Disease.

Kawasaki disease (KD) is a self-limiting systemic vasculitis of unknown etiology. KD is often complicated by coronary artery aneurysms (CAAs), which develop in about 20-25% of untreated children and 3-5% of children treated with intravenous immunoglobulin therapy. To identify the risk loci for CAA susceptibility in patients with KD, we performed a genome-wide association study (GWAS) using our previous Illumina HumanOmni1-Quad BeadChip data (296 KD patients) and a new replication study in an independent sample set (713 KD patients) by grouping KD patients without CAA (control) versus KD patients with extremely large aneurysms (diameter ≥ 5 mm) (case). Among 44 candidate single -nucleotide polymorphisms (SNPs) selected from the initial GWAS data (33 cases vs. 215 controls), a SNP (rs899162) located 7 kb upstream of the TIFAB gene on chromosome five was replicated in an independent sample (12 cases vs. 532 controls). In the combined analysis (45 cases vs. 747 controls), the SNP (rs899162) showed a highly significant association with CAA formation (diameter ≥ 5 mm) in patients with KD (odds ratio = 3.20, 95% confidence interval = 2.02-5.05, Pcombined = 1.95 × 10-7). These results indicate that the TIFAB gene may act as a CAA susceptibility locus in patients with KD.

Hereditary Hemorrhagic Telangiectasia with SMAD4 Mutations Is Associated with Fatty Degeneration of the Left Ventricle, Coronary Artery Aneurysm, and Abdominal Aortic Aneurysm.

A 52-year-old man with recurrent epistaxis and palpebral conjunctival telangiectasia visited our hospital for a follow-up checkup for gastrointestinal polyposis. At 48 years of age, he underwent Y-graft replacement for an abdominal aortic aneurysm. Arteriovenous malformation was detected in his lungs, and a genetic test revealed an SMAD4 mutation. Eventually, he was diagnosed with juvenile polyposis-hereditary hemorrhagic telangiectasia (JP-HHT) syndrome. In addition, fatty degeneration of the left ventricle and a coronary aneurysm were detected. This is the first report suggesting the possibility of an association between these manifestations and JP-HHT due to SMAD4 mutations. Examining cardiovascular disorders in JP-HHT patients is imperative.

Transcatheter Closure of Congenital Coronary Artery Fistulas with a Giant Coronary Artery Aneurysm in Children: Experiences from a Single Center.

BACKGROUND: Transcatheter closure of congenital coronary artery fistulas (CCAFs) is an alternative therapy to surgery; however, data regarding transcatheter closure for CCAF with a giant coronary artery aneurysm (CAA) in pediatric patients are still limited due to the rarity of the disease. We aimed to evaluate the efficacy and safety of transcatheter closure for CCAF with a giant CAA in a pediatric population at a single center. METHODS: Medical records of pediatric patients (<18 years old) who underwent transcatheter closure of CCAF with a giant CAA between April 2007 and September 2016 at Guangdong Cardiovascular Institute (Guangdong, China) were reviewed. RESULTS: Twelve patients (median age, 6.1 years; range, 1.9-11.0 years) underwent successful transcatheter closure procedures. One patient underwent closure at both the entry and exit points of the CAA, three patients underwent closure at the exit point of the CAA, and eight patients underwent closure at the entry point of the CAA. After a mean follow-up of 7.2 years (range, 0.5-9.8 years), one patient (with closure at the exit point of the CAA) underwent transcatheter re-intervention because of a significant residual shunt. She eventually underwent a surgical procedure due to aneurysm dilation after the second intervention. One patient experienced thrombus formation within the CAA after the procedure. Among those with closure at the entry point of the CAA, a mild-to-moderate residual shunt was detected in three patients. CONCLUSIONS: Transcatheter closure appears to be a safe and effective alternative therapy for CCAF with a giant CAA in the pediatric population. Closure at the entry point of the CAA, and closure at both the entry and exit points when feasible, may reduce the risk of postinterventional complications.

Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities.

BACKGROUND: Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility. METHODS AND RESULTS: To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10-4). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10-4). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele. CONCLUSIONS: Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.

Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease.

Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20-25% of untreated with IVIG and 3-5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10(-9); OR = 32.22) and rs7922552 (P = 8.43 × 10(-9); OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10(-9); OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine.

Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan.

Kawasaki disease (KD) is an acute, inflammatory, and self-limited vasculitis affecting infants and young children. Coronary artery aneurysm (CAA) formation is the major complication of KD and the leading cause of acquired cardiovascular disease among children. To identify susceptible loci that might predispose patients with KD to CAA formation, a genome-wide association screen was performed in a Taiwanese KD cohort. Patients with both KD and CAA had longer fever duration and delayed intravenous immunoglobulin treatment time. After adjusting for these factors, 100 susceptibility loci were identified. Four genes were identified from a single cluster of 35 using the Ingenuity Pathway Analysis (IPA) Knowledge Base. Silencing KCNQ5, PLCB1, PLCB4, and PLCL1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation with varying degrees of proinflammatory cytokine expression. PLCB1 showed the most significant inhibition. Endothelial cell inflammation was also inhibited by using a phospholipase C (PLC) inhibitor. The single nucleotide polymorphism rs6140791 was identified between PLCB4 and PLCB1. Plasma PLC levels were higher in patients with KD and CC+CG rs6140791genotypes, and these genotypes were more prevalent in patients with KD who also had CAA. Our results suggest that polymorphism of the PLCB4/B1 genes might be involved in the CAA pathogenesis of KD.

Association between SRC-1 gene polymorphisms and coronary artery aneurysms formation in Taiwanese children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) patients who experience a cardiovascular complication known as a coronary artery aneurysm (CAA) are at high risk of developing ischemic heart disease, which may lead to sudden death. The etiology of CAA in KD patients is unclear, and this study aims to clarify the relationship between steroid receptor coactivator-1 (SRC-1) gene polymorphisms and CAA pathogenesis. METHODS: We investigated four SRC-1 gene polymorphisms (rs11894248, rs17791703, rs7572475, and rs9309308) and their correlation with KD with CAA susceptibility in 327 Taiwanese people (279 KD patients without CAA and 48 KD patients with CAA). RESULTS: The results indicated a statistically significant difference in genotype and allele frequency distributions at the SRC-1 four single nucleotide polymorphisms (SNPs) between KD patients with and without CAA (P < 0.01). Additionally, Smad3 gene polymorphism (rs12901071) is well known to be associated with KD patients. In our results, Smad3 SNP did not provide a statistically significant difference between KD patients with and without CAA. CONCLUSION: Our data show that SRC-1 polymorphisms may be the underlying cause of CAA; therefore, the polymorphisms examined in this study warrant further investigation.