Inositol 1,4,5-trisphosphate 3-kinase C Research Articles

ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer.

Simple SummaryInositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene is a negative regulator of T cell activation and is a proven promoter of Kawasaki disease. Given the critical role of immune response in breast cancer, we aimed to determine the clinical relevance of ITPKC expression in breast cancer. ITPKC expression was highest in triple negative breast cancer, associated with its survival, and was its independent prognostic factor. Although high ITPKC expression was not associated with immune function nor with any immune cell fraction, low ITPKC triple negative breast cancer was significantly associated with activated cell proliferation, and they achieved a significantly rate in pathological complete response (disappearance of tumor) after neoadjuvant chemotherapy. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in triple negative breast cancer.Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC.

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice.

Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is the last identified member of the inositol 1,4,5-trisphosphate 3-kinases family which phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate. Although expression and function of the two other family members ITPKA and ITPKB are rather well characterized, similar information is lacking for ITPKC. Here, we first defined the expression of Itpkc mRNA and protein in mouse tissues and cells using in situ hybridization and new antibodies. Surprisingly, we found that cells positive for ITPKC in the studied tissues express either a multicilium (tracheal and bronchial epithelia, brain ependymal cells), microvilli forming a brush border (small and large intestine, and kidney proximal tubule cells) or a flagellum (spermatozoa), suggesting a role for ITPKC either in the development or the function of these specialized cellular structures. Given this surprising expression, we then analyzed ITPKC function in multiciliated tracheal epithelial cells and sperm cells using our Itpkc knock-out mouse model. Unfortunately, no significant difference was observed between control and mutant mice for any of the parameters tested, leaving the exact invivo function of this third Ins(1,4,5)P3 3-kinase still open.

Single-Nucleotide Polymorphism rs7251246 in ITPKC Is Associated with Susceptibility and Coronary Artery Lesions in Kawasaki Disease

Kawasaki disease (KD) is a multi-systemic vasculitis that preferentially affects children. A single nucleotide polymorphism (SNP) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) has been identified to be an important polymorphism in the risk of KD. This study was conducted to comprehensively investigate the associations between all tagging SNPs of ITPKC in the risk of KD in a Taiwanese population. A total of 950 subjects (381 KD patients and 569 controls) were recruited. Seven tagging SNPs (rs11673492, rs7257602, rs7251246, rs890934, rs10420685, rs2607420, rs2290692) were selected for TaqMan allelic discrimination assay. Clinical data of coronary artery lesions (CAL) and aneurysms were collected for analysis. A significant association was found between rs7251246 in ITPKC and CAL formation. Haplotype analysis for ITPKC polymorphisms also confirmed this association in the patients with CAL and aneurysm formation. This is the first study to identify that SNP rs7251246 in ITPKC is associated with the severity of KD.

Aadvances in genetic polymorphisms for Kawasaki disease

Kawasaki disease (KD) is a leading cause of acquired heart disease in children.The causes of KD are still not well understood.Interactions between genes and environmental factors may play important roles.In the last decade,the identification of several genomic regions linked to the pathogenesis of KD has made a major breakthrough in understanding the genetics of KD.A novel inositol 1,4,5-trisphosphate 3-kinase C(ITPKC)signaling pathway was recently found to be responsible for the susceptibility to KD.This review focuses on genetic polymorphisms associated with KD,such as cytokine polymorphism,human leukocyte antigen polymorphism,caspase-3 polymorphism,initial intravenous immunoglobulin treatment related polymorphism and so on. Key words: Kawasaki disease; Gene; Polymorphism

A functional polymorphism, rs28493229, in ITPKC and risk of Kawasaki disease: an integrated meta-analysis

Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case-control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case-control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34-1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P (heterogeneity) = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.

Genetic polymorphisms in the ITPKC gene and cervical squamous cell carcinoma risk.

Cervical cancer is caused primarily by infection with oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for the progression to cervical cancer. Host immunogenetic factors may involve in the development of this disease. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is recently shown to act as a negative regulator of T-cell activation. We aim to study if polymorphisms in the ITPKC gene are associated with the risk of cervical cancer in Taiwanese women. ITPKC rs28493229 C/G, rs890934 G/T, rs2303723 C/T, and rs10420685 A/G polymorphisms were genotyped in a hospital-based study of 465 women with cervical squamous cell carcinoma (CSCC) and 800 age-matched healthy control women. The presence and genotypes of HPV in CSCC were determined. The frequency of G/G genotype and G allele of the ITPKC rs28493229 polymorphism was significantly higher in patients with CSCC compared with controls (OR = 1.81, 95 % CI 1.20-2.73, P = 0.005, P (c) = 0.02; OR = 1.70, 95 % CI 1.14-2.54, P = 0.008, P (c) = 0.03, respectively). No significant associations were found for other 3 polymorphisms. Haplotype analysis revealed the distribution of haplotype CGTA was significantly reduced in women with CSCC (OR = 0.59, 95 % CI 0.40-0.89, P = 0.01, P (c) = 0.04). In conclusion, we found the G/G genotype and G allele of the ITPKC rs28493229 polymorphism may contribute to the risk of CSCC in Taiwanese women. This finding provides new insights into the mechanisms of immune activation in cervical cancer.

Single-nucleotide Polymorphism rs2290692 in the 3′UTR of ITPKC Associated With Susceptibility to Kawasaki Disease in a Han Chinese Population

Kawasaki disease (KD) is characterized by acute systemic vasculitis and frequently is complicated by coronary artery lesions (CALs). The inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene rs28493229 was recently found to be associated with the risk for KD in the Japanese population, suggesting that the ITPKC gene may contribute to KD susceptibility. This study investigated the association of ITPKC polymorphisms with KD in a Han Chinese population. Five ITPKC Single-nucleotide polymorphisms, including rs28493229, were genotyped in 223 unrelated patients who had KD and 318 non-KD control subjects. The allele, genotype, and haplotype frequencies were compared between the patients and the control subjects, between the patients with and those without CALs, and between patients resistant to intravenous immunoglobulin treatment and those responsive to such treatment. Multiple alleles were observed for rs28493229 and rs2290692. No significant differences in the frequencies of the C allele, the CC genotype, or the C carriers of rs28493229 were observed in the comparisons. Interestingly, significantly higher frequencies of the C allele (p < 0.001), the CC genotype (p = 0.001), and the C carriers (p = 0.003) were observed for rs2290692 among the patients than among the control subjects, and similar differences were observed between the patients with and those without CALs. The GC haplotype for rs28493229 and rs2290692 was more common among the patients than among the control subjects. The results indicate that the C allele of the ITPKC gene rs2290692 is linked to a significantly higher risk for KD in the studied population, which provides new evidence to support the importance of the ITPKC gene in the occurrence of KD. More notably, this finding suggests that there may be an unidentified ITPKC polymorphism in strong linkage disequilibrium to rs2290692, significantly affecting susceptibility to KD in the Han population.

Association study of a functional SNP rs28493229 of ITPKC gene and Kawasaki disease in a Chinese population

Kawasaki disease (KD) is a form of acute multi-systemic vasculitis with unknown etiology. It is the leading cause of acquired heart disease in children due to the frequent occurrence of coronary artery lesions (CALs). Recently, a C allele of rs28493229 (G/C) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene was found to significantly increase the risk for KD/CALs in Japanese population. It is important to confirm such finding in Chinese population to enable prognosis and personalized therapy for KD. A case-control study was performed. The patient group has included 206 unrelated patients with KD, and the control group included 285 age, gender and ethnically matched children who never had KD. Genotyping of rs28493229 was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. The allele, genotype and C allele carrier frequencies were compared between the two groups, patients with or without CALs, and patients who were resistant or responsive to (intravenous immunoglobulin, IVIG) treatment. Frequency of the C allele of rs28493229 was significantly lower in both groups than that in the Japanese population (P< 0.01). No significant difference was detected between the two groups in terms of allele, genotype and C carrier of rs28493229 frequencies. Such frequencies were also similar between patients with or without CALs, resistant or responsive to IVIG treatment. Our study has failed to prove any association between rs28493229 and KD/CALs in Chinese patients, which indicated that the C allele of rs28493229 may not be used as a molecular marker for determining KD susceptibility, prognosis and effect of treatment. The much lower frequency of C allele does not support its significance in the occurrence of KD/CALs in Chinese population. It is still necessary to find functional SNPs in ITPKC gene which is associated with KD/CALs in Chinese population.

ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Lack of Association between ORAI1/CRACM1 Gene Polymorphisms and Kawasaki Disease in the Taiwanese Children

Kawasaki disease (KD) is characterized by systemic vasculitis of an unknown cause. A previous study has indicated that a polymorphism of the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene is involved in the susceptibility to KD. ORAI (also known as CRACM1) is one of the components of store-operated calcium channels involved in regulating immune and inflammatory reactions. This study was conducted to investigate if polymorphisms in ORAI1/CRACM1, a gene downstream from ITPKC, are associated with KD susceptibility and clinical outcomes. A total of 1,056 subjects (341 KD patients and 715 controls) were investigated to identify five tagging single nucleotide polymorphisms (tSNPs) in ORAI1/CRACM1 (rs12313273, rs6486795, rs7135617, rs12320939, and rs712853) by using the TaqMan Allelic Discrimination assay. No significant associations between genotype and allele frequency of the five ORAI1/CRACM1 tSNPs were observed in the KD patients and controls. In KD patients, no significant associations between ORAI1/CRACM1 polymorphisms and coronary artery lesion (CAL) formation or intravenous immunoglobulin (IVIG) treatment response were observed. The results from haplotype analysis were insignificant. This study showed for the first time that ORAI1/CRACM1 polymorphisms are not associated with KD susceptibility, CAL formation, or IVIG treatment response in the Taiwanese population.

Clinical Implication of the C Allele of the ITPKC Gene SNP rs28493229 in Kawasaki Disease

a functional single nucleotide polymorphism (SNP) (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene has been linked to the susceptibility to Kawasaki disease (KD). The implication remains unclear.genotyping for the ITPKC polymorphism was conducted on 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. The clinical manifestations and laboratory data were systemically collected.the GC and CC genotypes of ITPKC gene SNP rs28493229 were overrepresented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than those in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR: 2.23, P = 0.001). In KD patients, those with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR: 1.96, P = 0.044). Such association was particularly strong in patients aged <20 months (OR: 3.26, P = 0.017). The other clinical manifestations were not related to this SNP. There were 160 (57.1%) patients with coronary arterial lesions. The development and the severity of coronary arterial lesion were also not associated with this SNP. Comparison between patients with and without BCG reactivation revealed only one difference: patients with reactivation were younger.in a cohort from a population with the world's third highest incidence of KD, we demonstrated that the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, although its frequency is lower than that in the Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility through induced hyperimmune function reflected in the BCG reactivation.

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

Kawasaki disease (KD) is an acute systemic vasculitis syndrome, which primarily affects in children under the age of 5 years. In 20-25% of cases, if untreated, coronary artery lesions develop, making KD the leading cause of acquired heart disease in children in both Japan and the United States. Since 1970, 19 nationwide surveys of KD in Japan have been conducted every 2 years and the data are stored in a database. Even though the etiology of KD remains unknown, despite enthusiastic research spanning more than 40 years, we have learnt a great deal about KD from this enormous database. These 19 epidemiologic studies indicate a strong genetic influence on the disease susceptibility, prompting us and other researchers to identify the responsible genes for KD by applying either the candidate gene approach or the genome-wide approach. We have employed a genome-wide linkage study using affected sibling pair data of KD in Japan and have identified several susceptibility loci. Further analysis focusing on a region of chromosome 19, where one of the linked loci was detected, identified a predisposing gene, which codes inositol 1,4,5-trisphosphate 3-kinase C (ITPKC). In this review, we summarize the cumulative knowledge regarding KD, and then outline our hypothesis of the role ITPKC plays in KD susceptibility and our trial that aims toward the implementation of personalized medicine for KD.

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.