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OBJECTIVE: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are characterized by joint hypermobility, joint subluxations and dislocations, hyperextensible skin, and chronic and progressive multiorgan comorbidities. Diagnosing hEDS and HSD is difficult because of variable phenotypes and unknown genetic etiology. In our clinic, we observed many patients with hEDS and HSD with a high serum level of unmetabolized folate, which suggests that hypermobility may be linked to methylenetetrahydrofolate reductase (MTHFR)-mediated folate metabolism. The present study aims to examine the prevalence of MTHFR polymorphisms, C677T and A1298C, among patients with hEDS and HSD. METHODS: Clinical and demographic information of patients visiting our hypermobility clinic from January 2023 to July 2023 were retrospectively reviewed. Continuous variables were reported as mean ± SD and range, whereas categorical variables were reported as total count and percentage. RESULTS: Among 157 patients, 93% of patients were female patients, 52.2% were diagnosed with hEDS, and 47.8% were diagnosed with HSD. Interestingly, 85% of the patients had MTHFR C677T and/or A1298C polymorphisms in heterozygous or homozygous state. MTHFR 677CT/TT genotype was present in 52.9% of cases, and 49.7% of patients had 1298AC/CC genotype. In addition,14% of patients with hypermobility exhibited MTHFR 677TT genotype, 10.2% showed 1298CC genotype, and 17.2% displayed combined heterozygosity, collectively representing 41.4% hypermobile patients with two copies of MTHFR variant alleles. CONCLUSION: There is a high prevalence of MTHFR polymorphisms among patients with hypermobility, which supports the hypothesis that hypermobility may be dependent on folate status.
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Craniofacial development is a complex process involving diverse cell populations. Various transgenic Cre lines have been developed to facilitate studying gene function in specific tissues. In this study, we have characterized the expression pattern of Six2Cre mice at multiple stages during craniofacial development. Our data revealed that Six2Cre lineage cells are predominantly present in frontal bone, mandible, and secondary palate. Using immunostaining method, we found that Six2Cre triggered reporter is co-expressed with Runx2. In summary, our data showed Six2Cre can be used to study gene function during palate development and osteogenesis in mouse models.
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Mandíbula , Osteogénesis , Ratones , Animales , Ratones TransgénicosRESUMEN
BACKGROUND: Mammalian calvarium is composed of flat bones developed from two origins, neural crest, and mesoderm. Cells from both origins exhibit similar behavior but express distinct transcriptomes. It is intriguing to ask whether genes shared by both origins play similar or distinct roles in development. In the present study, we have examined the role of Pdgfra, which is expressed in both neural crest and mesoderm, in specific lineages during calvarial development. RESULTS: We found that in calvarial progenitor cells, Pdgfra is needed to maintain normal proliferation and migration of neural crest cells but only proliferation of mesoderm cells. Later in calvarial osteoblasts, we found that Pdgfra is necessary for both proliferation and differentiation of neural crest-derived cells, but not for differentiation of mesoderm-derived cells. We also examined the potential interaction between Pdgfra and other signaling pathway involved in calvarial osteoblasts but did not identify significant alteration of Wnt or Hh signaling activity in Pdgfra genetic models. CONCLUSIONS: Pdgfra is required for normal calvarial development in both neural crest cells and mesoderm cells, but these lineages exhibit distinct responses to alteration of Pdgfra activity.
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Proteínas Tirosina Quinasas Receptoras , Cráneo , Animales , Diferenciación Celular , Cráneo/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Cresta Neural , Mesodermo/metabolismo , Mamíferos/metabolismoRESUMEN
Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease. It is transmitted as autosomal recessive trait with mutations in MEditerranean FeVer (MEFV) gene. Despite a typical clinical expression, many patients have either a single or no mutation in MEFV. The current work is aimed to revisit the genetic landscape of FMF disease using high-coverage whole genome sequencing. In atypical patients (carrying a single or no mutation in MEFV), we revealed many rare variants in genes associated with auto-inflammatory disorders, and more interestingly, we discovered a novel variant ( a 2.1-Kb deletion) in exon 11 of IL1RL1 gene, present only in patients. To validate and screen this patient-specific variant, a tandem of allele-specific PCR and quantitative real-time PCR was performed in 184 FMF patients and 218 healthy controls and we demonstrated that the novel deletion was absent in controls and was present in more than 19% of patients. This study sheds more light on the mutational landscape of FMF. Our discovery of a disease-specific variant in IL1RL1 gene may constitute a novel genetic marker for FMF. This finding suggesting a potential role of the IL33/ST2 signalling in the disease pathogenicity highlights a new paradigm in FMF pathophysiology.
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Fiebre Mediterránea Familiar/genética , Genoma Humano , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mutación/genética , Análisis de Secuencia de ADN , Transducción de Señal , Adolescente , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN/genética , Femenino , Eliminación de Gen , Genes Modificadores , Predisposición Genética a la Enfermedad , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Pirina/genéticaRESUMEN
The mammalian skull is composed of the calvarial bones and cartilages. Malformation of craniofacial cartilage has been identified in multiple human syndromes. However, the mechanisms of their development remain largely unknown. In the present study, we identified Pdgfra as a novel player of chondrocranial cartilage development. Our data show that Pdgfra is required for normal chondrocranial cartilage development. Using tissue-specific genetic tools, we demonstrated that Pdgfra is essential for chondrocyte progenitors formation, but not in mature chondrocytes. Further analysis revealed that Pdgfra regulates chondrocytes progenitors development at two stages: in embryonic mesenchymal stem cells (eMSCs), Pdgfra directs their differentiation toward chondrocyte progenitors; in chondrocytes progenitors, Pdgfra activation promotes cell proliferation. We also found that excessive Pdgfra activity causes ectopic cartilage formation. Our data show that Pdgfra directs eMSCs differentiation via inhibiting Wnt9a transcription and its downstream signaling, and activating Wnt signaling rescues ectopic cartilage phenotype caused by excessive Pdgfra activity. In summary, our study dissected the role of Pdgfra signaling in chondrocranial cartilage formation, and illustrated the underlying mechanisms at multiple stages.
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Cartílago/embriología , Diferenciación Celular , Condrocitos/metabolismo , Células Madre Multipotentes/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Cráneo/embriología , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Animales , Cartílago/citología , Condrocitos/citología , Ratones , Ratones Transgénicos , Células Madre Multipotentes/citología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Cráneo/citología , Proteínas Wnt/genética , beta Catenina/genéticaRESUMEN
In recent years, the prevalence of obesity, metabolic syndrome and type 2 diabetes is increasing dramatically. They share pathophysiological mechanisms and often lead to cardiovascular diseases. The ZDSD rat was suggested as a new animal model to study diabetes and the metabolic syndrome. In the current study, we have further characterized metabolic and hepatic gene expression changes in ZDSD rats. Immuno-histochemical staining of insulin and glucagon on pancreas sections of ZDSD and control SD rats revealed that ZDSD rats have severe damage to their islet structures as early as 15 weeks of age. Animals were followed till they were 26 weeks old, where they exhibited obesity, hypertension, hyperglycemia, dyslipidemia, insulin resistance and diabetes. We found that gene expressions involved in glucose metabolism, lipid metabolism and amino acid metabolism were changed significantly in ZDSD rats. Elevated levels of ER stress markers correlated with the dysregulation of hepatic lipid metabolism in ZDSD rats. Key proteins participating in unfolded protein response pathways were also upregulated and likely contribute to the pathogenesis of dyslipidemia and insulin resistance. Based on its intact leptin system, its insulin deficiency, as well as its timeline of disease development without diet manipulation, this insulin resistant, dyslipidemic, hypertensive, and diabetic rat represents an additional, unique polygenic animal model that could be very useful to study human diabetes.
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Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Hipertensión/metabolismo , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Aminoácidos/metabolismo , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Glucagón/análisis , Glucagón/metabolismo , Humanos , Hipertensión/genética , Hipertensión/patología , Insulina/análisis , Insulina/metabolismo , Metabolismo de los Lípidos/genética , Hígado/patología , Masculino , Síndrome Metabólico/genética , Síndrome Metabólico/patología , Herencia Multifactorial , Obesidad/genética , Obesidad/patología , Páncreas/patología , Ratas , Ratas Endogámicas , Ratas Sprague-Dawley , Ratas ZuckerRESUMEN
Formation of the calvaria is a multi-staged process and is regulated by multiple genetic factors. Disruption of normal calvarial development usually causes craniosynostosis, a prevalent birth defect characterized by premature fusion of calvarial bone. Recent studies have identified mutations of KMT2D allele in patients with craniosynostosis, indicating a potential role for Kmt2d in calvarial development. KMT2D mutations have also been implicated in Kabuki syndrome, which features a distinct facial appearance, skeletal abnormality, growth retardation and intellectual disability. However, the expression pattern of Kmt2d has not been fully elucidated. In the present study we examined the expression pattern of Kmt2d at multiple stages of embryo development in mice, with a focus on the craniofacial tissues. Our in situ hybridization results showed that Kmt2d mRNA is expressed in the developing calvarial osteoblasts, epithelia and neural tissues. Such an expression pattern is in line with the phenotypes of Kabuki syndrome, suggesting that Kmt2d plays an intrinsic role in normal development and homeostasis of these craniofacial tissues.
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N-Metiltransferasa de Histona-Lisina/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Cráneo/embriología , Animales , Diferenciación Celular , Células Epiteliales/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/genética , Osteoblastos/metabolismo , Cráneo/metabolismo , Transcriptoma/genéticaRESUMEN
The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases like cancer, diabetes, hypertension, cardiovascular, and autoimmune and dermatological diseases is being extensively explored. The non-classical function of vitamin D involves regulation of cellular proliferation, differentiation, apoptosis, and innate and adaptive immunity. In this review, we discuss and summarize the latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases.
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Vitamina D/metabolismo , Inmunidad Adaptativa/fisiología , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Humanos , Receptores de Calcitriol/metabolismoRESUMEN
BACKGROUND: Vitamin D is a secosteroid, which was initially known for its skeletal role; however, in recent years, its functions in different organs have been increasingly recognized. In this review, we will provide an overview of vitamin D functions in the skin physiology with specific focus on its role in certain inflammatory skin conditions such as psoriasis and atopic dermatitis. METHODS: A comprehensive literature search was carried out in PubMed and Google Scholar databases using keywords like "vitamin D," "skin," "atopic dermatitis," and "psoriasis." Only articles published in English and related to the study topic were included in this review. RESULTS: Vitamin D is integrally connected to the skin for its synthesis, metabolism, and activity. It regulates many physiological processes in the skin ranging from cellular proliferation, differentiation, and apoptosis to barrier maintenance and immune functions. Vitamin D deficiency is associated with the risk of psoriasis and atopic dermatitis, and several clinical/observational studies have suggested the beneficial effect of vitamin D in the therapy of these 2 inflammatory skin disorders. CONCLUSIONS: Vitamin D exerts a pleiotropic effect in the skin and could be an important therapeutic option for psoriasis and atopic dermatitis.
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Inflamación/metabolismo , Inflamación/patología , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patología , Piel/metabolismo , Piel/patología , Vitamina D/metabolismo , Animales , Dermatitis Atópica/patología , Humanos , Psoriasis/metabolismo , Psoriasis/patologíaRESUMEN
Recent genome-wide association studies (GWAS) have identified variants in phospholipase C epsilon1 (PLCE1) as novel susceptibility markers for esophageal squamous cell carcinoma (ESCC) in Chinese population. Although few studies have replicated this findings in other populations, but results are contradictory. So, we aimed to replicate association of two previously reported non-synonymous polymorphisms (rs2274223A>G and rs3765524C>T) from haplotype block 10 and evaluated a novel variant (rs7922612C>T) from haplotype block 2 of PLCE1 with susceptibility and prognosis of ESCC in northern Indian population. The genotyping of PLCE1 variants were performed in 293 histopathologically confirmed incident ESCC cases (including 177 follow-up cases) and 314 age-, gender-, and ethnicity-matched controls using PCR RFLP. All statistical analyses were performed through SPSS version 15.0. Modeling and functional prediction of two non-synonymous variants were carried out using bioinformatics tools. PLCE1 polymorphisms were not associated with susceptibility to ESCC or its clinical phenotypes (tumor location/lymph node metastasis). No interaction with environmental risk factors was found. In silico analysis suggested negligible effect on structure of PLCE1 protein due to PLCE1 rs2274223 (H1927R) and rs3765524 (T1777I) polymorphisms. Survival analysis showed PLCE1 rs7922612CT + TT genotype conferred adverse outcome to ESCC patients. Our study for the first time suggests that GWAS originated PLCE1 variants do not have independent role in susceptibility of ESCC in northern Indian population; however, a novel haplo-tagging SNP rs7922612 may modify survival outcome of ESCC patients.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Fosfoinositido Fosfolipasa C/genética , Polimorfismo de Nucleótido Simple/genética , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Haplotipos/genética , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Phospholipase C epsilon 1 (PLCE1) encodes a member of the phospholipase family of proteins that play crucial roles in carcinogenesis and progression of several cancers including esophageal cancer (EC). In two large scale genome-wide association studies (GWAS) single nucleotide polymorphisms (SNP, rs2274223A>G, rs3765524C>T) in PLCE1 were identified as novel susceptibility loci of esophageal cancer (EC) in China. The aim of the present study was to investigate this finding in Kashmir Valley, a high risk area. MATERIALS AND METHODS: We determined genotypes of three potentially functional SNPs (rs2274223A>G, rs3765524C>T and rs7922612C>T) of PLCE1 in 135 EC patients, and 195 age and gender matched controls in Kashmiri valley by PCR RFLP method. Risk for developing EC was estimated by binary logistic regression using SPSS. RESULTS: The selected PLCE1 polymorphisms did not show independent association with EC. However, the G2274223T3765524T7922612 haplotype was significantly associated with increased risk of EC (OR=2.92; 95% CI=1.30-6.54; p=0.009). Smoking and salted tea proved to be independent risk factors for EC. CONCLUSIONS: Genetic variations in PLCE1 modulate risk of EC in the high risk Kashmiri population.
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Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/genética , Fosfoinositido Fosfolipasa C/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Riesgo , Fumar/efectos adversos , Té/efectos adversosRESUMEN
BACKGROUND: Tumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. Therefore, in present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population. METHODS: We genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay. RESULTS: TNFA-308GA genotype was associated with increased risk of ESCC specifically in females and in patients with regional lymph node involvement, while, NFKBIA -826CT+TT genotype conferred decreased risk of ESCC in females. Haplotypes of NFKBIA -826C>T and 3'UTRA>G polymorphisms, C-826G3'UTR and T-826A3'UTR, were associated with reduced risk of ESCC. No independent role of NFkB1 -94ATTG ins/del polymorphism in susceptibility of ESCC was found. Multi-dimensionality reduction analysis showed three factor model TNFA-308, NFKBIA-826, NFKBIA 3'UTR as better predictor for risk of ESCC. Furthermore, combined risk genotype analysis of all studied polymorphisms showed increased risk of ESCC in patients with 1-3 risk genotype compared to '0' risk genotype. Survival analysis did not show any significant prognostic effect of studied polymorphisms. However, in stepwise multivariate analysis, metastasis was found to be independent prognostic predictor of ESCC patients. CONCLUSION: TNFA-308 and NFKBIA (-826C>T and 3'UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas I-kappa B/genética , Subunidad p50 de NF-kappa B/genética , Polimorfismo de Nucleótido Simple/genética , Factor de Necrosis Tumoral alfa/genética , Demografía , Ambiente , Carcinoma de Células Escamosas de Esófago , Femenino , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Inhibidor NF-kappaB alfa , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND AND OBJECTIVES: Phospholipase C epsilon 1 (PLCE1) plays crucial roles in carcinogenesis and progression of esophageal and gastric cancers. In the present study, we investigated association of GWAS identified rs2274223 A>G and. rs7922612 T>C polymorphism of PLCE1 with susceptibility to gallbladder cancer (GBC). METHODS: The study involved genotyping of selected PLCE1 variants in 416 GBC cases and 225 controls. Haplotype analysis was done by SNPStats. In silico analyses were performed using bioinformatic tools. RESULTS: PLCE1 rs2274223 [AG] and rs7922612 [CC] genotypes were found to be significantly associated with an increased risk of GBC [OR = 1.9, p = 0.002; OR = 2.0, p = 0.04, respectively]. PLCE1 haplotype [Grs2274223-Crs7922612] also showed significant association with GBC [OR = 1.8, p = 0.04]. The association was significant in females and GBC patients with stones and female GBC patients with gallstones [OR = 2.6, p = 0.01; OR = 3.3, p = 0.007], respectively. However, no significant associations with other risk factors such as tobacco usage and age of onset were found. Functional prediction of rs2274223 A>G suggested change in protein coding and splicing regulation. CONCLUSION: The present study found a significant association of PLCE1 rs2274223 and rs7922612 polymorphisms with susceptibility to GBC probably through gallstone-mediated inflammatory pathway.
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Neoplasias de la Vesícula Biliar/etiología , Cálculos Biliares/genética , Predisposición Genética a la Enfermedad , Fosfoinositido Fosfolipasa C/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Neoplasias de la Vesícula Biliar/epidemiología , Genotipo , Haplotipos , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND AND AIM: Esophageal cancer-related gene 1 (ECRG1) is a novel tumor suppressor gene known to affect matrix remodeling, cell growth, and differentiation. Previous studies in high incidence geographical regions of esophageal cancer (EC) have shown association of ECRG1â Arg290Gln polymorphism with risk of esophageal squamous cell carcinoma (ESCC); however, role of this variant in low incidence region is missing. So, we aimed to evaluate association of ECRG1â Arg290Gln with susceptibility and prognosis of EC patients in low-risk north Indian population. METHODS: The genotyping of ECRG1â Arg290Gln polymorphism was done in 310 incident EC cases (including 179 follow up cases) and 310 healthy controls through polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis applied were binary logistic regression for risk estimation and Kaplan-Meier/log-rank test for survival analysis. Meta-analysis of published studies, exploring role of ECRG1 polymorphism in ESCC risk, was carried out using MIX 2.0 software. RESULTS: ECRG1â Arg290Gln polymorphism significantly conferred 1.8-fold increased risk of EC in dominant model (odds ratio = 1.78, 95% confidence interval = 1.27-2.49, P = 0.001). Stratification based on clinical phenotypes showed pronounced risk in cases with ESCC histopathology and middle/lower third tumor locations. No significant interaction with environmental risk factors was observed. Meta-analysis also showed significant association of ECRG1â Arg290Gln polymorphism with risk of ESCC. Kaplan-Meier and Cox regression tests suggested that ECRG1 polymorphism did not modulate survival outcome of ESCC patients. CONCLUSIONS: ECRG1â Arg290Gln polymorphism significantly affects the susceptibility but not the prognosis of ESCC patients in low-risk north Indian population.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Predisposición Genética a la Enfermedad/genética , Proteínas de la Membrana/genética , Polimorfismo Genético , Serina Proteasas/genética , Carcinoma de Células Escamosas/epidemiología , Estudios de Casos y Controles , Neoplasias Esofágicas/epidemiología , Técnicas de Genotipaje , Humanos , India/epidemiología , Estimación de Kaplan-Meier , Metaanálisis como Asunto , Pronóstico , Modelos de Riesgos Proporcionales , Riesgo , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Phospholipase C epsilon 1 gene (PLCE1) encodes a phospholipase enzyme which regulates various physiological processes (cell growth, differentiation, and apoptosis) and is supposed to play a critical role in carcinogenesis. Recently, a single nucleotide polymorphism (rs2274223 A>G) in PLCE1 was reported as a novel susceptibility locus for esophageal and gastric cancers by genome-wide association studies performed in Chinese population. However, individual association studies replicating this finding showed inconclusive results. Therefore, we performed a meta-analysis of eligible studies to derive precise estimation of the association of PLCE1 rs2274223 A>G polymorphism with cancer risk. We performed pooled analysis of 12 casecontrol studies including 7,622 cases and 9,555 controls. Odds ratios and 95 % confidence interval were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity, cancer types, and source of controls. All statistical analyses were performed by MIX 2.0 software. We found that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of cancer in log additive/dominant model and at allele level (GG vs. AA: OR = 1.24, 95 % CI = 1.011.53, P = 0.039; AG vs. AA: OR = 1.24, 95 % CI = 1.161.32, P < 0.001; AG + GG vs. AA: OR = 1.22, 95 % CI = 1.121.34, P < 0.001; and G vs. A allele: OR = 1.15, 95 % CI = 1.051.25, P = 0.002). Further, stratified analysis showed elevated risk of only gastric and esophageal tumors. Sub-group analysis based on ethnicity suggests PLCE1 polymorphism conferred significant risk among Asian (Chinese) but not in Caucasian. In conclusion, PLCE1 rs2274223 polymorphism may be used as potential biomarker for cancer susceptibility particularly for esophageal/gastric cancer and for the Chinese population.
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Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , Fosfoinositido Fosfolipasa C/genética , Polimorfismo de Nucleótido Simple , Pueblo Asiatico/genética , Población Negra/genética , Estudios de Casos y Controles , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Neoplasias/etnología , Oportunidad Relativa , Factores de Riesgo , Neoplasias Gástricas/etnología , Neoplasias Gástricas/genética , Población Blanca/genéticaRESUMEN
Genetic variants in micro-RNAs (miRNA) have been shown to affect progression, diagnosis, and prognosis of various malignancies; however, their role in esophageal squamous cell carcinoma (ESCC) susceptibility is controversial. Therefore, we aimed to determine role of common genetic variants in cancer related pre-miRNA in susceptibility and survival outcome of north Indian ESCC patients. We genotyped four common polymorphisms in pre-miRNA: mir-196a-2C>T, mir-146aG>C, mir-499T>C, and mir-423C>A in 289 incident ESCC cases (including 153 follow-up cases) and 309 controls using PCR/PCR RFLP-based methods. Binary logistic regression was applied for risk estimation, while Kaplan-Meier and Cox Regression tests were performed for survival analysis. We observed that none of the pre-miRNA genetic variants were associated with ESCC or its clinical phenotypes independently, however, combined risk genotypes of four pre-miRNA polymorphisms increased risk of ESCC in dose-response manner (Ptrend = 0.011). Specifically, patients with 2-4 risk genotypes of pre-miRNA polymorphisms had 1.4-fold higher risk of ESCC compared to patients with 0-1 risk genotypes (OR = 1.43, 95% CI = 1.02-1.09, P-value = 0.037). The risk was more pronounced in ESCC cases with upper-third esophageal tumors. Moreover, cumulative but not independent effect of risk genotypes of pre-miRNA polymorphisms was observed on survival outcome of ESCC patients. Cases with 2-4 risk genotypes had significantly lower median survival (11.60 vs. 30.2 months) and 2.3-fold greater hazard of death compared to patients with 0-1 risk genotypes. In conclusion, the four studied common pre-miRNA polymorphisms cumulatively affect susceptibility and survival of ESCC patients in north Indian population. © 2012 Wiley Periodicals, Inc.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/mortalidad , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/cirugía , Estudios de Casos y Controles , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/cirugía , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
INTRODUCTION: NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2), involved in detoxification of environmental carcinogens and activation of chemotherapeutic agents, are supposed to play critical role in carcinogenesis. So, we aimed to investigate the association of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility and prognosis of Esophageal cancer (EC) in north Indian population. We also performed Meta analysis of published literatures on NQO1 609C>T polymorphism to systematically evaluate its association with EC. METHODS: We genotyped NQO1 609C>T and NQO2 -3423G>A polymorphisms in 200 incident EC cases (including 150 follow-up cases) and 200 controls using PCR RFLP based methods. Binary logistic regression was applied for risk estimation, while Kaplan Meier and Cox regression tests were applied for survival analysis. All Meta analysis tests were performed using MIX 2.0 software. RESULTS: The present study did not find any significant association of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility to EC or its clinical phenotypes (histopathology, tumor location or lymph node metastasis) or interactions with lifestyle risk factors (tobacco usage, smoking, alcohol habit and occupational exposures). Meta analysis of NQO1 polymorphism also indicated null association of the polymorphism with EC overall or with cancer cases stratified by tumor histopathology/ethnicity. Moreover, no prognostic implication of both polymorphisms was observed in EC. CONCLUSION: NQO1 609C>T and NQO2 -3423G>A polymorphisms do not seem to play any significant role in susceptibility or prognosis of EC in north Indian population and results of Meta-analysis further reinforces null association of NQO1 609C>T polymorphism with EC susceptibility.
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Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Quinona Reductasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , India , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Genetic variants in p53 and in its homologue p73 may modulate Esophageal Cancer (EC) risk because they are supposed to influence cell cycle progression, apoptosis and DNA repair. Therefore, we aimed to evaluate the association of p53 intron3 16 bp duplication and p73 G4C14-to-A4T14 polymorphisms with susceptibility to EC in a northern Indian population in 255 EC patients and 255 age and sex matched healthy controls. We found that p53 intron3 16 bp duplication polymorphism was not associated with EC and its clinical characteristics. However, p73 G4C14-to-A4T14 polymorphism was associated with significant higher risk of EC (OR = 1.74, 95% CI = 1.16-2.60, P = 0.007) in an allele dose-dependent manner (P(trend) = 0.0047). Stratification of subjects on the basis of clinical characteristics showed that p73 AT genotype carriers were at significant increased risk of developing esophageal squamous cell carcinoma (OR = 1.78, 95% CI = 1.18-2.67, P = 0.006) at middle third tumor location (OR = 1.87, 95% CI = 1.18-2.97, P = 0.007) with lymph node metastasis (OR = 1.77, 95% CI = 1.04-3.02, P = 0.035). No interaction with environmental risk factors was observed with any of the studied polymorphisms. In summary, p73 G4C14-to-A4T14 polymorphism but not the p53 intron3 16 bp duplication polymorphism is associated with EC and its clinical characteristics in northern Indian population.
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Proteínas de Unión al ADN/genética , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/genética , Predisposición Genética a la Enfermedad/genética , Proteínas Nucleares/genética , Polimorfismo Genético , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Estudios de Casos y Controles , Humanos , India/epidemiología , Intrones/genética , Oportunidad Relativa , Factores de Riesgo , Proteína Tumoral p73RESUMEN
BACKGROUND: Caspase8 influences carcinogenesis through regulation of apoptosis, hyperproliferation, and metastasis. Role of genetic variations in caspase8 has been explored in various cancers; however, their predictive and prognostic role in esophageal cancer is poorly understood. METHODS: We investigated the association of two potential caspase8 polymorphisms: CASP8 -652 6N del and CASP8 IVS12-19 G>A polymorphisms with susceptibility and survival of 259 esophageal squamous cell carcinoma (ESCC) cases and 259 cancer-free controls from northern Indian population using PCR/PCR RFLP method. RESULTS: CASP8 IVS12-19 AA genotype was found to be associated with significant increased risk of ESCC (odds ratio (OR) 3.28, 95% confidence interval (CI) 1.04-10.29) specifically in male subjects (OR 3.71, 95% CI 1.01-13.35) with lower third tumor anatomical location (OR 6.00, 95% CI 1.60-22.55). Kaplan-Meier and Cox Regression analysis showed lower median survival (7.13 months vs. 25.21 months) and greater hazard of death (HR 3.40, 95% CI 1.38-7.90) with CASP8 IVS12-19 AA genotype in ESCC cases compared to IVS12-19 GG genotype. However, no association of CASP8 -652 6N del polymorphism with susceptibility and prognosis of ESCC was observed. CONCLUSION: CASP8 IVS12-19 G>A but not CASP8 -652 6N del polymorphism may modulate risk of ESCC and its survival outcome in northern Indian population.
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Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Caspasa 8/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Polimorfismo Genético , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , India , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Factores SexualesRESUMEN
Early diagnosis and better prognosis of esophageal squamous cell carcinoma (ESCC) is still a challenge. Besides environmental risk factors, nutritional deficiencies have an established role in pathogenesis of ESCC. Folate deficiency and functional polymorphisms in folate metabolizing genes such as methylene tetrahydrofolate reductase (MTHFR) 677C>T may have oncogenic role through disruption of normal DNA methylation pattern, synthesis, and impaired DNA repair. MTHFR677C>T or A222V (rs1801133) polymorphism has conflicting role in susceptibility to ESCC among different populations. Thus, we aimed to study the role of MTHFR677C>T polymorphism in susceptibility, survival, and interaction with environmental risk factors in ESCC patients from a northern Indian population. A case control study was performed in 208 ESCC incident cases (including 114 follow-up cases) and 223 healthy controls, and genotyping was done by PCR-RFLP. Our results show no significant association of MTHFR677C>T polymorphism with ESCC, tumor locations, or gender of subjects. However, we found a trend of decreased risk of ESCC due to interaction of MTHFR677CT genotype with smoking and alcohol intake. Kaplan Meier, and Cox regression survival analysis showed no prognostic impact of MTHFR677C>T polymorphism in ESCC patients. In conclusion, MTHFR677C>T polymorphism does not seem to have significant role either in susceptibility or survival of ESCC in a northern Indian population.