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Background: Coronary artery disease (CAD) is a common complication of Type 2 diabetes mellitus (T2DM). Understanding the pathogenesis of this complication is essential in both diagnosis and management. Thus, this study aimed to characterize the presence of CAD in T2DM using molecular markers and pathway analyses. Methods: The study is a sex- and age-frequency matched case-control design comparing 23 unrelated adult Filipinos with T2DM-CAD to 23 controls (DM with CAD). Healthy controls served as a reference. Total RNA from peripheral blood mononuclear cells (PBMCs) underwent whole transcriptomic profiling using the Illumina HumanHT-12 v4.0 expression beadchip. Differential gene expression with gene ontogeny analyses was performed, with supporting correlational analyses using weighted correlation network analysis (WGCNA). Results: The study observed that 458 genes were differentially expressed between T2DM with and without CAD (FDR<0.05). The 5 top genes the transcription factor 3 (TCF3), allograft inflammatory factor 1 (AIF1), nuclear factor, interleukin 3 regulated (NFIL3), paired immunoglobulin-like type 2 receptor alpha (PILRA), and cytoskeleton-associated protein 4 (CKAP4) with AUCs >89%. Pathway analyses show differences in innate immunity activity, which centers on the myelocytic (neutrophilic/monocytic) theme. SNP-module analyses point to a possible causal dysfunction in innate immunity that triggers the CAD injury in T2DM. Conclusion: The study findings indicate the involvement of innate immunity in the development of T2DM-CAD, and potential immunity markers can reflect the occurrence of this injury. Further studies can verify the mechanistic hypothesis and use of the markers.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Perfilación de la Expresión Génica , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Enfermedad de la Arteria Coronaria/genética , Femenino , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Transcriptoma , Anciano , Adulto , Leucocitos Mononucleares/metabolismoRESUMEN
Introduction: Sulfonylureas (SUs) are commonly used drugs for type 2 diabetes mellitus (T2DM) in the Philippines. This study aimed to associate genetic variants with poor response to gliclazide and glimepiride among Filipinos. Methodology: Two independent, dichotomous longitudinal substudies enrolled 139 and 113 participants in the gliclazide and glimepiride substudies, respectively. DNA from blood samples underwent customized genotyping for candidate genes using microarray. Allelic and genotypic features and clinical associations were determined using exact statistical methods. Results: Three months after sulfonylurea monotherapy, 18 (13%) were found to be poorly responsive to gliclazide, while 7 (6%) had poor response to glimepiride. Seven genetic variants were nominally associated (p<0.05) with poor gliclazide response, while three variants were nominally associated with poor glimepiride response. For gliclazide response, 3 carboxypeptidase-associated variants (rs319952 and rs393994 of AGBL4 and rs2229437 of PRCP) had the highest genotypic association; other variants include rs9806699, rs7119, rs6465084 and rs1234315. For glimepiride response, 2 variants were nominally associated: CLCN6-NPPA-MTHFR gene cluster - rs5063 and rs17367504 - and rs2299267 from the PON2 loci. Conclusion: Genetic variants were found to have a nominal association with sulfonylurea response among Filipinos. These findings can guide for future study directions on pharmacotherapeutic applications for sulfonylurea treatment in this population.
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Diabetes Mellitus Tipo 2 , Gliclazida , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliclazida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
Preventive strategies for hypertension and its sequelae require an understanding of their predisposing conditions and recognition of at-risk individuals. Several factors, both genetic and nongenetic, are influential, and likely vary in their effects across ethnicities. This study aimed to identify dietary, lifestyle-related differences and genetic variants associated with hypertension in Filipinos. The study included 147 adult Filipino respondents of the 2013 Philippine National Nutrition Survey living in the National Capital Region. Data on the socio-demographic profile and selected lifestyle factors were obtained via face-to-face interviews. Blood pressure, anthropometric and biochemical indicators of health were determined using standard procedures. Hypertension incidence was determined following American College of Cardiology/American Heart Association guideline. Genotyping utilized the customized Illumina Golden Gate genotyping array, with subsequent allele and genotypic association analytics. Genetic variant effects were adjusted to clinical parameters via logistic regression. Between those with and without hypertension, there was relatively higher intake of dietary protein, fat but not carbohydrates in the latter (P<.05). Of note, other established risk factors for hypertension, such as high lipid levels and fasting blood sugar, were consistently frequently seen among hypertensive respondents. Of the gene markers, 3 SNPs (rs10492602 of APOC [3' UTR], rs12721054 of CYP2C19 [exon] and rs4244285 [intergenic between PCDH17-DIAPH3 locus]) remained significant after multivariable logistic regression. The study highlights that both nutrition and genetic information may contribute to hypertension among Filipinos. This could guide public health initiatives to identify Filipinos susceptible to hypertension and recommend control strategies in lowering its morbidity rate.
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Hipertensión , Adulto , Humanos , Hipertensión Esencial , Filipinas/epidemiología , Encuestas Nutricionales , Hipertensión/epidemiología , Hipertensión/genética , Factores de RiesgoRESUMEN
Purpose: A study among Filipinos revealed that only 15% of patients with diabetes achieved glycemic control, and poor response to metformin could be one of the possible reasons. Recent studies demonstrate how genetic variations influence response to metformin. Hence, the present study aimed to determine genetic variants associated with poor response to metformin. Methods: Using a candidate variant approach, 195 adult Filipino participants with newly diagnosed type 2 diabetes mellitus (T2DM) were enrolled in a case-control study. Genomic DNA from blood samples were collected. Allelic and genotypic associations of variants with poor response to metformin were determined using exact statistical methods. Results: Several polymorphisms were nominally associated with poor response to metformin (P uncorrâ <â 0.05). The most notable is the association of multiple variants in the SLC2A10 gene-rs2425911, rs3092412, and rs2425904-with common additive genetic mode of inheritance. Other variants that have possible associations with poor drug response include rs340874 (PROX-AS1), rs815815 (CALM2), rs1333049 (CDKN2B-AS1), rs2010963 (VEGFA), rs1535435 and rs9494266 (AHI1), rs11128347 (PDZRN3), rs1805081 (NPC1), and rs13266634 (SLC30A8). Conclusion: In Filipinos, a trend for the association for several variants was noted, with further observation that several mechanisms may be involved. The results may serve as pilot data for further validation of candidate variants for T2DM pharmacotherapy.
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ABSTRACT: Genetic variation is known to affect response to calcium channel blockers (CCBs) among different populations. This study aimed to determine the genetic variations associated with poor response to this class of antihypertensive drugs among Filipinos.One hundred eighty one hypertensive participants on CCBs therapy were included in an unmatched case-control study. Genomic deoxyribonucleic acid were extracted and genotyped for selected genetic variants. Regression analysis was used to determine the association of genetic and clinical variables with poor response to medication.The variant rs1458038 near fibroblast growth factor 5 gene showed significant association with poor blood pressure-lowering response based on additive effect (CT genotype: adjusted OR 3.41, Pâ=â.001; TT genotype: adjusted OR 6.72, Pâ<â.001).These findings suggest that blood pressure response to calcium channels blockers among Filipinos with hypertension is associated with gene variant rs1458038 near fibroblast growth factor 5 gene. Further studies are recommended to validate such relationship of the variant to the CCB response.
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Antihipertensivos , Bloqueadores de los Canales de Calcio , Factor 5 de Crecimiento de Fibroblastos/genética , Hipertensión , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Estudios de Casos y Controles , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , FilipinasRESUMEN
A common drug used for hypertension among Filipinos is beta-blockers. Variable responses to beta-blockers are observed, and genetic predisposition is suggested. This study investigated the association of genetic variants with poor response to beta-blockers among Filipinos. A total of 76 Filipino adult hypertensive participants on beta-blockers were enrolled in an unmatched case-control study. Genotyping was done using DNA from blood samples. Candidate variants were correlated with clinical data using χ2 and logistic regression analysis. The deletion of at least one copy of allele A of rs36217263 near Klotho showed statistically significant association with poor response to beta-blockers (dominant; odds ratio (OR) = 3.89; P = 0.017), adjusted for diabetes and dyslipidemia. This association is observed among participants using cardioselective beta-blockers (crude OR = 5.60; P = 0.008) but not carvedilol (crude OR = 2.56; P = 0.67). The genetic variant rs36217263 is associated with poor response to cardioselective beta-blockers, which may become a potential marker to aid in the management of hypertension.