RESUMO
Type 2 diabetes (T2D) and its secondary complications result from the complex interplay of genetic and environmental factors. To understand the role of these factors on disease susceptibility, the present study was conducted to assess the association of eNOS and MCP-1 variants with T2D and diabetic nephropathy (DN) in two ethnically and geographically different cohorts from North India. A total of 1313 subjects from two cohorts were genotyped for eNOS (rs2070744, rs869109213 and rs1799983) and MCP-1 (rs1024611 and rs3917887) variants. Cohort-I (Punjab) comprised 461 T2D cases (204 T2D with DN and 257 T2D without DN) and 315 healthy controls. Cohort-II (Jammu and Kashmir) included 337 T2D (150 T2D with DN and 187 T2D without DN) and 200 controls. Allele, genotype and haplotype frequencies were compared among the studied participants, and phenotype-genotype interactions were determined. Meta-analysis was performed to investigate the association between the selected variants and disease susceptibility. All three eNOS variants were associated with 1.5-4.0-fold risk of DN in both cohorts. MCP-1 rs1024611 conferred twofold risk towards DN progression in cohort-II, while rs3917887 provided twofold risk for both T2D and DN in both cohorts. eNOS and MCP-1 haplotypes conferred risk for T2D and DN susceptibility. Phenotype-genotype interactions showed significant associations between the studied variants and anthropometric and biochemical parameters. In meta-analysis, all eNOS variants conferred risk towards DN progression, whereas no significant association was observed for MCP-1 rs1024611. We show evidences for an association of eNOS and MCP-1 variants with T2D and DN susceptibility.
Assuntos
Quimiocina CCL2/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Predisposição Genética para Doença , Óxido Nítrico Sintase Tipo III/genética , Estudos de Casos e Controles , Estudos de Coortes , Etnicidade , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-IdadeRESUMO
Genetic contributions towards Type 2 diabetes (T2D) have been assessed through association studies across different world populations with inconsistencies. The majority of the T2D susceptibility loci are common across different races or populations but show ethnicity-specific differences. The pathogenesis of T2D involves genetic variants in the candidate genes. The interactions between the genes involved in insulin signaling and secretory pathways are believed to play an important role in determining an individual's susceptibility towards T2D. Therefore, the present study was initiated to examine the differences, if any, in the contribution of polymorphisms towards T2D susceptibility in the background of different ethnic specifications. The present case-control study included a total of 1216 T2D cases and healthy controls from three ethnic groups (Jat Sikhs, Banias and Brahmins) of North-West India. Polymorphisms were selected on the basis of information available in the literature for INS (rs689), INSR (rs1799816) and PP1G.G (rs1799999) in context to T2D. The genotyping was done using PCR-RFLP method. Statistical analysis was done using SPSS 16.0. The analyses revealed that INS (rs689) polymorphism conferred risk towards T2D susceptibility in all the three ethnic groups whereas INSR (rs1799816) polymorphism conferred risk towards T2D in Brahmins only and PP1G.G (rs1799999) polymorphism indicated T2D risk in Jat Sikhs only. Furthermore, interaction analyses indicated the cumulative role of three genetic variants in modulating T2D susceptibility in the three ethnic groups. In conclusion, our results substantiated the evidences for the role of ethnicity in differential susceptibility to T2D in the background of same genetic variants.
Assuntos
Antígenos CD/genética , Diabetes Mellitus Tipo 2/genética , Etnicidade/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor de Insulina/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Grupos Populacionais/genética , RiscoRESUMO
INTRODUCTION: Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes (T2D), results from complex interactions of genetic and environmental factors. Vascular endothelial growth factor (VEGF) and mouse model minute 2 (MDM2)are upregulated in the retina due to diabetes, which increases the risk of DR. VEGFA and MDM2 genetic variations can influence DR risk. The present case-control study was conducted to evaluate the association of VEGFA and MDM2 promoter variants with DR in a population from Punjab, Northwest India. METHODS: A total of 414 DR patients, 425 T2D patients without DR, and 402 healthy controls were screened for VEGFA -2578C/A (rs699947), VEGFA -2549I/D (rs35569394), VEGFA -7C/T (rs25648), and MDM2 rs3730485 polymorphisms using polymerase chain reaction (PCR)-based methods. RESULTS: VEGFA -2549 I allele (OR = 1.35 (1.00-1.81), p = 0.043) and II genotype (OR = 1.78 (1.00-3.15), p = 0.047) were significantly associated with increased risk of DR. VEGFA -7 CT genotype conferred reduced risk of DR (OR = 0.28 (0.20-0.38); p = <0.001). VEGFA -2578 and MDM2 rs3730485 showed no significant association with DR. A-I-T (OR = 0.30 (0.20-0.44); p = <0.001) and C-D-T (OR = 0.33 (0.16-0.65); p = 0.002) haplotypes of rs699947-rs35569394-rs25648 polymorphisms showed decreased risk of DR. CONCLUSIONS: I allele and II genotype of VEGFA -2549, CT genotype of VEGFA -7, and C-I-C and A-D-C haplotypes of rs699947-rs35569394-rs25648 polymorphisms were significantly associated with DR risk in a Northwest Indian population. This is the first study worldwide to report DR risk with VEGFA promoter variants together.
RESUMO
Osteoporosis, the most common bone metabolic disease affecting nearly 200 million people worldwide is under the strong influence of genetic components. Simultaneously, adipogenesis and osteogenesis are two highly coordinated processes imperative for the maintenance of bone quality and quantity, where any perturbation leads to pathological conditions of obesity, osteopenia and osteoporosis. To delineate this adipogenic-osteogenic connection, a total of 254 cases (T-score<-1.0 SD) and 250 age, gender and ethnicity matched healthy controls (T-score≥-1.0 SD) were recruited from North India after analyzing bone health status employing quantitative ultrasound (QUS) bone densitometer. The genetic variants of Perilipin 1 (PLIN1), Complement Factor D (CFD) and Adiponectin (ADIPOQ) were genotyped using the PCR-RFLP/ARMS-PCR approach. Subjects with CC+CT (PLIN1 rs2304795) and CC+CG (CFD rs1683563) genotypes conferred nearly 1.54-1.87 fold increased risk towards bone deterioration. Predicted RNA secondary structures of rs2304795 corroborated the risk associated with wild type C allele. G allele carriers at the ADIPOQ locus (rs1501299) were more likely to have a lower bone health (1.57-fold). Haplotype analysis revealed the ADIPOQ variants rs1501299 and rs3774261 in slight linkage disequilibrium (LD), nonetheless G/G haplotype was associated with increased risk. 3-locus and 5-locus gene-gene interaction models revealed a greater likelihood of bone deterioration. In conclusion, certain variants of adipogenic genes might serve as potential biomarkers for determining the genetic predisposition towards bone loss in the North Indian population, further, emphasizing the role of impaired metabolism in bone health.