RESUMO
The present work was aimed to study the association of one carbon genetic variants, hyperhomocysteinemia and oxidative stress markers, i.e., serum nitrite, plasma malondialdehyde (MDA) and glutathione (GSH) on intimal medial thickening (IMT) in patients with type 2 diabetes mellitus (T2D). A total number of 76 subjects from ACS Medical College and Hospital, Chennai, India were included in the study, i.e., Group I (n = 42) of T2D and Group II (n = 34) of age- and sex matched healthy controls. The glycated haemoglobin was measured by ion-exchange resin method; plasma homocysteine by Enzyme Linked Immunosorbant Assay method; serum nitrite (nitric oxide, NO), plasma MDA and GSH by spectrophotometric methods; the IMT by high frequency ultrasound. The polymorphisms of one carbon genetic variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism and amplified fragment length polymorphism methods. Results indicate that methyltetrahydrofolate homocysteine methyl transferase (MTR) A2756G allele was found to be protective in T2D and the other variants were not significantly associated with T2D. Glutamate carboxypeptidase II (GCP II) C1561T (r = 0.34; p = 0.05) and methylene tetrahydrofolate reductase (MTHFR) C677T (r = 0.35; 0.04) showed positive correlation with plasma homocysteine in T2D cases. In this study, MTR A2756G allele was found to be protective in T2D; GCP II C1561T and MTHFR C677T showed positive association with plasma homocysteine in T2D cases. Among all the genetic variants, MTR A2756G was found influence IMT. RFC 1 G80A and TYMS 5'-UTR 2R3R showed synergistically interact with MTR A2756G in influencing increase in IMT.
RESUMO
The rationale of this case-control study was to explore the association of Toll-like receptor 4 (TLR4) D299G, TLR4 T399I, TLR9 -1486 T>C, TIR-domain-containing adaptor protein (TIRAP) S180 L and tumor necrosis-α (TNF-α) promoter polymorphisms with susceptibility and phenotypic heterogeneity of systemic lupus erythematosus (SLE). PCR-RFLP, real-time PCR was used for the genetic analysis and expression studies and ELISA was used for the determination of specific autoantibodies. TLR4 D299G was associated with the risk for SLE (OR: 1.57, 95% CI: 1.08-2.28), while the TNF-α (-1031, -863, -857) CCC haplotype conferred protection. TLR4 and TIRAP polymorphisms were associated with reduced expression of HLA-DR. The presence of TLR4 and TLR9 polymorphisms increases the MHC2TA expression, while TIRAP polymorphism was associated with reduced expression. TLR4 D299 G showed an inverse association with pulmonary hypertension. TLR 4 T399I and TLR9 -1486 T>C showed a positive association with seizures and photosensitivity, respectively. TIRAP S180 L showed a positive association with alopecia and malar rashes, while an inverse association with psychosis was observed. TLR4 T399I (r = 0.14, p = 0.05) and TIRAP S180 L (r = 0.15, p = 0.03) showed a positive association with anti-Ro antibodies. On the other hand, TLR9 -1486 T>C showed an inverse association with anti-La antibodies (r = -0.20, p = 0.006). To conclude, TLR4 D299G increases the risk for SLE, while TNF-α CCC haplotype reduces the risk for SLE. All these polymorphisms contribute toward phenotypic heterogeneity. TLR4 T399I, TLR9 -1486 T>C and TIRAP S180 L influence specific autoantibody production in SLE.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-1/genética , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Fator de Necrose Tumoral alfa/genética , Alopecia/genética , Estudos de Casos e Controles , Expressão Gênica , Haplótipos , Humanos , Hipertensão Pulmonar/genética , Índia , Redução Dimensional com Múltiplos Fatores , Proteínas Nucleares/genética , Fenótipo , Regiões Promotoras Genéticas , Transtornos Psicóticos/genética , Fatores de Risco , Convulsões/genética , Transativadores/genéticaRESUMO
To optimize the warfarin dose, a population-specific pharmacogenomic algorithm was developed using multiple linear regression model with vitamin K intake and cytochrome P450 IIC polypeptide9 (CYP2C9(*)2 and (*)3), vitamin K epoxide reductase complex 1 (VKORC1(*)3, (*)4, D36Y and -1639 G>A) polymorphism profile of subjects who attained therapeutic international normalized ratio as predictors. New algorithm was validated by correlating with Wadelius, International Warfarin Pharmacogenetics Consortium and Gage algorithms; and with the therapeutic dose (r=0.64, P<0.0001). New algorithm was more accurate (Overall: 0.89 vs 0.51, warfarin resistant: 0.96 vs 0.77 and warfarin sensitive: 0.80 vs 0.24), more sensitive (0.87 vs 0.52) and specific (0.93 vs 0.50) compared with clinical data. It has significantly reduced the rate of overestimation (0.06 vs 0.50) and underestimation (0.13 vs 0.48). To conclude, this population-specific algorithm has greater clinical utility in optimizing the warfarin dose, thereby decreasing the adverse effects of suboptimal dose.
