Incremental Accuracy of Blood Biomarkers for Predicting Clinical Outcomes After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with high mortality, morbidity, and recurrence. Studies have reported the accuracy of several blood biomarkers in predicting clinical outcomes; however, their independent contribution in prediction remains to be established. AIM: To investigate the incremental accuracy in predicting clinical outcomes in patients with ICH in a north Indian population using blood-based biomarkers. METHODS: In this study, a total of 250 ICH cases were recruited within 72 hours of onset. Baseline clinical and CT scan measurement were recorded. Homocysteine (HCY), C-reactive protein (CRP), matrix metalloproteinase-9 (MMP9), E-selectin (SELE), and P-selectin (SELP) levels were measured through ELISA. Telephonic follow-up was done by using mRS scale at three months. RESULTS: The mean age of cohort was 54.9 (SD±12.8) years with 64.8% patients being male. A total of 109 (43.6%) deaths were observed over three months follow-up. Area under the receiver operating characteristics curve-(AUROC) for 90-day mortality were 0.55 (HCY), 0.62 (CRP), 0.57 (MMP9), 0.60 (SELE) and 0.53 (SELP) and for poor outcome at 90-day (mRS: 3-6) were 0.60 (HCY), 0.62 (CRP), 0.54 (MMP9), 0.67 (SELE) and 0.54 (SELP). In multivariable model including age, ICH volume, IVH and GCS at admission, serum SELE (p=0.004) significant for poor outcome with improved AUROC (0.86) and HCY (p=0.04), CRP (p=0.003) & MMP9 (p=0.02) for mortality with least Akaike's Information Criterion-(AIC) (1060.5). CONCLUSIONS: Our findings suggest that the serum SELE is a significant predictor of poor outcome and HCY, CRP & MMP9 for Mortality in patients with ICH in the north Indian population.

Association of transforming growth factor-ß1 gene C509T, G800A and T869C polymorphisms with intracerebral hemorrhage in North Indian Population: a case-control study.

Transforming growth factor-ß1 (TGF-ß1) is a multifunctional pro-inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-ß1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-ß1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-ß1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-ß1 G800A (OR 9.07; 95% CI 2.3-35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9-13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D' = 0.53, r(2) = 0.23). Our results suggest that TGF-ß1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH.

Association between lymphotoxin alpha (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke in North Indian population: a hospital-based case-control study.

PURPOSE: Lymphotoxin alpha (LTA), a proinflammatory cytokine, plays an important role in promoting atherosclerosis which is an independent risk factor for stroke. Recent genetic studies have suggested that polymorphisms in the LTA gene, which affect its expression and biological function, may contribute to the development of stroke. The aim of this case-control study was to determine the association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke. METHODS: Genotyping was determined by using SNaPshot method for 250 ischemic stroke (IS) patients, 250 age and sex matched IS free controls, 100 intracerebral hemorrhage (ICH) patients and 100 age and sex matched ICH free controls. Conditional logistic regression analysis with adjusting multiple demographic and risk factor variables was used to calculate the strength of association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of stroke. The linkage disequilibrium (LD) was analyzed by using HaploView 4.2 software. RESULTS: The distribution of LTA (-252 A/G and -804 C/A) genotypes was consistent with Hardy-Weinberg equilibrium. Adjusted conditional logistic regression analysis showed no significant association between LTA (-252 A/G and -804 C/A) gene polymorphisms and risk of both IS and ICH. Based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, a significant association between LTA -252 A/G gene polymorphism and small vessel disease subtype of IS under dominant model (OR, 2.06; 95% CI, 1.03-4.12; p value 0.04) with the risk of IS was observed. No LD was observed for both single nucleotide polymorphisms (SNPs) in north Indian population. CONCLUSION: Neither -252 G/A nor -804 C/A polymorphism of the LTA gene was found to be associated with overall stroke as well as any subtype of IS excluding SVD in North Indian population.

Association between Interleukin-10 -1082G/A Gene Polymorphism and Risk of Stroke in the North Indian Population: A Case-Control Study.

BACKGROUND: Anti-inflammatory interleukin-10 (IL-10) cytokine and its genetic variations may play an important role in the pathogenesis of various human diseases including stroke. OBJECTIVE: The aim of this present case-control study was to determine the association between IL-10 -1082G/A (rs1800896) gene polymorphism and risk of stroke in the North Indian population. METHODS: Genotyping was carried out by using SNaPshot method (Applied Biosystems, Foster City, California, United States) for 250 ischemic stroke (IS) patients, 250 age- and sex-matched IS free controls, 100 intracerebral hemorrhage (ICH) patients, and 100 age- and sex-matched ICH free controls. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis with adjustment for multiple demographic and risk factor variables was used to calculate the strength of association between IL-10 (-1082G/A) polymorphism and risk of stroke. RESULTS: Conditional logistic regression analysis showed an independent association between IL-10 -1082G/A and risk of IS under a dominant model (odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.34-4.27, P = .003) and an allelic model (OR = 2.49, 95% CI 1.71-3.63, P < .001). An independent association between IL-10 -1082G/A, under the dominant model (OR = 6.8, 95% CI 2.2-20.7, P < .001) and the allelic model (OR = 3.4, 95% CI 1.8-6.3, P < .001), and the risk of ICH was also observed. CONCLUSION: Our results suggest that IL-10 -1082G/A gene polymorphism is an independent risk factor for the risk of IS and ICH in the North Indian population. Our findings indicate that IL-10 -1082G/A polymorphism may be used as a genetic marker for identifying individuals at increased risk of developing stroke.

The Relationship Between Tumor Necrosis Factor-Alpha (-308G/A, +488G/A, -857C/T, and -1031T/C) Gene Polymorphisms and Risk of Intracerebral Hemorrhage in the North Indian Population: A Hospital-Based Case-Control Study.

INTRODUCTION: Genetic factors may play a role in the susceptibility of intracerebral hemorrhage (ICH). The present case-control study hypothesized that genetic polymorphisms in tumor necrosis factor- α (TNF-α) gene may affect the risk of ICH. MATERIALS AND METHODS: In this study, we investigated the association of four single nucleotide polymorphisms (-308G/A, +488G/A, -857C/T, and -1031T/C) within TNF-α gene promoter and their haplotypes with the risk of ICH in a North Indian population. Genotyping was determined by using the SNaPshot method for 100 ICH patients and 100 age and sex-matched ICH-free controls. Conditional logistic regression analysis with adjusting multiple demographic and risk factor variables was used to calculate the strength of association between TNF-α gene polymorphisms and risk of ICH. Haplotypes were reconstructed using PHASE 2.0, and patterns of linkage disequilibrium (LD) analysis were performed using Haploview version 4.2 software. RESULTS: TNF-α +488G/A gene polymorphism was found to be independently associated with the risk of ICH under dominant [GG + GA vs. AA] (OR = 3.1; 95% CI = 1.2-8.2; P = 0.001) and allelic [G vs. A] (OR = 2.2; 95% CI = 1.2-4.2; P = 0.007) models. However, no significant association between -308G/A, -857C/T, and -1031T/C gene polymorphisms and risk of ICH was observed. Haplotype analysis showed that 308A-488G-857C-1031T and 308G-488A-857T-1031T haplotypes were significantly associated with an increased risk of ICH. Strong LD was observed for + 488G/A and -857C/T TNF-α polymorphisms (D' = 0.72, r2= 0.01). CONCLUSION: Our findings suggest that the TNF-α +488G/A polymorphism may be an important risk factor for ICH, whereas -308G/A, -857C/T, and -1031T/C gene polymorphisms may not be associated with risk of ICH in North Indian population.

Transforming growth factor-ß1 (C509T, G800A, and T869C) gene polymorphisms and risk of ischemic stroke in North Indian population: A hospital-based case-control study.

BACKGROUND: Transforming growth factor-beta 1 (TGF-ß1) is a multifunctional pleiotropic cytokine involved in inflammation and pathogenesis of cerebrovascular diseases. There is limited information on the association between variations within the TGF-ß1 gene polymorphisms and risk of ischemic stroke (IS). The aim of this study was to investigate the association of the TGF-ß1 gene (C509T, G800A, and T869C) polymorphisms, and their haplotypes with the risk of IS in North Indian population. METHODS: A total of 250 IS patients and 250 age- and sex-matched controls were studied. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis was used to calculate the strength of association between TGF-ß1 gene polymorphisms and risk of IS. Genotyping was performed using SNaPshot method. RESULTS: Hypertension, diabetes, dyslipidemia, alcohol, smoking, family history of stroke, sedentary lifestyle, and low socioeconomic status were found to be associated with the risk of IS. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium in the IS and control groups. Adjusted conditional logistic regression analysis showed a significant association of TGF-ß1 C509T (odds ratio [OR], 2.1; 95% CI; 1.2-3.8; P = 0.006), G800A (OR, 4.4; 95% CI; 2.1-9.3; P < 0.001) and T869C (OR, 2.6; 95% CI; 1.5-4.5; P = 0.001) with the risk of IS under dominant model. Haplotype analysis showed that C509-A800-T869 and T509-G800-C869 haplotypes were significantly associated with the increased risk of IS. C509T and T869C were in strong linkage disequilibrium (D' =0.51, r2 = 0.23). CONCLUSION: Our results suggest that TGF-ß1 polymorphisms and their haplotypes are significantly associated with the risk of IS in North Indian population.

Association between interleukin-6 (G174C and C572G) promoter gene polymorphisms and risk of ischemic stroke in North Indian population: a case-control study.

BACKGROUND: Polymorphisms of G174C and C572G in the interleukin-6 (IL-6) promoter gene can affect both transcription and secretion of IL-6 and may be involved in inflammation related to and pathogenesis of ischemic stroke (IS). Whether these IL-6 gene polymorphisms are risk factors for IS or not, remains controversial. OBJECTIVE: The aim of this study was to determine the association between IL-6 G174C and C572G gene polymorphisms and susceptibility to ischemic stroke in North Indian Population. METHODS: Two hundred and fifty IS patients and 250 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Stroke was classified using Trial of Org 10172 in acute stroke treatment classification. Conditional logistic regression analysis was used to calculate the strength of association between IL-6 (G174C and C572G) polymorphisms and risk of IS. RESULTS: Hypertension, diabetes, dyslipidemia, alcohol, smoking, family history of stroke, sedentary life style and low socioeconomic status were found to be associated with the risk of IS. Conditional logistic regression analysis showed a significant association of IL-6 G174C with the risk of IS under dominant model (OR, 1.61; 95%CI, 1.0-2.4; P value 0.02) and allelic model (OR, 1.5; 95%CI, 1.0-2.1; P value 0.02). For IL-6 C572G, multivariate adjusted analysis showed a significant association with the risk of IS under dominant model for overall IS (OR, 1.81; 95%CI, 1.04-3.15; P value 0.03) and small vessel disease subtype of IS (OR, 2.8; 95%CI, 1.3-6.0; P value 0.006). CONCLUSION: Our results suggest that IL-6 (G174C) polymorphism is significantly associated with the risk of IS in North Indian population. However, IL-6 (C572G) polymorphism is found significantly associated with the risk of IS after adjusting the demographic and risk factors variables. Prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing IS.

Tumor necrosis factor-alpha (- 308G/A, + 488G/A, - 857C/T and -1031 T/C) gene polymorphisms and risk of ischemic stroke in north Indian population: A hospital based case-control study.

BACKGROUND: Genetic factors may play a role in the susceptibility of Ischemic stroke (IS). Previous studies have shown that Tumour necrosis factor-α (TNF-α) gene polymorphisms were associated with the risk of IS in multiple ethnicities. The present case-control study tested the hypothesis that genetic polymorphisms of the TNF-α gene may affect the risk of IS in North Indian population. We investigated the association of four single nucleotide polymorphisms (- 308G/A, + 488G/A, - 857C/T and -1031 T/C) within TNF-α gene promoter and their haplotypes with the risk of IS. METHODS: IS was classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification. Genotyping was performed for 250 IS patients and 250 age- and sex-matched IS free controls by using SNaPshot technique. Multivariate logistic regression was used to control the confounding effects of demographic and risk factor variables. Haplotype analyses were done by using PHASE software and Linkage disequilibrium (LD) analyses were done by using Haploview version 4.2 software. RESULTS: An independent association between TNF-α + 488G/A (OR = 2.59; 95%CI 1.46 to 4.60; p = 0.001) and -857C/T (OR = 1.77; 95%CI 1.01 to 3.11; p < 0.04) and risk of IS was observed under dominant model. However, no significant association between -308G/A and -1031 T/C gene polymorphisms and risk of IS was observed. Haplotype analysis showed that A308-G488-C857-T1031 haplotypes were significantly associated with the increased risk of IS [OR = 1.66; 95%CI 1.02 to 2.71; p = 0.003]. Strong linkage disequilibrium (LD) was observed for + 488G/A and -857C/T (D' = 0.41, r(2) = 0.004). CONCLUSIONS: Two SNPs (+ 488G/A and -857C/T) of TNF-α gene and their haplotypes are significantly associated with the risk of IS in the population enrolled from North India. Our findings indicate that polymorphisms and haplotypes of TNF-α gene may be used as a genetic marker for identifying individuals at increased risk for developing IS.