Dataset Information

Genotyping and meta-analysis of KIF6 Trp719Arg polymorphism in South Indian Coronary Artery Disease patients: A case-control study.

ABSTRACT: The KIF6 719Arg allele is an interesting genomic variant widely screened in various populations and is reported to be associated with the risk of Coronary Artery Disease (CAD) and statin treatment outcome. Recent population based clinical studies and large-scale meta-analyses pondered over the role of 719Arg variant in CAD risk and treatment response. We screened the KIF6 Trp719Arg polymorphism (rs20455) in south Indian CAD patients in a case-control approach. A total of 1042 samples (510 CAD patients and 532 controls) were screened for the KIF6 Trp719Arg SNP by TaqMan SNP genotyping assay, followed by meta-analysis of the genotype data of non-Europeans reports. The 719Arg risk genotype (GG) was observed in 29.6% of CAD cases and in 30.1% of controls with an odds ratio (OR) of 1.07 (95% CI: 0.76-1.50), p value = 0.709. No significant difference in the genotype frequency was observed between CAD and controls in both dominant model (AG + GG vs AA) and allelic model (719Arg vs 719Trp) with an OR of 1.11 (p = 0.491) and 1.03 (p = 0.767), respectively. The covariate analysis indicated that smoking & alcohol consumption increased the risk for MI among CAD patients. Meta-analysis showed that the KIF6 719Arg allele is not associated with CAD risk in both fixed effect (p = 0.515, OR = 1.023, 95% CI = 0.956-1.094) and random effect (p = 0.547, OR = 1.022, 95% CI = 0.953-1.096). The symmetrical shape of the Egger's funnel plots revealed that there is no publication bias. These results suggest that there is no association of KIF6 719Arg allele with CAD risk in South Indian population and the meta-analysis confirms the same among non-European population.

SUBMITTER: Vishnuprabu D

PROVIDER: S-EPMC4513186 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Genotyping and meta-analysis of KIF6 Trp719Arg polymorphism in South Indian Coronary Artery Disease patients: A case-control study.

Vishnuprabu Durairajpandian D Geetha Subramanian S Bhaskar Lakkakula V K S LV Mahapatra Nitish R NR Munirajan Arasambattu K AK

Meta gene 20150715

The KIF6 719Arg allele is an interesting genomic variant widely screened in various populations and is reported to be associated with the risk of Coronary Artery Disease (CAD) and statin treatment outcome. Recent population based clinical studies and large-scale meta-analyses pondered over the role of 719Arg variant in CAD risk and treatment response. We screened the KIF6 Trp719Arg polymorphism (rs20455) in south Indian CAD patients in a case-control approach. A total of 1042 samples (510 CAD pa ...[more]

PMID: 26236646

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Project description:BackgroundCase-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the KIF6 Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the KIF6 Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using KIF6 Trp719Arg as an example.ResultsTen replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among KIF6 Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between KIF6 genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the KIF6 719Arg variant, should also attenuate the KIF6 719Arg odds ratio in case-control studies.ConclusionsThese computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of KIF6 719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.

Project description:INTRODUCTION:Several Single Nucleotide Polymorphisms (SNPs) in lipid transport genes have been shown to be associated with Coronary Artery Disease (CAD). The Hepatic Lipase (HL)glycoprotein is a key component that catalyzes the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. AIM:We studied whether the HL gene-250G/A polymorphism affect blood lipid level and the CAD in a North Indian population. MATERIALS AND METHODS:A total number of 477 subjects were enrolled in the study after approval of the Institutional Ethics Committee. Out of 477 subjects, 233 were with coronary artery disease as study group and 244 subjects without coronary artery disease as control group. All subjects recruited with matched ethnicity in age group of 40-70 years. Blood samples were collected in EDTA vials and genomic DNA was extracted from blood using the phenol-chloroform method. Lipid profile was estimated by using a commercially available kit. Polymorphisms in the HL (-250 G/A) gene were analysed by using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) method. The effect of this polymorphism on plasma lipids, lipoproteins and coronary artery disease was determined. RESULTS:In Human Hepatic Lipase (LIPC)-250G/A genotype, the frequencies of GG, GA and AA genotype in CAD group was 80.69%, 15.45% and 3.86%, respectively; in the control group, the corresponding frequencies were 90.16%, 9.02% and 0.82%, respectively. A significant difference was found in the genotype (LIPC-250G/A) distribution between the two groups. Further logistic regression analysis indicated that the GA and AA genotypes in SNP-250G/A were significantly associated with CAD in all genetic models (In codominant model- GA vs. GG, OR=1.91, 95% CI=1. 09-3.37, p=0. 03 and AA vs. GG, OR= 5.26, 95% CI= 1.10-24.60, p=0.04; in dominant model- GA+AA vs. GG, OR=2.19, p=0.004 and in recessive model- AA vs. GG+GA, OR=5.26, p=0.04 whereas, A allele at nucleotide -250G/A in the LIPC gene had an association with increased risk of CAD (OR=2.33, p=<0.008). CONCLUSION:Our findings indicated that the higher frequency of a dominant model (GA+AA) as well as mutant allele A of LIPC-250 G/A polymorphism is significantly associated with risk of CAD and the lipid profile can be used as a predictor of CAD.

Project description:IntroductionCoronary artery disease (CAD), the leading cause of mortality worldwide, is characterised by an earlier onset and more severe disease in South Asians as compared to Western populations.MethodsThis is an observational study on 928 individuals who attended three tertiary care centres in Kerala, India from 2014-to 2017. The demographic, anthropometric, behavioural factors and the lipoprotein (Lp(a)) and cholesterol values were compared between the two groups and across disease severity. The Chi-square test was used to compare the categorical variables and independent sample t-test for the continuous variables. Multivariable logistic regression was performed to investigate the association of demographic, clinical and behavioural factors with the disease. Odds ratios are presented with a 95% confidence interval. In individuals below 50 years, two logistic regression models were compared to investigate the improvement in modelling the association of the independent factors and Lp(a) with the occurrence of the disease.ResultsWe included 682 patients in the diseased group and 246 patients treated for non-coronary conditions in the control group. Those in the control group were significantly younger than in the diseased group(p<0.002). Significantly more patients were diabetic, hypertensive, tobacco users and consumers of alcohol in the diseased group. Multivariable logistic regression on data from all age groups showed that age (OR = 2.55, 95% CI 1.51-4.33, p = 0.01), diabetes (OR = 3.71, 95% CI 2.42-5.70, p = 0.01), hypertension (OR = 3.03, 95% CI 2.12-4.34, p = 0.01) and tobacco use (OR = 5.44, 95% CI 3.39-8.75, p = 0.01) are significantly associated with the disease. Lp(a) (OR = 1.22, 95% CI 0.87-1.72) increased the odds of the disease by 22% but was not statistically significant. In individuals below 50 years, Lp(a) significantly increased the likelihood of CAD (OR = 3.52, 95% CI 1.63-7.57, p = 0.01). Those with diabetes were seven times more likely to be diseased (OR = 7.06, 95% CI 2.59-19.21, p = 0.01) and the tobacco users had six times the likelihood of disease occurrence (OR = 6.38, 95% CI 2.62-15.54, p = 0.01). The median Lp(a) values showed a statistically significant increasing trend with the extent/severity of the disease in those below 50 years.ConclusionAge, diabetes, hypertension and tobacco use appear to be associated more with the occurrence of coronary artery disease in adults of all ages. Lipoprotein(a), cholesterol and BMI categories do not seem to be related to disease status in all ages. However, in individuals below 50 years, diabetes, tobacco use and lipoprotein (a) are significantly associated with the occurrence of the disease.

Dataset Information

Genotyping and meta-analysis of KIF6 Trp719Arg polymorphism in South Indian Coronary Artery Disease patients: A case-control study.

Publications

Genotyping and meta-analysis of KIF6 Trp719Arg polymorphism in South Indian Coronary Artery Disease patients: A case-control study.

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