Haplotypes on 9p21 Modify the Risk for Coronary Artery Disease Among Indians

Manickaraj, Ashok Kumar; Cosson, E.; Dhandapany, Perundurai S.; Rani, Deepa Selvi; SaiBabu, Ramineni; Cherian, Kootturathu Mammen; Thangaraj, Kumarasamy

doi:10.1089/dna.2010.1046

Cited by 15 publications

(8 citation statements)

References 28 publications

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“…The rs1333049 was identified in WTCCC GWA study as the strongest SNP associated with CAD risk (WTCCC, 2007). Although other variants at the 9p21 locus have been studied in Indians (Kumar et al, 2010;AshokKumar et al, 2011;Bhanushali et al, 2011;Maitra et al, 2009), no information is available to date on this variant. The results of our study determine for the first time the frequency of this SNP in the select population from Western India as well as confirm the association with CAD risk.…”

Section: Discussionmentioning

confidence: 99%

“…In a study from South India (AshokKumar et al, 2011), GWAS identified SNPs rs2383207 and rs10757278 at the 9p21 locus and nine additional flanking SNPs were evaluated for increased risk of CAD. In the North Indian population study (Kumar et al, 2010), six SNPs were genotyped in a case-control association study in which three SNPs (rs10116277, rs1333040 and rs2383206) present at the locus 9p21 were significantly associated with CAD.…”

Section: Introductionmentioning

confidence: 99%

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Variant at 9p21 rs1333049 is associated with age of onset of coronary artery disease in a Western Indian population: a case control association study

Bhanushali¹,

Contractor²,

Das³

2013

Genet. Res.

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The 9p21 chromosomal region has been associated with coronary artery disease (CAD) in many genome wide association studies (GWAS). To date no information exists regarding the rs1333039 SNP which showed the strongest association in the WTCCC GWAS with CAD risk in the Indian population. The present study attempts to replicate the findings in the Indian population. Genotyping for rs1333049 was done in 229 cases and 151 controls by allele-specific real-time assay. A higher frequency of the risk allele rs1333049C was seen in cases (0·60) as compared with controls (0·49), which associated with CAD risk both in univariate (OR = 1·564, 95%CI = 1·154-2·119, P = 0·003) and multivariate analysis (OR = 2·460, 95%CI = 1·139-5·314, P = 0·022). Increased frequency of the risk allele was seen in younger individuals with CAD where 40% individuals in the age group 30-55 years had the CC genotype as compared with 29 and 24·5% in the age group 56-65 years and > 65 years, respectively (CC versus GG, P = 0·045). Higher incidence of the CC genotype was seen in MI patients, but missed significance when compared with controls (OR = 1·361, 95%CI = 0·954-1·942, P = 0·084). In conclusion, the rs1333049 variant is significantly associated with CAD risk and also with age of onset in the Western Indian population. However there are differences in the haplotype structure of this SNP with the neighbouring rs10757278 SNP, these differences emphasize the importance of genotyping all risk variants at this locus which could underlie the differences in risk susceptibility to CAD across populations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variant at 9p21 rs1333049 is associated with age of onset of coronary artery disease in a Western Indian population: a case control association study

Bhanushali¹,

Contractor²,

Das³

2013

Genet. Res.

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“…In 2007, independent genome-wide association studies revealed nine highly correlated SNPs (r 2 > 0.8) in a new locus in the region of chromosome 9 (9p21.3), showing the greatest association with heterogeneous CAD of all of the loci analyzed so far (Helgadottir et al, 2007;McPherson et al, 2007;Samani et al, 2007). Since then, numerous studies have confirmed the association of this locus with CAD or myocardial infarction (MI) in populations of European origin (Abdullah et al, 2008;Anderson et al, 2008;Assimes et al, 2008;Lemmens et al, 2009;Koch et al, 2011) as well as Eastern (Shen et al, 2008a;Ding et al, 2009) and Southern Asia origin (AshokKumar et al, 2011). However, genetic heterogeneity was shown in Black subjects (Assimes et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

The rs10757278 Polymorphism of the 9p21.3 Locus Is Associated with Premature Coronary Artery Disease in Polish Patients

Niemiec

Górczyńska-Kosiorz²,

Iwanicki³

et al. 2012

Genetic Testing and Molecular Biomarkers

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Recently, genome-wide association studies have revealed a locus associated with coronary artery disease (CAD) and myocardial infarction, namely, 9p21.3. Its participation in the conditioning of the disease has been proven in many populations of European descent, but not yet in Slavs. Allelic variants of the rs10757278 polymorphism functionally affect the activity of the 9p21.3 locus; therefore, we conducted a study to determine whether the rs10757278 is associated with premature CAD in Polish patients. We studied 320 subjects aged 25-55 years, divided into two groups matched by sex and age: (1) patients with angiographically proven premature CAD (n = 160), and (2) blood donors as a control group (n = 160). The rs10757278 was genotyped using the method of fluorescently labeled allelespecific oligonucleotides. The frequency of the G allele was significantly higher in patients than in controls (58.2% vs. 42.8%, respectively, p = 0.011) and was similar to the frequency of the GG homozygotes (30.6% vs. 17.5%, respectively, p = 0.006). Both the GG homozygosity (odds ratio [OR] = 2.08, 95% confidence interval [CI]: 1.19-3.66) as well as the G allele (OR = 1.49, 95% CI: 1.08-2.07) have been associated with CAD in the analyzed population. These variants may be considered as risk factors, also in the Polish population.

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“…There are limited studies on the 9p21.3 locus in Asian Indians (7,22,23) where the primary focus has been on genotype/haplotype association of 9p21.3 common variants with CAD. The first ever report published on Asian Indians showed a high frequency of the G allele (0.56) in rs10757278 variant (0.56) and was associated with >2-fold risk for CAD (OR 2.15, 95% confidence interval [CI] 1.02 -4.60) and a high population attributable risk of up to 46% in men (7).…”

Section: Introductionmentioning

confidence: 99%

“…The first ever report published on Asian Indians showed a high frequency of the G allele (0.56) in rs10757278 variant (0.56) and was associated with >2-fold risk for CAD (OR 2.15, 95% confidence interval [CI] 1.02 -4.60) and a high population attributable risk of up to 46% in men (7). The risk attribute of 9p21.3 common allele is said to be modulated by the flanking SNPs in this region (22). In the present study, we have investigated the 9p21.3 locus with respect to the association of five common genetic variants with CAD, compared the relative expression of ANRIL splice variants and other candidate genes in the 9p21.3 locus in a representative case-control cohort of Asian Indians, and finally observing the consequent effect of using short interfering RNA (siRNA) targeted against specific exons in ANRIL, on the neighbouring candidate genes.…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of the 9p21.3 CAD risk locus in Asian Indians

Shanker¹,

Arvind²,

Jambunathan³

et al. 2014

Thromb Haemost

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The 9p21.3 locus is the best replicated region to date for coronary artery disease (CAD). We investigated the association of 9p21.3 common variants with CAD, candidate gene expression including ANRIL, a non-coding RNA, followed by in vitro validation. Five variants, rs10757278, rs10757274, rs2383206, rs1333049 and rs4977574 were genotyped in 1,034 cases and 1,034 controls. Gene expression of C9orf5, MTAP1, MTAP 2, p16INK4a, p14ARF, p15INK4b and two ANRIL splice variants, NR_003529 and EU741058, were measured in 100 cases and 100 controls. Human aortic smooth muscle cells (HuAoSMCs) were transfected with siRNA targeting ANRIL exon 19 (siRNA-1) or exon 2 (siRNA-2) and consequent effect determined. rs2383206 showed the highest association with CAD (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.56 -2.62) and an adjusted OR of 2.55, 1.33-2.88 along with rs10757278. Conventional risk factors (conventional RFs), rs2383206 and rs10757278 variants together yielded a higher c index (OR 0.790, 95% CI 0.770 -0.810) as compared to conventional RFs (OR 0.783, 95% CI 0.763-0.803) or genetic variants (OR 0.561, 95% CI 0.536-0.586) alone. GAAAA haplotype showed significant protective association with CAD compared to CGGGG risk haplotype (OR 0.45, 95% CI 0.27-0.77). Expression of p16INK4a, p14ARF and p15INK4b as well as plasma CDKN2A levels were lower in cases than controls. GG genotype was associated with higher EU741058 expression and lower p16INK4a expression. HuAoSMCs transfected with siRNA-1 showed lower NR_003529, p16INK4aand p14ARFexpression. Our study provides further evidence on the significance of 9p21.3 locus for CAD wherein the risk allele regulate the expression of ANRIL and adjacent tumour suppressor genes which in turn alter smooth muscle proliferation, a fundamental process in atherosclerosis.

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Haplotypes on 9p21 Modify the Risk for Coronary Artery Disease Among Indians

Cited by 15 publications

References 28 publications

Variant at 9p21 rs1333049 is associated with age of onset of coronary artery disease in a Western Indian population: a case control association study

Variant at 9p21 rs1333049 is associated with age of onset of coronary artery disease in a Western Indian population: a case control association study

The rs10757278 Polymorphism of the 9p21.3 Locus Is Associated with Premature Coronary Artery Disease in Polish Patients

Genetic analysis of the 9p21.3 CAD risk locus in Asian Indians

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