Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease

Shanker Jayashree, Perumal Ganapathy, Rao, Khadrinarasimhiah, John Shibu, Hebbagodi Sridhara, Mukherjee Manjari, Kakkar

Description

The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. Methods & results Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h 2 48% – 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis ( P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) ( P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively ( P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. Conclusion The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2008
• Nombre de lectures: 19
• Langue: English

Extrait

Lipids in Health and Disease

BioMedCentral

Open Access Research Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease 1 12 Jayashree Shanker*, Ganapathy Perumal, Veena S Rao, 2 33 Natesha B Khadrinarasimhiah, Shibu John, Sridhara Hebbagodi, 1,2 1,2,3,4 Manjari Mukherjeeand Vijay V Kakkar

1 2 Address: Maryand Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India,Tata Proteomics & Coagulation 3 Unit, Thrombosis Research Institute, Bangalore, India,Elizabeth & Emmanuel Kaye Bioinformatics and Statistics Unit, Thrombosis Research 4 Institute, Bangalore, India andThrombosis Research Institute, London, UK

Email: Jayashree Shanker*  [e-mail]; Ganapathy Perumal  [e-mail]; Veena S Rao  [e-mail]; Natesha B Khadrinarasimhiah  [e-mail]; Shibu John  [e-mail]; Sridhara Hebbagodi  [e-mail]; Manjari Mukherjee  [e-mail]; Vijay V Kakkar  sarahvvk@trilondon.ac.uk * Corresponding author

Published: 19 September 2008Received: 15 July 2008 Accepted: 19 September 2008 Lipids in Health and Disease2008,7:33 doi:10.1186/1476-511X-7-33 This article is available from: http://www.lipidworld.com/content/7/1/33 © 2008 Shanker et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. Methods & results:Genotyping and lipid assays were carried out using standard protocols. 2 Plasma lipids showed a strong heritability (h48% – 70%;P< 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi- point analysis (LOD score 7.42,P< 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P< 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P< 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P< 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. Conclusion:The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.

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