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


RESULTS
Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h2 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.


CONCLUSIONS
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.
Shanker
Jayashree
J
Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Institute, Bangalore, India. jayashreeshanker@triindia.org.in
Perumal
Ganapathy
G
Rao
Veena S
VS
Khadrinarasimhiah
Natesha B
NB
John
Shibu
S
Hebbagodi
Sridhara
S
Mukherjee
Manjari
M
Kakkar
Vijay V
VV
D000328:Adult; D017668:Age of Onset; D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics*; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics*; D001208:Asia / Q000208:ethnology; D044466:Asian People / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007194:India; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012044:Regression Analysis
C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D005819:Genetic Markers
Hum Mol Genet. 2004 May 15;13(10):1049-56
15044382
Genet Epidemiol. 2004 Jul;27(1):53-63
15185403
Atherosclerosis. 2004 Nov;177(1):119-26
15488874
Atherosclerosis. 1991 Mar;87(1):75-86
1678604
Am J Psychiatry. 2000 Mar;157(3):402-8
10698816
Am J Hum Genet. 1996 Jun;58(6):1347-63
8651312
J Lipid Res. 2004 Dec;45(12):2174-84
15375185
Am J Hum Genet. 1998 Aug;63(2):577-85
9683614
Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):215-26
9484986
Natl Med J India. 2003 Jul-Aug;16(4):189-92
14606765
Atherosclerosis. 2001 Jul;157(1):1-11
11427198
Circulation. 1990 Aug;82(2):495-506
2372896
Metabolism. 2006 Dec;55(12):1574-81
17142127
Ann Hum Biol. 2001 Sep-Oct;28(5):481-90
11572515
Hum Mol Genet. 2008 Jul 1;17(13):2039-46
18378515
Atherosclerosis. 2006 Apr;185(2):353-60
16125709
Ann Saudi Med. 1999 May-Jun;19(3):201-5
17283453
J Hum Genet. 2004;49(8):433-9
15258834
Pediatr Res. 2001 Apr;49(4):514-8
11264435
Nucleic Acids Res. 1988 Feb 11;16(3):1215
3344216
Mol Cells. 1998 Feb 28;8(1):12-8
9571626
Mol Cell Biochem. 2004 Apr;259(1-2):59-66
15124908
Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R117-23
16987874
Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):167-74
14551155
Hum Hered. 2006;61(2):87-96
16710093
J Lipid Res. 1996 Feb;37(2):309-19
9026529
Circ Res. 2004 Apr 16;94(7):993-9
15001527
J Lipid Res. 2008 May;49(5):1034-8
18245017
Genomics. 2004 May;83(5):912-23
15081120
Clin Chem. 1989 Feb;35(2):256-9
2914370
Atherosclerosis. 2001 Sep;158(1):173-81
11500189
J Biol Chem. 2005 Apr 1;280(13):12559-66
15649902
Dis Markers. 2005;21(4):169-74
16403951
Hum Mol Genet. 2002 Nov 15;11(24):3039-46
12417525
Atherosclerosis. 1993 May;100(2):157-69
8102848
Bioinformatics. 2005 May 15;21(10):2556-7
15746282
Atherosclerosis. 1999 Jul;145(1):187-95
10428310
Nat Genet. 2002 Jan;30(1):97-101
11731797
BMC Med Genet. 2006;7:76
17032446
Circ J. 2006 Aug;70(8):1030-6
16864937
Atherosclerosis. 1996 Dec 20;127(2):255-62
9125316
J Clin Invest. 1997 Mar 1;99(5):953-61
9062353
Hum Mol Genet. 2006 Nov 15;15(22):3351-60
17035246
J Lipid Res. 2008 May;49(5):945-53
18263854
J Clin Invest. 1996 Jul 15;98(2):372-7
8755647
J Cardiometab Syndr. 2007 Fall;2(4):267-75
18059210
Genet Epidemiol. 1985;2(1):85-97
3863778
J Lipid Res. 2005 Dec;46(12):2605-13
16192625
Science. 2001 Oct 5;294(5540):169-73
11588264
Am J Hum Genet. 2008 Jan;82(1):139-49
18179892
Circulation. 1994 Feb;89(2):567-77
8313545
Vasc Health Risk Manag. 2007;3(6):1063-8
18200825
BMC Med Genet. 2007;8 Suppl 1:S17
17903299