Human Molecular Genetics Advance Access published online on April 28, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn132
Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE Study
1 Department of Medicine, Stanford University School of Medicine, Stanford, 94305, USA 2 Institute for Human Genetics, University of California San Francisco, San Francisco, 94143, USA 3 Division of Research, Kaiser Permanente of Northern California, Oakland, 94612, USA 4 Department of Genetics, Stanford University School of Medicine, Palo Alto, 94304, USA 5 Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA 6 Department of Radiology, Stanford University School of Medicine, Stanford, 94305, CA 7 Department of Epidemiology and Biostatistics, University of California, San Francisco, 94107, USA 8 Department of Medicine, University of California, San Francisco, 94107, USA
* Corresponding author: Themistocles L. Assimes Falk Cardiovascular Research Building, Stanford, CA 94305-5406 USA email: tassimes{at}cvmed.stanford.edu Tel: 650-498-4154 Fax: 650-725-1599
Received November 20, 2007; Revised April 18, 2008; Accepted April 18, 2008
A susceptibility locus for CAD at chromosome 9p21 has been recently reported which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent in other racial/ethnic groups by genotyping three SNPs in the risk interval in the ADVANCE study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics, and U.S. East Asians. None of the SNPs was associated with CAD in African Americans although the power to detect an OR in this group equivalent to that seen in whites was only 24% to 30%. ORs were higher in Hispanics and East Asians and lower in African Americans but in all groups the 95% confidence intervals overlapped with ORs observed in whites. The high risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (p=0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high risk allele and presenting with CAD at an age>than 50 years. Further investigations in other populations are needed to confirm or refute our findings.
The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as first authors