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Abstract 335: Allelic Imbalance at the Coronary Heart Disease Associated Locus 6q23.2 Identifies Causal Variation in the TCF21 Gene

Recent genome-wide association studies have identified novel loci associated with coronary heart disease (CHD). One locus identified through the large-scale Coronary ARtery DIsease Genome wide Replication And Meta-analysis (CARDIoGRAM) study is located on chromosome 6 at q23.2, within the locus encoding the basic helix-loop-helix (bHLH) transcription factor TCF21. This class of transcription factors is well known to regulate cell fate decisions that are critical for embryonic developmental and disease-related pathways, and TCF21 expression has been shown to mark progenitor cells that give rise to the coronary circulation. Six of the most highly associated SNPs in the CARDIoGRAM study are correlated expression quantitative trait loci (eQTL) for TCF21, identifying this as the causal gene. To enable further study of the mechanisms by which allelic variation at 6q23.2 regulates TCF21 expression, we have pursued studies to identify which of the CHD-associated SNPs is causal. The best approach is to investigate allelic-expression imbalance, to compare the relative levels of expression of the two alleles in subjects heterozygous for SNPs in the coding region and then relating any observed imbalance to the genotype at associated SNPs. Peripheral blood samples from the GenePAD study have been used for the isolation of both genomic DNA and white blood cell total RNA, and allelic imbalance determined by Taqman genotyping assays at rs12190287. We identified a significant difference in allele expression in 13 heterozygous Caucasian subjects, with a normalized mean Taqman CT value from the disease major allele (C) to be 2.35, and 1.94 for the minor protective allele (G), P <0.0001. These data are consistent with disease association related to decreased TCF21 expression, and are consistent with rs12190287 being the disease-associated variation in this locus.