Abstract 402: Association of Neuropeptide Y2 Receptor Polymorphisms With Phenotypes of Left-Ventricular Hypertrophy
Left ventricular hypertrophy (LVH) is a powerful predictor of morbidity and mortality from myocardial infarction, stroke, and congestive heart failure. A significant portion of the interindividual variability of left ventricular mass is determined by genetic factors. We performed linkage analysis and identified LVH linkage regions in African American (AA) and Caucasian families and evaluated positional candidate genes in a linkage region on chromosome 4 (HyperGEN study). The Neuropeptide Y type 2 receptor gene (NPY2R) was selected for further analysis.
METHODS: We fully resequenced the NPY2R gene in 24 AA and Caucasian individuals in order to identify single nucleotide polymorphisms (SNPs) and determine the haplotype structure. Family-based association analysis was performed using the QTDT program in 470 (AA) families (n=1,085) and 274 Caucasian families (n=671).
RESULTS: We typed 10 SNPs in each population which represent 3 haplotype blocks. In AA single point association analysis showed significant associations for SNP 4199 with diastolic relative wall thickness (RWT p=0.0007) and posterior wall diameter both in M-Mode as well as 2D measurements (LVPW2D p=0.0002; PWTMM p=0.0009) in a model adjusting for age, sex and BMI. Additional markers in linkage disequilibrium also showed significant associations (P=0.01). These findings were confirmed using a haplotype analysis grouping SNPs in haplotypes based on the LD structure (r=0.8). Haplotype block B showed significant associations for RWT (p=0.006) and PWTMM (p=0.001) and LVPW2D (p=0.0014). In addition a haplotype spanning the full gene showed association with LV mass (LVMHt2.7 p<0.05). These findings were confirmed in the Caucasian sample. We detected significant associations for RWT, PWTMM and LVPW2D (each p<0.05) for SNP 4199. Functional analyses of a likely functional SNP in a transcription factor binding site in the promoter region show a significantly different activity between the two alleles. Further studies in an animal model of hypertensive LVH demonstrate that the inhibition of NPY2R ameliorates hypertensive LVH (abstract submitted to this meeting).
CONCLUSION: SNPs in the NPY2R gene are associated with LVH phenotypes. NPY2R emerges as a novel drug target for hypertensive LVH.