P-198 MP-2: Polymorphisms at the chromogranin A and B loci are risk factors for hypertensive end-stage renal disease in African Americans

Chomogranins A (CHGA) and B (CHGB), soluble, acidic proteins stored in neuroendocrine secretory vesicles, are differentially expressed in genetic hypertension, both human and rodent. Since hypertensive end-stage renal disease (HT-ESRD) is far more prevalent in African Americans than in the general population, we examined whether common polymorphisms at CHGA/B predict HT-ESRD in blacks. We genotyped 24 CHGA/B single nucleotide polymorphisms (SNPs) in n=58 blacks with a diagnosis of HT-ESRD, and n=150 non-disease black controls. Three genomic regions were associated with HT-ESRD: 2 at CHGA and 1 at CHGB. In the CHGA promoter region G-462A→T-415C→C-89A, ATC was more frequent in the HT-ESRD group (OR=2.29; 95% CI: 1.00–5.24). The second ESRD-associated CHGA haplotype spanned a portion of the coding region: G8540C[Glu246Asp]→C9610T[Arg381Trp]→G12602C. This region contained 2 haplotypes acting in opposing fashion: the CCG haplotype conferred risk of HT-ESRD (OR=2.78; 95% CI: 1.14–7.81), while the GCC was protective (OR=0.21; 95% CI: 0.07–0.65). In CHGB region C10501T→A11727G[Glu348Glu], the CA haplotype was protective against development of HT-ESRD (OR= 0.34; 95% CI: 0.16–0.70). The coding haplotypes of CHGA were associated with a proximate biochemical phenotype (p=0.024): a progressive rise in CHGA116–439 from subjects with the protection haplotype (GCC), through the reference group, to the risk haplotype (CCG) group. Thus, the risk haplotype activated gene expression in vivo, while the protection diminished expression. A similar trend was seen with CHGB. In conclusion, common variants at both CHGA/B appear to be associated with risk of HT-ESRD in African Americans. These haplotypes were also associated with altered plasma levels of CHGA/B peptide fragments, consistent with augmented chromaffin granule biogenesis and sympathetic nervous hyperactivity by the risk variants. The results indicate that common genetic variants in the catecholamine storage and release pathway confer risk of HT-ESRD, and suggest novel approaches for prediction, diagnosis, and treatment of this disorder.