Adrenergic beta-1 receptor genetic variation predicts longitudinal rate of GFR decline in hypertensive nephrosclerosis

Abstract

Background: End-stage renal disease (ESRD) due to hypertension is common and displays familial aggregation in African Americans, suggesting genetic risk factors, including adrenergic activity alterations which are noted in both hypertension and ESRD.

Methods: We analysed 554 hypertensive nephrosclerosis participants (without clinically significant proteinuria) from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) African American Study of Kidney Disease and Hypertension (AASK) cohort to determine whether decline in glomerular filtration rate (GFR) over approximately 3.8 years was predicted by common genetic variation within the adrenergic beta-1 (ADRB1) receptor at non-synonymous positions Ser49Gly and Arg389Gly.

Results: The polymorphism at Ser49Gly (though not Arg389Gly, in only partial linkage disequilibrium at r(2) = 0.18) predicted the chronic rate of GFR decline, with minimal decline in Gly(49)/Gly(49) (minor allele) homozygotes compared to Ser(49) carriers; concordant results were observed for haplotypes and diploid haplotype pairs at the locus. An independent replication study in 1244 subjects from the San Diego Veterans Affairs Hypertension Cohort confirmed that Gly(49)/Gly(49) homozygotes displayed the least rapid decline of eGFR over approximately 3.6 years.

Conclusion: We conclude that GFR decline rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway, particularly at ADRB1. The results suggest novel strategies to approach the role of the adrenergic system in the risk and treatment of progressive renal disease.

Fig. 1

Pictoral depiction of human adrenergic beta-1 receptor (ADRB1) gene. The illustration shows the only two common (minor allele frequency >5%) non-synonymous polymorphisms found in humans: Ser49Gly and Arg389Gly. Based on <www.gpcr.org>.

Fig. 2

Adrenergic beta-1 receptor (ADRB1) genetic variants: Effects on chronic glomerular filtration (GFR) decline rate in the NIDDK AASK cohort. AASK subjects without clinically significant proteinuria (urine protein/creatinine ratio <0.22 g/g) were evaluated. Analyses were performed by univariate ANOVA. Model shown is unadjusted without covariates, but Table 3 notes that there were no significant differences in the models which include covariates. [Model 1: sex and age at start of study; Model 2: baseline GFR and urine protein: creatinine ratio (UPCR); Model 3: baseline GFR, baseline UPCR, age at start, sex, randomization blood pressure goal and drug]. (A) ADRB1 polymorphism, Ser49Gly. Minor allele homozygosity (Gly₄₉/Gly₄₉) predicted a slower decline of GFR compared to wild-type (Ser₄₉/Ser₄₉) or heterozygous (Ser₄₉/Gly₄₉) genotype, unadjusted P = 0.003. (B) ADRB1 haplotype across Ser49Gly→Arg389Gly. Subjects with two copies of haplotype 3 (Gly₄₉Arg₃₈₉) had a slower decline in GFR compared to those with zero or one copy, unadjusted P = 0.002. (C) ADRB1 diploid haplotype: haplotype-3 (Gly₄₉Arg₃₈₉) and haplotype-1 (Ser₄₉Gly₃₈₉). Homozygotes for haplotype-3 (Gly₄₉Arg₃₈₉) had a slower decline in GFR compared with those with one or two copies of haplotype-1 (Ser₄₉Gly₃₈₉), unadjusted P = 0.001. (D) ADRB1 diploid haplotype: haplotype-3 (Gly₄₉Arg₃₈₉) and haplotype-2 (Ser₄₉Arg₃₈₉). Homozygotes for haplotype-3 (Gly₄₉Arg₃₈₉) had a slower decline in GFR compared with those with one or two copies of haplotype-2 (Ser₄₉Arg₃₈₉), unadjusted P = 0.014.

Fig. 3

Replication of adrenergic beta-1 receptor (ADRB1) genotype: Effects on estimated glomerular filtration (eGFR) decline rate in the San Diego Veterans Affairs Hypertension Cohort. ADRB1 Ser49Gly polymorphism predicts the longitudinal decline in eGFR (P = 0.043), adjusted for sex, age at the start of the study and race. The P-value for genotype-by-time interaction on eGFR is determined by linear mixed model analysis. eGFR decline (mL/min/1.73 m²/year) is plotted on the Y-axis and time in weeks from start of study is plotted on the X-axis. The mean function was plotted by genotype using an adaptive regression cubic spline approach [38], with 95% confidence intervals (dashed lines) for fitted curves. The mean curve for Ser₄₉/Ser₄₉ (solid black line), Ser₄₉/Gly₄₉ (dark grey line) and Gly₄₉/Gly₄₉ (dashed grey line) are plotted and show a similar pattern to the AASK cohort, in that Gly₄₉/Gly₄₉ (minor allele) homozygotes display the slowest decline in eGFR over time.