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NDT Advance Access published online on September 10, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp471
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Maple M. Fung1,*, Yuqing Chen2,*,$, Michael S. Lipkowitz3,*, Rany M. Salem1,4, Vibha Bhatnagar5, Manjula Mahata1, Caroline M. Nievergelt6, Fangwen Rao1, Sushil K. Mahata1, Nicholas J. Schork4, Victoria H. Brophy7, Daniel T. O’Connor1 and for the AASK Co-Investigators

1 Department of Medicine, University of California, San Diego, and San Diego Veterans Affairs Healthcare System, La Jolla, CA, USA 2 Renal Division, Peking University First Hospital, Beijing, China 3 Renal Division, Mount Sinai School of Medicine, New York, NY 4 Department of Molecular and Experimental Medicine, The Scripps Research Institute 5 Department of Family and Preventive Medicine 6 Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA 7 Department of Human Genetics, Roche Molecular Systems, Inc., Pleasanton, CA, USA

Correspondence and offprint requests to: Daniel T. O’Connor; E-mail: doconnor{at}ucsd.edu



  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 ~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 r2 = 0.18) predicted the chronic rate of GFR decline, with minimal decline in Gly49/Gly49 (minor allele) homozygotes compared to Ser49 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 Gly49/Gly49 homozygotes displayed the least rapid decline of eGFR over ~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.

Keywords: AASK; African Americans; glomerular filtration rate; kidney disease; sympathetic nervous system

* These co-first authors contributed equally.

$ Supported by a fellowship from the International Society of Nephrology.

Received for publication: 25. 6.09
Accepted in revised form: 17. 8.09


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