Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.
BACKGROUND
African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease.


METHODS
We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 +/- 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 x 3 block design: to intensively lowered (MAP < or = 92 mm Hg) versus 'usual' (MAP = 102-107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus.


RESULTS
Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowly in individuals with haplotype-1 (-804G-->173T-->16Gly-->27GIn), and faster in those who carried haplotype-3 (-804G-->173T-->16Arg-->27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001-0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks.


CONCLUSIONS
The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.
Chen
Yuqing
Y
Renal Division, Peking University First Hospital, Beijing, China.
Lipkowitz
Michael S
MS
Salem
Rany M
RM
Fung
Maple M
MM
Bhatnagar
Vibha
V
Mahata
Manjula
M
Nievergelt
Caroline M
CM
Rao
Fangwen
F
Mahata
Sushil K
SK
Schork
Nicholas J
NJ
Hicks
Pamela J
PJ
Bowden
Donald W
DW
Freedman
Barry I
BI
Brophy
Victoria H
VH
O'Connor
Daniel T
DT
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018450:Disease Progression; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009400:Nephrosclerosis / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D055815:Young Adult
D000959:Antihypertensive Agents; D018343:Receptors, Adrenergic, beta-2