The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk.
OBJECTIVE
The risk of diabetic nephropathy (DN) can be increased by elevated intraglomerular pressure and glomerular filtration rate, leading to glomerular damage. This can be controlled by the renin-angiotensin-aldosterone (RAA) system, which has an important function regulating both systemic and intrarenal blood pressure. Smoking increases the risk of DN, but not all diabetic patients who smoke develop DN. There is a possibility that smoking has different effects depending on the different genotypes of the individual. We investigated the association of DN with seven polymorphisms in the RAA system and their possible interaction with smoking.


METHODS
In the present case-control study, type 1 diabetic patients with diabetes duration > or =20 years, without albuminuria and without antihypertensive treatment (n=197), were included as controls. An albumin excretion rate (AER) of 20-200 microg/min (n=73) was considered as incipient DN, and an AER >200 microg/min was considered as overt DN (n=48). Smoking habits were obtained from questionnaires.


RESULTS
Homozygosity for the A allele, of the angiotensin II type 1 receptor (AGTR1) A1166C polymorphism, was associated with increased risk of overt DN (OR=3.04; 99% CI=1.02-9.06), independently of the other associated variables: age, duration of diabetes, ever smoking, HbA1c, and sex. The effect of the AA genotype was enhanced to a four times risk increase among ever-smoking patients. Two alleles of the microsatellite marker adjacent to the angiotensinogen gene were less common among nephropathy cases than among controls, but this was not significant when controlling for the same variables as above.


CONCLUSIONS
The risk of having overt DN was increased in patients homozygous for the A1166 allele, and smoking seemed to enhance the effect of the AGTR1 genotype.
Möllsten
Anna
A
Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden. anna.mollsten@pediatri.umu.se
Kockum
Ingrid
I
Svensson
Maria
M
Rudberg
Susanne
S
Ugarph-Morawski
Anna
A
Brismar
Kerstin
K
Eriksson
Jan W
JW
Dahlquist
Gisela
G
D000328:Adult; D000419:Albuminuria / Q000652:urine; D000483:Alleles; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000652:urine; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects
D006442:Glycated Hemoglobin; D044140:Receptor, Angiotensin, Type 1