Lack of synergism between long-term poor glycaemic control and three gene polymorphisms of the renin angiotensin system on risk of developing diabetic nephropathy in type I diabetic patients.
OBJECTIVE
Reports on a putative synergism between poor glycaemic control and carriage of the angiotensin II type 1 receptor (AGTR1) C1166-allele and risk of diabetic nephropathy have been conflicting. Therefore, we investigated the interaction between long-term glycaemic control and three polymorphisms in the genes coding for AGTR1 (A1166-->C), angiotensin converting enzyme (ACE/ID) and angiotensinogen (M235T) on risk of developing diabetic nephropathy. Furthermore, we investigated the relation between a random measurement and long-term measurements of haemoglobin A1c (HbA1c).


METHODS
We studied Caucasian patients with Type I (insulin-dependent) diabetes mellitus and nephropathy (120 men 74 women, age 41.1 +/- 9.6 years, diabetes duration 28 +/- 8 years) and long-standing Type I diabetic patients with persistent normoalbuminuria (112 men 69 women, age 42.5 +/- 10.0 years, diabetes duration 27 +/- 9 years). Genotyping was PCR-based and metabolic control estimated from all measurements of HbA1c done in each patient [average (range) n = 31 (6-74)]. The median observation time (range) was 13.5 (2-14) years.


RESULTS
Type I diabetic patients with a history of poor glycaemic control (HbA1c above the median, 8.7%) had an increased risk of diabetic nephropathy compared with patients with a better metabolic control, OR (95% CI): 9.2 (5.8-14.7). The magnitude of this risk was similar in carriers and non-carriers of the mutations. The risk of nephropathy in patients with HbA1c above compared with below the median in carriers of the mutant C1166-allele, D-allele, or T235-allele were 7.6 (95% CI: 3.9-14.8), 10.4 (6.0-17.8) and 9.8 (5.4-17.9), respectively. A significant correlation (r = 0.74, p < 0.001) existed between a random and long-term measurements of HbA1c with a small mean difference (limits of agreement) [0.2 (-1.8 to 2.1)%] between the two estimates.


CONCLUSIONS
Poor metabolic control is a major risk factor for diabetic nephropathy in Caucasian Type I diabetic patients. This risk was similar in carriers and non-carriers of the mutant alleles of the AGTR1 (A1166-->C), ACE/ID and angiotensinogen-M235T polymorphisms. The HbA1c value measured at random reflects rather closely average long-term HbA1c values.
Tarnow
L
L
Steno Diabetes Centre, Gentofte, Denmark.
Kjeld
T
T
Knudsen
E
E
Major-Pedersen
A
A
Parving
H H
HH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000419:Albuminuria; D019943:Amino Acid Substitution; D000808:Angiotensinogen / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors
D000808:Angiotensinogen; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007703:Peptidyl-Dipeptidase A; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin