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

Aims/hypothesis. 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 (A¹⁶⁶⁶→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 A(1c) (HbA(1c)). 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 HbA(1c) 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 (HbA(1c) 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 HbA(1c) 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 HbA(1c) with a small mean difference (limits of agreement) [0.2 (-1.8 to 2.1) %] between the two estimates. Conclusion/interpretation. 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 HbA (1c) value measured at random reflects rather closely average long-term HbA(1c) values.