Genetic influence on diabetic kidney disease

DIABETIC KIDNEY disease (diabetic nephropathy) is a common cause of kidney failure in India. Once the kidney failure occurs, kidney transplantation is the only final solution. However, it is known that only 30 - 40 per cent of type 1 diabetics (insulin dependent diabetics) develop kidney disease after 20 - 25 years of diabetes.

A similar risk has also been reported in type 2 (Noninsulin dependent) diabetics. Therefore there seems to be a `fixed' risk of diabetic kidney disease (DKD) which suggests that genetic factors play a role in its development.

In some patients clinicians have witnessed the development of diabetic complications in patients despite near normal blood glucose control. While some others with poor diabetic control are spared. This observation raises the possibility that underlying genetic factors may increase the chances of the kidney complication. A number of studies have reported a familial clustering of diabetic kidney disease.

A study of the Pima Indians in Arizona USA reported interesting observations in type 2 diabetics. If both parents had diabetic kidney disease 45 per cent of their diabetic offspring also had the disease.If one parent alone had the disease, 22.9 per cent of the diabetic offspring had the disease, too.

Two groups of diabetic siblings of type 2 diabetic patients were compared. The first group were siblings of type 2 diabetics with kidney disease while the second group were siblings of patients without kidney disease. 50 per cent of the siblings in the first group had evidence of kidney involvement (proteinuria) compared to none in the second group. This comparison of sibling pairs matched for age, duration of diabetes and level of metabolic control showed that there was a strong familial clustering of diabetic kidney disease in South Indian type 2 diabetic patients.

ACE gene (Anglotensin Converting Enzyme gene):

In 1990, Rigat identified a potentially deleterious polymorphism known as the angiotensin converting enzyme (ACE) gene. ACE is encoded in humans by a gene located on chromosome 17 and is expressed in a wide range of tissues including lung, vascular endothelium, kidney, heart and testes.The biallelic ACE polymorphism is characterized either by the absence (deletion 'D) or presence (insertion 'I) of a 287 base pair ALU repeat sequence inside intron 16.

Studies done have demonstrated that the D allele is associated with both an increased incidence and severity of diabetic nephropathy Studies have also showed that homozygotes for the D allele (deletion allele) have a significantly reduced renal survival rate, in that there was a shorter time period from the onset of nephropathy to the necessity for renal replacement therapy.

Vijay and colleagues from Diabetes Research Centre, Chennai and Dr. Kumar Sharma and colleagues from the Thomas Jellerson University, Philadelphia, USA recently reported a signfficantly higher prevalence of the `D' allele of ACE gene among patients with diabetic nephropathy in South India.

The study was done in 109 South Indian type 2 diabetic patients of whom 86 patients had diabetic nephropathy and 23 patients had normal urine albumin (Male : Female ratio was 72 : 37, mean age 56.7 + 9.0 years). D allele was present in 80.2 per cent of nephropathy subjects and 57 per cent of normoalbuminuric subjects.

This study has shown a positive association between the `D' allele (ID and DD genotype) of the ACE polymorphism and diabetic Iddney disease in South Indian type 2 diabetic patients. Our findings are in keeping with several earlier studies showing a strong association of the D allele of the ACE gene with diabetic nephropathy.

Diabetic kidney disease appears to be influenced to some extent by genetic factors such as the ACE gene. However factors such as high blood sugar levels, hypertension, protein intake have also been shown to have a major influence on this condition.

Vijay Viswanathan

Diabetes Research Centre, Chennai

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