DIABETIC NEPHROPATHY IS ASSOCIATED WITH AGT POLYMORPHISM T235 - RESULTS OF A FAMILY-BASED STUDY

Diabetic nephropathy is a serious and frequent complication of insulin -dependent diabetes mellitus (IDDM) that has a strong genetic componen t. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specificall y the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be in troduced by unrecognized differences in the populations selected for c ases and control subjects. In contrast, family-based approaches, such as the transmission/disequilibrium test, assess whether a particular v ariant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own contro l, thereby eliminating spurious results caused by mismatched populatio n samples. To take advantage of this study design for further investig ation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free pati ents with long-duration IDDM, and, very importantly, parents of all th ese individuals. We found that among males (but not females) the T all ele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (P=.0 5). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal dis ease (P=.04). In conclusion, results obtained in our family-based stud y support a role of the angiotensinogen gene M235T polymorphism and sp ecifically the T allele, in the development of diabetic nephropathy in IDDM.