Genetic variation of the heparan sulfate proteoglycan gene (perlecan gene). Association with urinary albumin excretion in IDDM patients.

Both in patients with IDDM (1) and in healthy control subjects (2,3), increased urinary albumin excretion rate (AER) is associated with high relative morbidity and mortality. In IDDM patients, genetic susceptibility factors are most likely contributing to an increased AER (4,5) resulting in a cumulative incidence of nephropathy (AER >300 mg/24 h) of -30% (6). So far, candidate genes, proposed as susceptibility markers linked to abnormal albuminuria, have been identified because of the knowledge of pathophysiological events related to diabetic nephropathy. Heparan sulfate proteoglycan (HSPG, i.e., Perlecan) constitutes an integrated part of the glomerular basement membrane. It consists of a central core protein to which anionic sulfated polysaccharide chains (heparan sulfate [HS]) are linked (7), thus contributing to the negative charge of the glomerular filtration barrier and thereby indirectly to the composition of the glomerular filtration product (8,9). In IDDM patients, it has been demonstrated that increased AER is reduced by the administration of heparin (10) most likely because of a stimulating effect on the HS synthesis (11). The aim of the present study was for the first time to identify and characterize polymorphisms within the HSPG gene (HSPG2) and subsequently evaluate a possible association between such markers and nephropathy in a case-control study design comprising large groups of Caucasian IDDM patients with and without diabetic nephropathy from Denmark and U.K. The Danish population comprised 260