Diabetic Nephropathy Is Associated With AGT Polymorphism T235

Abstract

Abstract-Diabetic nephropathy is a serious and frequent complication of insulin-dependent diabetes mellitus (IDDM) that has a strong genetic component. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specifically the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be introduced by unrecognized differences in the populations selected for cases and control subjects. In contrast, family-based approaches, such as the transmission/ disequilibrium test, assess whether a particular variant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own control, thereby eliminating spurious results caused by mismatched population samples. To take advantage of this study design for further investigation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free patients with long-duration IDDM, and, very importantly, parents of all these individuals. We found that among males (but not females) the T allele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (Pϭ.05). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal disease (Pϭ.04). In conclusion, results obtained in our family-based study support a role of the angiotensinogen gene M235T polymorphism, and specifically the T allele, in the development of diabetic nephropathy in IDDM. (Hypertension. 1998;31:627-631.)

Glomerular Hyperfiltration, High Renin, and Low- Extracellular Volume in High Blood Pressure

“…54,55 However, we could find no association of GFR and plasma active renin with these ACE and angiotensinogen polymorphisms or those of the renin gene. Our results do not exclude small phenotypic effects of these polymorphisms or the involvement of other polymorphisms of these or other genes.…”

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

“…The RAS is a strong candidate as prior studies have demonstrated a more consistent association between ACE and Atg gene variants with the progression of renal insufficiency in various renal diseases, compared to the initiation of renal inflammation. [24][25][26][27] The results of this study suggest that DNA sequence variation in the ACE and Atg genes significantly influences the rate of progression of renal disease, and potentially survival, in LN patients. Previous studies in LN have been limited to the ACE I/D polymorphism, and have yielded highly discordant results.…”

The C825T polymorphism in the human G-protein β3 subunit gene is not associated with diabetic nephropathy in Type I diabetes mellitus

“…The design of this study allows us to investigate the role of candidate genes involved in diabetic nephropathy susceptibility within these families without the effects of confounding due to population stratification. The use of families with a Type I diabetic offspring without nephropathy allows us to exclude excess transmission that may be seen at a Type I diabetes susceptibility locus [16]. Since we have observed no significant deviation in either families with or without diabetic nephropathy, we are confident that transmission of alleles at this polymorphism do not contribute substantially to nephropathy risk.…”

“…The role of candidate genes can also be assessed in family-based association studies [15]. We have recently reported, for the first time, the use of such a family association study in assessing candidate genes in diabetic nephropathy susceptibility [16]. The basis of this study is the transmission disequilibrium test (TDT), a powerful method to assess susceptibility alleles in the causation of polygenic disease [15,17].…”

“…The basis of this study is the transmission disequilibrium test (TDT), a powerful method to assess susceptibility alleles in the causation of polygenic disease [15,17]. A nephropathy susceptibility allele will be observed to be transmitted more often to a Type I diabetic offspring with nephropathy and less often to a Type I diabetic offspring without nephropathy [16]. The TDT is equivalent to a randomized experiment and therefore is resistant to confounding.…”