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Studies og genetic and non-genetic factors affecting the pathogenesis and progression of deabetic nephropathy in type 1 diabetic patients with focus on AMDA, BNP, CYP2C9 and CYP11B2

 

Maria Stenkil Lajer

Summary

The aim of this PhD thesis is to give a short introduction to genetic and non-genetic factors involved in the pathogenesis and progression of diabetic nephropathy among patients with type 1 diabetes and methods used for identifying and investigating genes involved in complex diseases such as diabetic nephropathy will be discussed. The focus will be the impact of three candidate genes, Aldosterone synthase (CYP11B2), BNP, and CYP2C9 and one biomarker (ADMA) based on my own and other relevant studies from the literature.Diabetic nephropathy is a major complication of diabetes and develops in up to 30% of patients with type 1 diabetes. Diabetic nephropathy is characterized by persistent albuminuria, increased arterial blood pressure, a relentless decline in GFR and a highly elevated risk of cardiovascular morbidity and mortality. The pathogenesis of this severe complication is still not fully understood. In addition to hyperglycemia, the activity of the renin-angiotensin-aldosterone system (RAAS) is elevated affecting blood pressure regulation, and plays an important role in the hemodynamic and non-hemodynamic pathogenic mechanisms involved in diabetic nephropathy and cardiovascular disorders. Furthermore, familial clustering and diversity between ethnic groups offers strong evidence for genetic factors being involved in the development and progression of diabetic nephropathy. Additionally, specific genetic interactions with drug response, pharmacogenetics, have shown to modulate rate of progression of already established diabetic nephropathy.The absolute number of patients with diabetic nephropathy and subsequently ESRD is increasing because of better survival and the epidemic of diabetes. Thus a growing burden exists for the health care system to identify the patients at risk of diabetic nephropathy and ESRD to aid the management of diabetes and its complications. Major risk factors for development and progression of diabetic nephropathy needs to be determined in order to generate new therapeutic targets for better therapeutic outcome and subsequently successful prevention and treatment of both diabetic nephropathy, ESRD, and CVD among patients with diabetes.In the first study, the aldosterone synthase promoter polymorphism -344T/C was examined for associations with development and progression of diabetic nephropathy as well as quantitative traits related to diabetic nephropathy in type 1 diabetes mellitus. In a population-based sample of 422 type 1 diabetic patients with overt diabetic nephropathy and 479 patients with persistent normoalbuminuria and longstanding type 1 diabetes the -344T/C variant did not associate with diabetic nephropathy. A quantitative trait analysis in normoalbuminuric patients revealed no differences in sex distribution, age, duration of diabetes, blood pressure, HbA1C, or urinary albumin excretion rate across genotypes. However, the T-allele made a statistically significant contribution to both systolic and diastolic pressure but not on rate of decline in GFR, during 6 years of follow-up among 163 type 1 diabetic patients with diabetic nephropathy treated with ACE-inhibitiors.In the second study, 197 cases with diabetic nephropathy and 183 longstanding normoalbuminuric control subjects no significant difference in allele or genotype distribution were found for the -381T/C and 1551G/A polymorphisms. However, a genotype-phenotype analysis among the 164 normoalbuminuric patients without antihypertensive or diuretic treatment and previous CVD revealed that the circulating levels of NT-proBNP were increased with approximately 50% among patients carrying either the -381CC or CT genotype compared with TT-carriers.The third study is a prospective, 11 year observational follow-up study including 397 patients with type 1 diabetes and overt diabetic nephropathy and 175 patients with longstanding normoalbuminura. Plasma ADMA levels above the median predicted fatal and non-fatal cardiovascular events even after adjustment of conventional risk factors in patients with type 1 diabetic nephropathy. Furthermore, elevated levels of ADMA tended to predict a faster decline in GFR and time to development of ESRD. Among the 175 patients with persisting normoalbuminuria, elevated ADMA levels predicted an increased overall mortality rate.In the fourth study, the *3 polymorphism of the CYP2C9 was associated with poorer systolic blood pressure response to losartan mono-therapy among 60 hypertensive type 1 diabetic patients with diabetic nephropathy. However, addition of other antihypertensive therapies resulted in a similar blood pressure lowering response and preservation of GFR in patients with or without the CYP2C9*3 allele during long-term treatment. A greater understanding of genetic factors and how they interact may increase drug efficacy, prevent or reduce adverse drug reactions, or lower the overall costs of therapy in the future.