Genetic, Epigenetic and Clinical Studies of Diabetes and Diabetic Nephropathy

Diabetes has become epidemic worldwide. In 2015, 415 million people had diabetes, and by 2040 this number will rise to 642 million. The diabetes patients often develop diabetic nephropathy (DN). This complication is the single most common cause of end stage renal disease (ESRD), a condition which requires treatment with dialysis or kidney transplantation. The treatment costs of patients with DN are increasing and impose a substantial burden on the healthcare system. Currently, the urinary albumin excretion (UAE) rate is used as biomarker for predicting DN. This marker, however, is a late predictor and therefore less useful for the early diagnosis needed in prevention programs targeting DN. Therefore, it is important to discover new biomarkers for early diagnosis and prediction of DN.

Identifying new targets and testing them in phase II clinical trials are two key steps in the development of new biomarkers and/or drugs in DN, and programs based upon information from genetic study and molecular genome analysis are most likely to be successful. In the recent 15 years, we have done genetic, epigenetic and clinical studies of DN. Based upon these studies and surveys of public databases we have selected several candidates for our further study. We have collected well-characterized cohorts of non-diabetic control subjects and diabetes patients with and without DN. We will determine plasma levels of the candidates in the subjects of non-diabetic control, diabetes patients without DN and the patients with DN by using new methodologies such as proximity ligation assay. In parallel, we identify the functional DNA polymorphisms in the protein coding genes and analyze concentrations of the corresponding protein products according to the genotypes. We also perform replication and prospective studies. This translation research aims to evaluates the candidates that could serve as new biomarkers for predicting DN and is expected to lead to development of specific protocols and/or kits that can be applied in the practical diabetes care for instance by early diagnosis and as part of prevention programs.


Selected publications:

1: Abu Seman N, Anderstam B, Wan Mohamud WN, Östenson CG, Brismar K, Gu HF. Genetic, epigenetic and protein analyses of intercellular adhesion molecule 1 in Malaysian subjects with type 2 diabetes and diabetic nephropathy. J Diabetes Complications. 2015 29(8):1234-9.

2: Abu Seman N, He B, Ojala JR, Wan Mohamud WN, Östenson CG, Brismar K, Gu HF. Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy. Am J Nephrol. 2014 40(5):408-16.

3: Gu T, Falhammar H, Gu HF, Brismar K. Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy. Clin Epigenetics. 2014 6(1):10.

4: Abu Seman N, Witasp A, Wan Mohamud WN, Anderstam B, Brismar K, Stenvinkel P, Gu HF. Evaluation of the association of plasma pentraxin 3 levels with type 2 diabetes and diabetic nephropathy in a Malay population. J Diabetes Res. 2013 298019.

5: Gu HF, Zheng X, Abu Seman N, Gu T, Botusan IR, Sunkari VG, Lokman EF, Brismar K, Catrina SB. Impact of the hypoxia-inducible factor-1 α (HIF1A) Pro582Ser polymorphism on diabetes nephropathy. Diabetes Care. 2013 36(2):415-21.

6: Sandholm N, Salem RM, McKnight AJ … Gu HF … Maxwell AP. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. 2012 8(9):e1002921.

7: Gu T, Horová E, Möllsten A, Seman NA, Falhammar H, Prázný M, Brismar K, Gu HF. IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy. J Diabetes Complications. 2012 26(5):393-8.

8: Zhang D, Gu T, Forsberg E, Efendic S, Brismar K, Gu HF. Genetic and functional effects of membrane metalloendopeptidase on diabetic nephropathy development. Am J Nephrol. 2011 34(5):483-90.

9: Gu HF, Alvarsson A, Efendic S, Brismar K. SOX2 has gender-specific genetic effects on diabetic nephropathy in samples from patients with type 1 diabetes mellitus in the GoKinD study. Gend Med. 2009 6(4):555-64.

10: Zhang D, Freedman BI, Flekac M, Santos E, Hicks PJ, Bowden DW, Efendic S, Brismar K, Gu HF. Evaluation of genetic association and expression reduction of TRPC1 in the development of diabetic nephropathy. Am J Nephrol. 2009 29(3):244-51.

11: Zhang D, Ma J, Brismar K, Efendic S, Gu HF. A single nucleotide polymorphism alters the sequence of SP1 binding site in the adiponectin promoter region and is associated with diabetic nephropathy among type 1 diabetic patients in the Genetics of Kidneys in Diabetes Study. J Diabetes Complications. 2009 23(4):265-72.

12: Ma J, Nordman S, Möllsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF. Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type  1 diabetes and diabetic nephropathy among Swedish and American populations. Eur J Endocrinol. 2007 157(5):641-5.

13: Ma J, Möllsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF. Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy. J Diabetes Complications. 2007 21(1):28-33.

14: Gu HF, Abulaiti A, Ostenson CG, Humphreys K, Wahlestedt C, Brookes AJ, Efendic S. Single nucleotide polymorphisms in the proximal promoter region of the adiponectin (APM1) gene are associated with type 2 diabetes in Swedish caucasians. Diabetes. 2004 53 Suppl 1:S31-5.

15: Gu HF, Efendic S, Nordman S, Ostenson CG, Brismar K, Brookes AJ, Prince JA. Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes. 2004 53(8):2137-42.