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Genetics of complications in patients with type 2 diabetes

Alkayyali, Sami LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:26.
Abstract (Swedish)
Popular Abstract in English

Type 2 diabetes (T2D) is a polygenic disorder characterized by impaired insulin secretion or insulin action in which genes interact with the environment to cause the disease. T2D represent 90% of all patients with diabetes. The disease is increasing globally, with an estimated prevalence of 592 million affected by 2035. According to World Health Organization records, approximately 80% of diabetes-related mortality occurs in low- and middle-income countries.

The disease is associated with devastating complications such as chronic microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary heart disease and stroke) consequences.

Hyperglycaemia and duration... (More)
Popular Abstract in English

Type 2 diabetes (T2D) is a polygenic disorder characterized by impaired insulin secretion or insulin action in which genes interact with the environment to cause the disease. T2D represent 90% of all patients with diabetes. The disease is increasing globally, with an estimated prevalence of 592 million affected by 2035. According to World Health Organization records, approximately 80% of diabetes-related mortality occurs in low- and middle-income countries.

The disease is associated with devastating complications such as chronic microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary heart disease and stroke) consequences.

Hyperglycaemia and duration of disease were considered the strongest risk factors for development of diabetic complications. Prospective studies have demonstrated that some patients with T2D experience complications despite well-controlled blood glucose levels, whereas some patients with uncontrolled blood glucose levels with long disease duration do not experience any complications. These observations suggest that genetic factors might be operative in the predisposition to diabetic complications. Also, family studies have reported 50% heritability for ischemic heart disease, 36% to 75% for diabetes nephropathy, and 52% for diabetes retinopathy.

Our study aimed to (1) identify genetic markers associated with diabetic complications among patients with T2D, and (2) examine exposure of famine as a risk factor for progression to diabetes complications using susceptibility loci for cardiometabolic traits in T2D patients from Ukraine (a population with a high risk for cardiovascular disease).

We have identified a genetic locus in the HMGA2 gene for association with DN and declined kidney function. Also, we identified a variant in the KCNJ11 gene to be associated with increased risks for all-cause and cardiovascular mortality among patients with T2D. Our data demonstrated a shared genetic susceptibility between microvascular and macrovascular complications in a Ukrainian population. Furthermore, the data suggest that famine exposure in early life can modify the risk for diabetes complications in adulthood. (Less)
Abstract
Type 2 diabetes (T2D) is a polygenic disease caused by an interaction between genetic and environmental factors such as low physical activity, smoking, and obesity. The disease is associated with devastating chronic microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary heart disease and stroke) complications. Genome-wide associated studies (GWASs) have been an unbiased and successful approach to identify genetic susceptibility loci for T2D. The overall aim of this thesis was to explore whether variants influencing T2D and/or cardiometabolic traits were also associated with an increased risk for diabetes complications. The additional aim was to investigate the effect of famine exposure and genetic... (More)
Type 2 diabetes (T2D) is a polygenic disease caused by an interaction between genetic and environmental factors such as low physical activity, smoking, and obesity. The disease is associated with devastating chronic microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary heart disease and stroke) complications. Genome-wide associated studies (GWASs) have been an unbiased and successful approach to identify genetic susceptibility loci for T2D. The overall aim of this thesis was to explore whether variants influencing T2D and/or cardiometabolic traits were also associated with an increased risk for diabetes complications. The additional aim was to investigate the effect of famine exposure and genetic susceptibility loci for the development of diabetes complications in patients with T2D from Ukraine, a population with a high risk for cardiovascular diseases. Results from the present studies suggested shared genetic susceptibility between T2D and the development of diabetes complications for a number of loci including variants in the HMGA2, KCNJ11, and GIPR. Furthermore, our results suggest that the link between famine exposure and diabetes complications may involve genomic regions regulating immune response (PIK3GC), nutrient sensing (PPARG), stress (ADRA2A), imprinting (KCNQ1), and organ development (HNF1A, ELMO1, DYNQL11).

In summary, studies presented in this thesis provide an important contribution to the field of genetics of diabetes and its complications. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Johansson, Stefan, University of Bergen, Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
genetics, genome-wide association studies, type 2 diabetes, diabetes complications.
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:26
pages
158 pages
publisher
Department of Clinical Sciences, Lund University
defense location
CRC Aula
defense date
2015-02-20 09:00
ISSN
1652-8220
ISBN
978-91-7619-105-7
language
English
LU publication?
yes
id
b2a5d618-6400-4e83-8fec-530fca7f5e0b (old id 5101359)
date added to LUP
2015-02-24 12:08:15
date last changed
2016-09-19 08:44:50
@phdthesis{b2a5d618-6400-4e83-8fec-530fca7f5e0b,
  abstract     = {Type 2 diabetes (T2D) is a polygenic disease caused by an interaction between genetic and environmental factors such as low physical activity, smoking, and obesity. The disease is associated with devastating chronic microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary heart disease and stroke) complications. Genome-wide associated studies (GWASs) have been an unbiased and successful approach to identify genetic susceptibility loci for T2D. The overall aim of this thesis was to explore whether variants influencing T2D and/or cardiometabolic traits were also associated with an increased risk for diabetes complications. The additional aim was to investigate the effect of famine exposure and genetic susceptibility loci for the development of diabetes complications in patients with T2D from Ukraine, a population with a high risk for cardiovascular diseases. Results from the present studies suggested shared genetic susceptibility between T2D and the development of diabetes complications for a number of loci including variants in the HMGA2, KCNJ11, and GIPR. Furthermore, our results suggest that the link between famine exposure and diabetes complications may involve genomic regions regulating immune response (PIK3GC), nutrient sensing (PPARG), stress (ADRA2A), imprinting (KCNQ1), and organ development (HNF1A, ELMO1, DYNQL11). <br/><br>
In summary, studies presented in this thesis provide an important contribution to the field of genetics of diabetes and its complications.},
  author       = {Alkayyali, Sami},
  isbn         = {978-91-7619-105-7},
  issn         = {1652-8220},
  keyword      = {genetics,genome-wide association studies,type 2 diabetes,diabetes complications.},
  language     = {eng},
  pages        = {158},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetics of complications in patients with type 2 diabetes},
  volume       = {2015:26},
  year         = {2015},
}