Identification of the susceptibility genes in type 1 diabetes and diabetic nephropathy
Author: Ma, Jun
Date: 2007-11-23
Location: Rolf Luft Auditorium, L1:00, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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Abstract
Genetic susceptibility plays an important role in the pathogenesis of
type 1 diabetes (T1D) and diabetic nephropathy (DN). The present study
aims to investigate the association between single nucleotide
polymorphisms (SNPs) in candidate genes and DN. Three candidate genes,
the intercellular adhesion molecule-1 (ICAM-1), adiponectin (AdipoQ) and
neuropeptide Y (NPY), have been selected based upon the approaches: i)
from the specific chromosomal regions predicted as important for
development of DN by the previous genome wide scan and linkage studies;
ii) from the main regulatory steps in the pathways participating in
development of diabetic micro-vascular complications. The studied
subjects include 445 Swedish T1D patients with and without DN and 1282
American T1D patients with and without DN selected from the Genetics of
Kidneys in Diabetes (GoKinD) study. Genotyping experiments were performed
using dynamic allele specific hybridization (DASH). Pyrosequencing and
direct sequencing techniques were used for confirmation experiments.
Both ICAM-1 and AdipoQ genes are the strong positional and biological candidates for genetic association study in T1D and DN. We first carried out a genetic association study of the ICAM-1 gene in Swedish subjects and found that SNP rs5498 E469K(A/G) had a high heterozygous index. Frequencies of the allele G in this SNP were decreased gradually from non-diabetic controls, to T1D patients without DN and the patients with DN. Direct sequencing analysis for the subjects with high heterozygous index was performed, but no duplicon in the genomic region around the SNP was found. We further evaluated association between the ICAM-1 genetic polymorphisms and DN with the GoKinD subjects, and found that the allele G in SNP rs5498 E469K(A/G) was significantly associated with the decreased risk susceptibility of DN in female T1D patients. To evaluate the association of AdipoQ genetic polymorphisms with DN in T1D, we have identified 4 binding sites of transcriptional stimulatory protein (SP1) in the AdipoQ putative promoter. The allele G of SNP -11377C/G in the promoter altered the sequence for one of SP1 binding sites. This promoter polymorphism and its common diplotype (haplotypic genotype) constructed with this SNP and -11391G/A are found to be associated with DN in female T1D patients among the GoKinD population. Leu7Pro polymorphism in the NPY gene is found to be associated with DN and coronary heart disease in Finnish women with T1D. We replicated a genetic association study of this polymorphism in both Swedish and GoKinD subjects. The allele C frequency of Leu7Pro polymorphism in Swedish T1D was higher than in the GoKinD population. This polymorphism was found to be significantly associated with DN in Swedish female T1D patients.
The present study provides evidence that ICAM-1, AdipoQ and NPY genetic polymorphisms are associated with DN in T1D. Genetic susceptibility of the polymorphisms may be influenced by many factors, including gender specificity and ethnic stratification.
Both ICAM-1 and AdipoQ genes are the strong positional and biological candidates for genetic association study in T1D and DN. We first carried out a genetic association study of the ICAM-1 gene in Swedish subjects and found that SNP rs5498 E469K(A/G) had a high heterozygous index. Frequencies of the allele G in this SNP were decreased gradually from non-diabetic controls, to T1D patients without DN and the patients with DN. Direct sequencing analysis for the subjects with high heterozygous index was performed, but no duplicon in the genomic region around the SNP was found. We further evaluated association between the ICAM-1 genetic polymorphisms and DN with the GoKinD subjects, and found that the allele G in SNP rs5498 E469K(A/G) was significantly associated with the decreased risk susceptibility of DN in female T1D patients. To evaluate the association of AdipoQ genetic polymorphisms with DN in T1D, we have identified 4 binding sites of transcriptional stimulatory protein (SP1) in the AdipoQ putative promoter. The allele G of SNP -11377C/G in the promoter altered the sequence for one of SP1 binding sites. This promoter polymorphism and its common diplotype (haplotypic genotype) constructed with this SNP and -11391G/A are found to be associated with DN in female T1D patients among the GoKinD population. Leu7Pro polymorphism in the NPY gene is found to be associated with DN and coronary heart disease in Finnish women with T1D. We replicated a genetic association study of this polymorphism in both Swedish and GoKinD subjects. The allele C frequency of Leu7Pro polymorphism in Swedish T1D was higher than in the GoKinD population. This polymorphism was found to be significantly associated with DN in Swedish female T1D patients.
The present study provides evidence that ICAM-1, AdipoQ and NPY genetic polymorphisms are associated with DN in T1D. Genetic susceptibility of the polymorphisms may be influenced by many factors, including gender specificity and ethnic stratification.
List of papers:
I. Ma J, Möllsten A, Prázny M, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2006). "Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy." Diabet Med 23(10): 1093-9
Pubmed
II. Ma J, Zhang D, Brismar K, Efendic S, Gu HF (2007). "Further evaluation of association between ICAM-1 genetic polymorphisms and diabetic nephroapthy in American GoKinD population." (Submitted)
III. Ma J, Mollsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2007). "Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy. " J Diabetes Complications 21(1): 28-33
Pubmed
IV. Zhang D, Ma J, Brismar K, Efendic S, Gu HF (2007). "Genetic Influence of the Adiponectin Promoter polymorphisms in the patients with type 1 diabetes and diabetic nephropathy." (Submitted)
V. Ma J, Nordman S, Mollsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2007). "Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations." Eur J Endocrinol 157(5): 641-645
I. Ma J, Möllsten A, Prázny M, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2006). "Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy." Diabet Med 23(10): 1093-9
Pubmed
II. Ma J, Zhang D, Brismar K, Efendic S, Gu HF (2007). "Further evaluation of association between ICAM-1 genetic polymorphisms and diabetic nephroapthy in American GoKinD population." (Submitted)
III. Ma J, Mollsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2007). "Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy. " J Diabetes Complications 21(1): 28-33
Pubmed
IV. Zhang D, Ma J, Brismar K, Efendic S, Gu HF (2007). "Genetic Influence of the Adiponectin Promoter polymorphisms in the patients with type 1 diabetes and diabetic nephropathy." (Submitted)
V. Ma J, Nordman S, Mollsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF (2007). "Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations." Eur J Endocrinol 157(5): 641-645
Issue date: 2007-11-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-398-6
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