Genetic analysis of candidate susceptibility genes for type 1 diabetes
Author: Asad, Samina
Date: 2012-10-26
Location: CMM, Föreläsningssalen L8:00
Time: 09.30
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
Abstract
Type 1 diabetes (T1D) is a complex disease where the pancreatic β-cells are destroyed in an autoimmune attack. For the patients, this leads to lifelong daily insulin treatment and increased risk for various kinds of complications. It is thought that both environmental as well as genetic factors act in concert to cause T1D. The Human Leukocyte Antigen (HLA) region located on chromosome 6 accounts for about 50% of the genetic risk to develop T1D. Several other genes are also known to contribute to disease risk.
Paper I: Previous publications indicate that the programmed cell death 1 (PDCD1) gene (chr.2) is associated to various autoimmune diseases. PDCD1 is involved in maintaining self tolerance. The aim of our study was to test the involvement of the PDCD1 gene in T1D susceptibility. However, when two separate Swedish cohorts were analyzed no association or linkage was found between T1D and the PDCD1 gene. Nor did we observe any association in a meta-analysis with a previous study reporting association between PDCD1 and T1D.
Paper II: We have in a previous study observed suggestive linkage to the chromosome 5p13-q13 region in Scandinavian T1D families. This region showed stronger evidence of linkage, when only the Swedish families were investigated. Genotyping of more than 70 markers in the Swedish families revealed two associated candidate genes: 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A) and ringfinger protein 180 (RNF180). Association of both genes has been confirmed by us in Danish families. The two genes are in strong linkage disequilibrium with each other. However conditional analysis data suggest that HTR1A may be most strongly associated. Further, we report that HTR1A is expressed in human β-cells and α-cells.
Paper III: The class II transactivator (CIITA) gene (chr.16) is crucial for MHC II gene regulation and has been reported to associate with susceptibility to a number of complex diseases. By genotyping SNPs in Swedish T1D cohorts and the combined control material from previous studies of CIITA we have observed significant difference in the genotype distribution for three markers in CIITA with respect to age, in the collected control material. This phenomenon was confirmed in an independent control material. After adjusting for age we detect association to T1D for two markers in our T1D material. Further, we observed interaction between markers in CIITA and the protective HLA DR15 haplotype. These findings suggest that a polymorphism in the CIITA gene area may be associated with type 1 diabetes susceptibility. Importantly, results also suggest that control groups should be properly matched for the cases.
Paper IV: In complex diseases genes seldom act alone in disease susceptibility. Instead it is thought that genes may interact with each other. The aim of our investigation was to study the interaction of the most significantly associated genes in T1D (HLA-DRB1, HLA-DQB1, INS and PTPN22). This was done by comparing four different models for studying interaction; multiplicative and additive interaction models, Multifactor dimensionality reduction (MDR) model and Bayesian Networks (BN) model. Results indicate several interaction terms mainly in the additive model. Further, we show that the additive interaction model has the strongest prediction accuracy rate indicating that this is the model of preference.
In summary, in order to better understand the cause of T1D the aim of this thesis was to identify single genes as well as gene-gene interactions which may influence the risk of T1D development.
Paper I: Previous publications indicate that the programmed cell death 1 (PDCD1) gene (chr.2) is associated to various autoimmune diseases. PDCD1 is involved in maintaining self tolerance. The aim of our study was to test the involvement of the PDCD1 gene in T1D susceptibility. However, when two separate Swedish cohorts were analyzed no association or linkage was found between T1D and the PDCD1 gene. Nor did we observe any association in a meta-analysis with a previous study reporting association between PDCD1 and T1D.
Paper II: We have in a previous study observed suggestive linkage to the chromosome 5p13-q13 region in Scandinavian T1D families. This region showed stronger evidence of linkage, when only the Swedish families were investigated. Genotyping of more than 70 markers in the Swedish families revealed two associated candidate genes: 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A) and ringfinger protein 180 (RNF180). Association of both genes has been confirmed by us in Danish families. The two genes are in strong linkage disequilibrium with each other. However conditional analysis data suggest that HTR1A may be most strongly associated. Further, we report that HTR1A is expressed in human β-cells and α-cells.
Paper III: The class II transactivator (CIITA) gene (chr.16) is crucial for MHC II gene regulation and has been reported to associate with susceptibility to a number of complex diseases. By genotyping SNPs in Swedish T1D cohorts and the combined control material from previous studies of CIITA we have observed significant difference in the genotype distribution for three markers in CIITA with respect to age, in the collected control material. This phenomenon was confirmed in an independent control material. After adjusting for age we detect association to T1D for two markers in our T1D material. Further, we observed interaction between markers in CIITA and the protective HLA DR15 haplotype. These findings suggest that a polymorphism in the CIITA gene area may be associated with type 1 diabetes susceptibility. Importantly, results also suggest that control groups should be properly matched for the cases.
Paper IV: In complex diseases genes seldom act alone in disease susceptibility. Instead it is thought that genes may interact with each other. The aim of our investigation was to study the interaction of the most significantly associated genes in T1D (HLA-DRB1, HLA-DQB1, INS and PTPN22). This was done by comparing four different models for studying interaction; multiplicative and additive interaction models, Multifactor dimensionality reduction (MDR) model and Bayesian Networks (BN) model. Results indicate several interaction terms mainly in the additive model. Further, we show that the additive interaction model has the strongest prediction accuracy rate indicating that this is the model of preference.
In summary, in order to better understand the cause of T1D the aim of this thesis was to identify single genes as well as gene-gene interactions which may influence the risk of T1D development.
List of papers:
I. Samina. Asad, P. Nikamo, C. Törn, M. Landin-Olsson, Å. Lernmark, M. Alarcón-Riquelme, I. Kockum, Diabetes Incidence in Sweden Study Group. No evidence of association of the PDCD1 gene with Type 1 diabetes. Diabetic Medicine. 2007, 24, 1473-1477.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Samina. Asad, P. Nikamo, A. Gyllenberg, H. Bennet, O. Hansson, N. Wierup, Diabetes Incidence in Sweden Study Group, A. Carlsson, G. Forsander, S-A. Ivarsson, H. Larsson, Å. Lernmark, B. Lindblad, J. Ludvigsson, C. Marcus, K. S Rønningen, J. Nerup, F. Pociot, H. Luthman, M. Fex, I. Kockum. HTR1A a novel type 1 diabetes susceptibility gene on chromosome 5p13- q13. Plos ONE. 2012, vol. 7, Issue 5, e35439.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. A. Gyllenberg, Samina. Asad, F. Piehl, M. Swanberg, L. Padyukov, B. Van Yserloo, E. A Rutledge, B. McNeney, J. Graham, M. Orho-Melander, E. Lindholm, C. Graff, C. Forsell, K. Åkesson, M. Landin-Olsson, A. Carlsson, G. Forsander, S-A. Ivarsson, H. Larsson, B. Lindblad, J. Ludvigsson, C. Marcus, Å. Lernmark, L. Alfredsson, K. Åkesson, T. Olsson, I. Kockum for the Swedish Childhood Diabetes Study Group, the Diabetes Incidence in Sweden Study Group, and the Better Diabetes Diagnosis Study group. Age Dependent Variation of Genotypes in Major Histocompatibility Complex Class II Transactivator in Controls and Association to Type 1 Diabetes. [Accepted]
Pubmed
View record in Web of Science®
IV. Samina. Asad, H. Westerlind, P. Nikamo, L. Goop, A. Carlsson, C. Marcus, J. Ludvigsson, Å. Lernmark, S-A. Ivarsson, H. Larsson, G. Forsander, B. Lindblad, H. Källberg, T. Koski, I. Kockum for the Swedish Childhood Diabetes Study Group and the Diabetes Incidence in Sweden Study Group. Investigation of interaction between DRB1*04-DQA1*03:01- DQB1*03:02, DRB1*03-DQA1*05:01-DQB1*02:01, DRB1*15- DQA1*01:02-DQB1*06:02, Insulin and PTPN22 using four different interaction models. [Manuscript]
I. Samina. Asad, P. Nikamo, C. Törn, M. Landin-Olsson, Å. Lernmark, M. Alarcón-Riquelme, I. Kockum, Diabetes Incidence in Sweden Study Group. No evidence of association of the PDCD1 gene with Type 1 diabetes. Diabetic Medicine. 2007, 24, 1473-1477.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Samina. Asad, P. Nikamo, A. Gyllenberg, H. Bennet, O. Hansson, N. Wierup, Diabetes Incidence in Sweden Study Group, A. Carlsson, G. Forsander, S-A. Ivarsson, H. Larsson, Å. Lernmark, B. Lindblad, J. Ludvigsson, C. Marcus, K. S Rønningen, J. Nerup, F. Pociot, H. Luthman, M. Fex, I. Kockum. HTR1A a novel type 1 diabetes susceptibility gene on chromosome 5p13- q13. Plos ONE. 2012, vol. 7, Issue 5, e35439.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. A. Gyllenberg, Samina. Asad, F. Piehl, M. Swanberg, L. Padyukov, B. Van Yserloo, E. A Rutledge, B. McNeney, J. Graham, M. Orho-Melander, E. Lindholm, C. Graff, C. Forsell, K. Åkesson, M. Landin-Olsson, A. Carlsson, G. Forsander, S-A. Ivarsson, H. Larsson, B. Lindblad, J. Ludvigsson, C. Marcus, Å. Lernmark, L. Alfredsson, K. Åkesson, T. Olsson, I. Kockum for the Swedish Childhood Diabetes Study Group, the Diabetes Incidence in Sweden Study Group, and the Better Diabetes Diagnosis Study group. Age Dependent Variation of Genotypes in Major Histocompatibility Complex Class II Transactivator in Controls and Association to Type 1 Diabetes. [Accepted]
Pubmed
View record in Web of Science®
IV. Samina. Asad, H. Westerlind, P. Nikamo, L. Goop, A. Carlsson, C. Marcus, J. Ludvigsson, Å. Lernmark, S-A. Ivarsson, H. Larsson, G. Forsander, B. Lindblad, H. Källberg, T. Koski, I. Kockum for the Swedish Childhood Diabetes Study Group and the Diabetes Incidence in Sweden Study Group. Investigation of interaction between DRB1*04-DQA1*03:01- DQB1*03:02, DRB1*03-DQA1*05:01-DQB1*02:01, DRB1*15- DQA1*01:02-DQB1*06:02, Insulin and PTPN22 using four different interaction models. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Kockum, Ingrid
Issue date: 2012-09-25
Rights:
Publication year: 2012
ISBN: 978-91-7457-842-3
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