Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches

Cecilia Lindgren

Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches

Cecilia Lindgren

Department of Clinical Sciences, Malmö

Research output: Thesis › Doctoral Thesis (compilation)

Abstract

Type 2 diabetes mellitus is a multifactorial disorder characterized by chronic hyperglycemia resulting from pancreatic dysfunction and insulin resistance. It is a common disorder with a complex pattern of inheritance, likely to reflect the influence of multiple genetic and environmental factors on the diabetes risk. The aim of thesis was to identify genetic risk factors for type 2 diabetes. In a genome wide scan, we identified three putative type 2 diabetes susceptibility loci on chromosomes 9p13-q21, 12q24 and 17p12-q12. Five SNPs in ANXA1, on chromosome 9q21 were identified and tested for association to type 2 diabetes in using the TDT. As no significant association with diabetes was observed, we concluded that the gene is unlikely to be a type 2 diabetes susceptibility gene. We also investigated the contribution of known and unknown genetic causes in families enriched with early onset diabetes. We found that about 25% of diabetes in our families could be explained by known genetic variants. In a subsequent genome wide scan we found three putative EOD susceptibility loci on chromosomes 1p31.11, 20q11 and 22q11-13. We also looked at gene expression profiles from skeletal muscle biopsies from subjects with normal glucose tolerance compared to individuals with hyperglyceamia as well as biopsies taken before and after an euglycemic hyperinsulinemic clamp using microarrays. We identified 131 genes that show differential expression (SNR > 2) between the glycemic stages and 86 genes that show differential expression as an acute insulin response. In summary, we have identified several putative diabetes susceptibility loci and genes. In light of the large number of genetic markers available, along with new knowledge about the haplotype structure of the genome, we plan to further examine these loci and genes with extensive LD mapping in an attempt to identify and confirm genetic causes for type 2 diabetes mellitus.

Original language	English
Qualification	Doctor
Awarding Institution	Department of Clinical Sciences, Malmö
Supervisors/Advisors	[unknown], [unknown], Supervisor, External person
Award date	2002 Feb 22
Publisher	Cecilia Lindgren, UMAS ing. 46, 205 02 Malmö, Sweden,
ISBN (Print)	91-628-5043-1
Publication status	Published - 2002

Bibliographical note

Defence details

Date: 2002-02-22
Time: 09:15
Place: Medical Research Center (Jubileumsaulan), Malmö University Hospital

External reviewer(s)

Name: Peltonen, Leena
Title: Professor
Affiliation: University of Helsinki, Finland, and University of California, Los Angeles, California, USA

---

Article: I. C. M. Lindgren, M.M. Mahtani, E. Widén, M.I. McCarthy, M.J. Daly, A. Kirby, M.P. Reeve, L. Kruglyak, A. Parker, J. Meyer, P. Almgren, M. Lehto, T. Kanninen, T. Tuomi, L.C. Groop & E.S. Lander Genome wide search for type 2 diabetes mellitus susceptibility loci in Finnish families (The Botnia Study). Am J Hum Genet. 2002 Feb;70(2):509-16.II. C. M. Lindgren, A. Nilsson, M. Orho-Melander, P. Almgren & L. C. Groop. Characterization of the Annexin I gene and evaluation of its role in type 2 diabetes. Diabetes. 2001 Oct;50(10):2402-5.

Article: III. C. M. Lindgren, E. Widén, T. Tuomi, H. Li, P. Almgren, T. Kanninen, O. Melander, J. Weng, M. Lehto & L. C. Groop. Contribution of known and unknown susceptibility genes to early-onset diabetes in Scandinavia - evidence for heterogeneity. In print in Diabetes.

Article: IV. C.M. Lindgren, J. Lehar, J. Hirschorn, E. Carlsson, A. Vaag, P. Poulsen, M. Gaasenbeek, C. Ladd, K-F. Eriksson, M.J. Daly, P. Tamayo, M. Ridderstråle, E. Lander, D. Altschuler & L. Groop. Effect of glucose tolerance and insulin on gene expression profiling in human skeletal muscle. Manuscript.

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Endocrinology (013241500), Pediatrics/Urology/Gynecology/Endocrinology (013240400)

Subject classification (UKÄ)

Endocrinology and Diabetes

Free keywords

single nucleotide polymorphism (SNP)
transmission-disequilibrium test (TDT)
genetic variation
single strand conformational polymorphism (SSCP)
gene expression
insulin
glucose
genome-wide scan
linkage
genetic association
Type 2 diabetes
early onset diabetes (EOD)
sekretion
diabetologi
Endokrinologi
diabetology
Endocrinology
secreting systems
signal-to-noise ratio (SNR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@phdthesis{7a7d51bbefef431b859f9c192dfe59b2,

title = "Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches",

abstract = "Type 2 diabetes mellitus is a multifactorial disorder characterized by chronic hyperglycemia resulting from pancreatic dysfunction and insulin resistance. It is a common disorder with a complex pattern of inheritance, likely to reflect the influence of multiple genetic and environmental factors on the diabetes risk. The aim of thesis was to identify genetic risk factors for type 2 diabetes. In a genome wide scan, we identified three putative type 2 diabetes susceptibility loci on chromosomes 9p13-q21, 12q24 and 17p12-q12. Five SNPs in ANXA1, on chromosome 9q21 were identified and tested for association to type 2 diabetes in using the TDT. As no significant association with diabetes was observed, we concluded that the gene is unlikely to be a type 2 diabetes susceptibility gene. We also investigated the contribution of known and unknown genetic causes in families enriched with early onset diabetes. We found that about 25% of diabetes in our families could be explained by known genetic variants. In a subsequent genome wide scan we found three putative EOD susceptibility loci on chromosomes 1p31.11, 20q11 and 22q11-13. We also looked at gene expression profiles from skeletal muscle biopsies from subjects with normal glucose tolerance compared to individuals with hyperglyceamia as well as biopsies taken before and after an euglycemic hyperinsulinemic clamp using microarrays. We identified 131 genes that show differential expression (SNR > 2) between the glycemic stages and 86 genes that show differential expression as an acute insulin response. In summary, we have identified several putative diabetes susceptibility loci and genes. In light of the large number of genetic markers available, along with new knowledge about the haplotype structure of the genome, we plan to further examine these loci and genes with extensive LD mapping in an attempt to identify and confirm genetic causes for type 2 diabetes mellitus.",

keywords = "single nucleotide polymorphism (SNP), transmission-disequilibrium test (TDT), genetic variation, single strand conformational polymorphism (SSCP), gene expression, insulin, glucose, genome-wide scan, linkage, genetic association, Type 2 diabetes, early onset diabetes (EOD), sekretion, diabetologi, Endokrinologi, diabetology, Endocrinology, secreting systems, signal-to-noise ratio (SNR)",

author = "Cecilia Lindgren",

note = "Defence details Date: 2002-02-22 Time: 09:15 Place: Medical Research Center (Jubileumsaulan), Malm{\"o} University Hospital External reviewer(s) Name: Peltonen, Leena Title: Professor Affiliation: University of Helsinki, Finland, and University of California, Los Angeles, California, USA --- Article: I. C. M. Lindgren, M.M. Mahtani, E. Wid{\'e}n, M.I. McCarthy, M.J. Daly, A. Kirby, M.P. Reeve, L. Kruglyak, A. Parker, J. Meyer, P. Almgren, M. Lehto, T. Kanninen, T. Tuomi, L.C. Groop & E.S. Lander Genome wide search for type 2 diabetes mellitus susceptibility loci in Finnish families (The Botnia Study). Am J Hum Genet. 2002 Feb;70(2):509-16.II. C. M. Lindgren, A. Nilsson, M. Orho-Melander, P. Almgren & L. C. Groop. Characterization of the Annexin I gene and evaluation of its role in type 2 diabetes. Diabetes. 2001 Oct;50(10):2402-5. Article: III. C. M. Lindgren, E. Wid{\'e}n, T. Tuomi, H. Li, P. Almgren, T. Kanninen, O. Melander, J. Weng, M. Lehto & L. C. Groop. Contribution of known and unknown susceptibility genes to early-onset diabetes in Scandinavia - evidence for heterogeneity. In print in Diabetes. Article: IV. C.M. Lindgren, J. Lehar, J. Hirschorn, E. Carlsson, A. Vaag, P. Poulsen, M. Gaasenbeek, C. Ladd, K-F. Eriksson, M.J. Daly, P. Tamayo, M. Ridderstr{\aa}le, E. Lander, D. Altschuler & L. Groop. Effect of glucose tolerance and insulin on gene expression profiling in human skeletal muscle. Manuscript. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Endocrinology (013241500), Pediatrics/Urology/Gynecology/Endocrinology (013240400)",

year = "2002",

language = "English",

isbn = "91-628-5043-1",

publisher = "Cecilia Lindgren, UMAS ing. 46, 205 02 Malm{\"o}, Sweden,",

type = "Doctoral Thesis (compilation)",

school = "Department of Clinical Sciences, Malm{\"o}",

}

TY - THES

T1 - Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches

AU - Lindgren, Cecilia

N1 - Defence details Date: 2002-02-22 Time: 09:15 Place: Medical Research Center (Jubileumsaulan), Malmö University Hospital External reviewer(s) Name: Peltonen, Leena Title: Professor Affiliation: University of Helsinki, Finland, and University of California, Los Angeles, California, USA --- Article: I. C. M. Lindgren, M.M. Mahtani, E. Widén, M.I. McCarthy, M.J. Daly, A. Kirby, M.P. Reeve, L. Kruglyak, A. Parker, J. Meyer, P. Almgren, M. Lehto, T. Kanninen, T. Tuomi, L.C. Groop & E.S. Lander Genome wide search for type 2 diabetes mellitus susceptibility loci in Finnish families (The Botnia Study). Am J Hum Genet. 2002 Feb;70(2):509-16.II. C. M. Lindgren, A. Nilsson, M. Orho-Melander, P. Almgren & L. C. Groop. Characterization of the Annexin I gene and evaluation of its role in type 2 diabetes. Diabetes. 2001 Oct;50(10):2402-5. Article: III. C. M. Lindgren, E. Widén, T. Tuomi, H. Li, P. Almgren, T. Kanninen, O. Melander, J. Weng, M. Lehto & L. C. Groop. Contribution of known and unknown susceptibility genes to early-onset diabetes in Scandinavia - evidence for heterogeneity. In print in Diabetes. Article: IV. C.M. Lindgren, J. Lehar, J. Hirschorn, E. Carlsson, A. Vaag, P. Poulsen, M. Gaasenbeek, C. Ladd, K-F. Eriksson, M.J. Daly, P. Tamayo, M. Ridderstråle, E. Lander, D. Altschuler & L. Groop. Effect of glucose tolerance and insulin on gene expression profiling in human skeletal muscle. Manuscript. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Endocrinology (013241500), Pediatrics/Urology/Gynecology/Endocrinology (013240400)

PY - 2002

Y1 - 2002

N2 - Type 2 diabetes mellitus is a multifactorial disorder characterized by chronic hyperglycemia resulting from pancreatic dysfunction and insulin resistance. It is a common disorder with a complex pattern of inheritance, likely to reflect the influence of multiple genetic and environmental factors on the diabetes risk. The aim of thesis was to identify genetic risk factors for type 2 diabetes. In a genome wide scan, we identified three putative type 2 diabetes susceptibility loci on chromosomes 9p13-q21, 12q24 and 17p12-q12. Five SNPs in ANXA1, on chromosome 9q21 were identified and tested for association to type 2 diabetes in using the TDT. As no significant association with diabetes was observed, we concluded that the gene is unlikely to be a type 2 diabetes susceptibility gene. We also investigated the contribution of known and unknown genetic causes in families enriched with early onset diabetes. We found that about 25% of diabetes in our families could be explained by known genetic variants. In a subsequent genome wide scan we found three putative EOD susceptibility loci on chromosomes 1p31.11, 20q11 and 22q11-13. We also looked at gene expression profiles from skeletal muscle biopsies from subjects with normal glucose tolerance compared to individuals with hyperglyceamia as well as biopsies taken before and after an euglycemic hyperinsulinemic clamp using microarrays. We identified 131 genes that show differential expression (SNR > 2) between the glycemic stages and 86 genes that show differential expression as an acute insulin response. In summary, we have identified several putative diabetes susceptibility loci and genes. In light of the large number of genetic markers available, along with new knowledge about the haplotype structure of the genome, we plan to further examine these loci and genes with extensive LD mapping in an attempt to identify and confirm genetic causes for type 2 diabetes mellitus.

AB - Type 2 diabetes mellitus is a multifactorial disorder characterized by chronic hyperglycemia resulting from pancreatic dysfunction and insulin resistance. It is a common disorder with a complex pattern of inheritance, likely to reflect the influence of multiple genetic and environmental factors on the diabetes risk. The aim of thesis was to identify genetic risk factors for type 2 diabetes. In a genome wide scan, we identified three putative type 2 diabetes susceptibility loci on chromosomes 9p13-q21, 12q24 and 17p12-q12. Five SNPs in ANXA1, on chromosome 9q21 were identified and tested for association to type 2 diabetes in using the TDT. As no significant association with diabetes was observed, we concluded that the gene is unlikely to be a type 2 diabetes susceptibility gene. We also investigated the contribution of known and unknown genetic causes in families enriched with early onset diabetes. We found that about 25% of diabetes in our families could be explained by known genetic variants. In a subsequent genome wide scan we found three putative EOD susceptibility loci on chromosomes 1p31.11, 20q11 and 22q11-13. We also looked at gene expression profiles from skeletal muscle biopsies from subjects with normal glucose tolerance compared to individuals with hyperglyceamia as well as biopsies taken before and after an euglycemic hyperinsulinemic clamp using microarrays. We identified 131 genes that show differential expression (SNR > 2) between the glycemic stages and 86 genes that show differential expression as an acute insulin response. In summary, we have identified several putative diabetes susceptibility loci and genes. In light of the large number of genetic markers available, along with new knowledge about the haplotype structure of the genome, we plan to further examine these loci and genes with extensive LD mapping in an attempt to identify and confirm genetic causes for type 2 diabetes mellitus.

KW - single nucleotide polymorphism (SNP)

KW - transmission-disequilibrium test (TDT)

KW - genetic variation

KW - single strand conformational polymorphism (SSCP)

KW - gene expression

KW - insulin

KW - glucose

KW - genome-wide scan

KW - linkage

KW - genetic association

KW - Type 2 diabetes

KW - early onset diabetes (EOD)

KW - sekretion

KW - diabetologi

KW - Endokrinologi

KW - diabetology

KW - Endocrinology

KW - secreting systems

KW - signal-to-noise ratio (SNR)

M3 - Doctoral Thesis (compilation)

SN - 91-628-5043-1

PB - Cecilia Lindgren, UMAS ing. 46, 205 02 Malmö, Sweden,

ER -

Search for Type 2 Diabetes Susceptibility Genes Using Multiple Approaches

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Fingerprint

Cite this