The genetic bases BY Casey Jaroche Diabetes The genetic bases BY Casey Jaroche

Stats and Facts 7.8% of people in the US have diabetes (23.6 million people) 7th leading cause of death in US 2006 was diabetes Estimated diabetes costs in the US in 2007 was $174 billion 1.6 million new cases of diabetes diagnosed in 2007 Center for Disease Control and Prevention (2007)

Key Terms HLA -Human Leucocyte Antigen NIMA -Non-Inherited Maternal Antigen T1D -Type 1 Diabetes T2D -Type 2 Diabetes MHC -Major Histocompatibility Complex T-cells -antigen and immune cells IDDM -Insulin Dependent Diabetes Mellitus INS -The Insulin Gene MODY -Maturity Onset Diabetes in the Young VNTR -Variable Number Tandem Repeats DR-3 -an HLA haplotype, frequently associated with autoimmune diseases DR-4 -an HLA haplotype, frequently associated with autoimmune diseases

Diagrams of T1D and T2D www.dev.nsta.org/evwebs/1150/presenttech.htm

Differences between T1D and T2D Type One Diabetes T1D Type Two Diabetes T2D The body’s immune system destroys pancreatic beta cells. Cells do not use insulin properly Patients need insulin delivered by injection or pump Patients need a controlled diet, regular exercise, medication 5-10% of diagnosed cases 90-95% of diagnosed cases Risk factors: genetic, age, obesity, race/ ethnicity Risk factors: genetic, autoimmune, environmental Rich, 2009

Background of Type 1 Diabetes Autoimmune disorder Inherited risk Environmental factors 18 regions of the genome are linked with diabetes risk Horenstein, 2004

Diabetes Susceptibility Loci Dean, 2004

IDDM1 Contains the HLA Genes HLA genes encode MHC proteins found on the surface of cells They help the immune system distinguish between its own cells and bad cells HLA genes are found on chromosome 6 within the IDDM1 region Two classes of MHC proteins; antigens and immune cells (T cells) In healthy bodies T cells bind to chains from infectious organisms Diabetes occurs when HLA genes tell the T cells to bind to body’s healthy cells The diabetes linked HLA genes are call DR3 and DR4 DR3 and DR 4 are found in 95% of people with T1D Dean, 2004

IDDM2 Contains the Insulin Gene Mutation of INS causes a rare form of diabetes INS is the only gene that produces insulin VNTR is a variable number tandem repeat 3 classes of VNTR Class I has 26-63 repeats Class II has around 80 repeats Class III has 141-209 repeats Class I is associated with a high risk for diabetes Class III is associated with protection against diabetes VNTR affects the transcription of the insulin gene Dean, 2004

2008 Study of HLA affect on risk for T1D Hypothesis: HLA that is not inherited from the mother, affects the risk for T1D Studied the genes of 849 children from Sweden 563 with T1D and 286 non-diabetic children DR3 and DR4 are risk haplotypes when inherited from either parents. The genetic disposition is primarily conferred by HLA on human chromosome 6 Findings: “We detected a highly significant increase in T1D positively associated NIMA among healthy individuals compared with T1D patients.” When DR3 and DR4 are present as NIMA there is a reduced risk for T1D NIMA positively associated to T1D might provide protection from T1D. Results indicate that a person is less likely to develop T1D if the NIMA is positively associated with T1D. Akesson, 2009

Technology Due to the variety of risk factors diabetes is very hard to predict and prevent Future technology: Diabetes risk profile Cell therapy Use of cord blood Therapeutic drugs Clinical Islet Transplantation Each case of diabetes could be treated individually Cord blood used to regenerate immune cells Transplants islet cells from a donors pancreas to a T1D patient DRI, 2010

References Akesson K, Carlsson A, Ivarsson S, Johansson C, Weidby M, Ludvigsson J, Gustavsson B, Lernmark A, Kockum I. 2009. The non-inherited maternal HLA haplotype affects the risk for type 1 diabetes. International Journal of Immunogenetics 36 (1): 1-8. Centers for Disease Control and Prevention. 2007. National diabetes fact sheet: general information and national estimates on diabetes in the United States. Atlanta, GA: U.S. Department of Health and Human Services. Dean L, McEntyre J. 2004. The genetic landscape of diabetes. Beck B, editor. England: NCBI. Horenstein R, Shuldiner A. 2004. Genetics of diabetes. Kluwer Academic Publishers. Netherlands: Reviews in Endocrine and Metabolic Disorders 5: 25-36. Rich S, Gumuscu S, Concannon P. 2009. Recent progress in the genetics of diabetes. Hormone Research 71 (1):17-23. Diabetes Research Institute. 2010. Florida. [Cited 2010 April 23]. Available from: www.diabetesresearch.org