THE GENETIC BASES

B Y

C A S E Y J A R O C H E

Diabetes

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

www.dev.nsta.org/evwebs/1150/presenttech.htm

Diagrams of T1D and T2D

Differences between T1D and T2D

Type One Diabetes T1D Type Two Diabetes T2D

Rich, 2009

• 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,

autoimmune, environmental

• Risk factors: genetic, age,

obesity, race/ ethnicity

Background of Type 1 Diabetes

• Autoimmune disorder

• Inherited risk

• Environmental factors

• 18 regions of the genome are linked with diabetes riskHorenstein, 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 insulinVNTR is a variable number tandem repeat3 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 patientDRI, 2010

References1. 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.

2. 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.

3. Dean L, McEntyre J. 2004. The genetic landscape of diabetes. Beck B, editor. England: NCBI.

4. Horenstein R, Shuldiner A. 2004. Genetics of diabetes. Kluwer Academic Publishers.

Netherlands: Reviews in Endocrine and Metabolic Disorders 5: 25-36.

5. Rich S, Gumuscu S, Concannon P. 2009. Recent progress in the genetics of diabetes.

Hormone Research 71 (1):17-23.

6. Diabetes Research Institute. 2010. Florida. [Cited 2010 April 23]. Available from:

www.diabetesresearch.org