Genetics of Diabetes

Question 1

What is the background risk for type 1 diabetes?

Answer 1

To develop by 20 years of age

0.3-0.4%

Question 2

What is the risk for type 1 diabetes if a sibling has it?

Answer 2

5-6%

Question 3

What is heritability index?

Answer 3

The role of genetics vs the role of the environment

Question 4

How is the heritability index calculated?

Answer 4

Risk of sibling: background risk

Question 5

What does the heritability index make clear?

Answer 5

> 1 genes involved

<100 environment still involved

Question 6

What is the heritability index of cystic fibrosis?

Answer 6

750

Question 7

What is the evidence that type 1 diabetes has a genetic link?

Answer 7

Sibling relative risk
Heritability index
Concordane in monozygotic twins = 0.5
Concordance in dizygotic twins = 0.05/0.06

Question 8

What is the epidemiology of type 1 diabetes?

Answer 8

Increase in incidence over the last 50 years
Geographical distribution highest in Europe, middle in Africa and lowest in Asia
Highest in Northern Europe vs Mediterannean

Question 9

Give a brief history of type 1 diabetes genetics

Answer 9

1970s linkage study identified MHC region on chromosome 6
1990s large linkage study supported this as most important region
2000s GWAS identified over 40 loci, functional studies showed gene variants alter immune function
Incomplete self-tolerance to beta cell antigens

Question 10

What gene polymorphisms have been identified?

Answer 10

IDDM1 of HLA region of MHC, chromosome 6p21
DRB1 and DQB1
~40% of genetic risk

Question 11

What is MHC?

Answer 11

Major histocompatibility complex
Associated with autoimmune diseases
140 protein coding gense
HLA class 1 and 2 associated with type 1 diabetes
Present antigens to T lymphocytes
Over 200 alleles
Recent, environmentally modulated selection

Question 12

What is HLA?

Answer 12

Human leukocyte antigen
Presents antigens to T cells
Classes I, II and III
Highly polymorphic
Heterozygosity giving widest possible variety of affinities for different pathogens

Question 13

What HLA variants have highest risk?

Answer 13

B8 allele
DRB301-DQB201
DRB401-DQA301-DQA302

Question 14

What HLA allele is protective?

Answer 14

DQB602

Question 15

What is the amino acid role?

Answer 15

HLA
Amino acid other than aspartate at p57
Type 1 pathogenicity

Question 16

What is IDMM2?

Answer 16

Insulin gene region 11p
10% of total risk
Encodes pre-pro-insulin
Leads to incomplete thymic insulin expression
Incomplete tolerance to insulin

Question 17

What is VNTR?

Answer 17

IDDM2
Variable number of tandem repeats
26-63 risk for type I
140-210 protective for type I
Does not effect pancreas

Question 18

What was the Wellcome trust case control consortium?

Answer 18

Investigated 2000 patients for 7 diseases including type I and II diabetes
With a 500,000 SNP gene chip
Case vs control odds of having allele

Question 19

What were limitations of the Wellcome trust case control consortium?

Answer 19

Common variants across cases
SNP coverage limited
No established mechanisms
Controls may yet to be develop condition
Specific to White British

Question 20

What were the results of the Wellcome trust case control consortium?

Answer 20

10 more gene regions of interest

Question 21

What is the effect of type 1 gene variants on T cells?

Answer 21

Downregulation of cascade, compromise immune tolerance
T cells recognise self antigen as foreign
Genes promote or inhibit T cell activation

Question 22

What is the relative risk of gene variants?

Answer 22

General population: 0.25%
With HLA or DR4 = 4.5%
Heterozygous for PTPN2 = 0.45%

Question 23

What environmental risk factors have been identified?

Answer 23

None