GENETIC FACTORS IN DIABETES MELLITUS

Birmingham Study
A random sample of 4886 birth. Comparison between the most valid data: 2432 North European babies 956 British Pakistani babies Couple family relation in the two group: 0.4% North European 69% British Pakistani Prevalence of congenital and genetic disorders: 4.3% North European 7.9% British Pakistani
80

60

Corrected congenital malformation Disability

40

Death 1 month - 5 years Death <1 month (lethal malformation)

20
Genetic abortion

0
North European British Pakistani

IDDM 1
HLA alleles documented in the 1970s. Locus contains many diabetes susceptibility genes. The most important alleles are DQB1 & DRB1. Sequences in DQB1 gene that code for an amino acid other than aspartic acid at position 57 (non-ASP57) are highly associated with type 1 diabetes.
Class II
DP DQ DR Class II

Chromosome 6

B C Class III

Class I

CLIIA2

DP

DN

DM

LMP2 LMP7

DO

DQ

DR

Protective HLA haplotypes is: DQA1*0102,DQB1*0602

Class III

B2 A2 B1 A1

A B

B2A2B1A1

B1B2B3B9 A

CYP21

Hsp70

G7a

TNF

C4BC4ABfC2

2 1Hom

A B

Class I

Genetic Factors in Type 1 Diabetes

18 regions of the genome have been linked with influencing type 1 diabetes risk. The most well studied HLA gene is IDDM 1. Non-HLA genes like: IDDM 2 (insulin gene) CTLA4 (immune response)

Designation

Nature

Chromosome

IDDM 1 IDDM 2

MHC Insulin

6 11

Weaker susceptibility loci:

IDDM 3 IDDM 4 IDDM 5

? ? ?

15 11 6

Diabetes susceptibility loci

18 regions of the genome have been linked with influencing type 1 diabetes risk.

Chromosome 2

Chromosome 5

Chromosome 6
IDDM1

Chromosome 10

IDDM10 IDDM15 IDDM7 IDDM12 IDDM13

IDDM18

IDDM5 IDDM8

IDDM17

Chromosome 11
IDDM2

Chromosome 14

Chromosome 15

Chromosome 18

IDDM4

IDDM17 IDDM11 IDDM3

Genetic Factors in Type 1 Diabetes

Empiric Risk of type 1 Diabetes

Relative with
Type 1 Diabetes Modifying

Factor

Risk of
Diabetes (%)

Identical twin Father Mother Sibling First degree relatives

HLA HLA HLA HLA

DR3 DR3 DR2 DR2

& DR4 or DR4 with DQB1*0502 with DQB1*0602

70 6 2 5 20 5 5 <0.2

Genetic Factors in Type 1 Diabetes

The Barts Oxford population-based family study:
To examine familial risk of disease in relation to age at onset in 1,299 families.

The cumulative risk of type 1 diabetes by age 20 years

Age
Siblings (No 1,430): Before age 5 years 5 9 years 10 14 years Parents (No 2,419): Before age 5 years 5 9 years 10 14 years

%
11.7 3.6 2.3 5.9 3.7 3.7

Genetic Factors in Type 2 Diabetes

Strong family history of diabetes add to other factor like obesity and its distribution. Ethnicity and family history show the genetic factor in type 2 diabetes.
12 11 10
Impact of diabetogenes on obesity induced insulin resistance

Insulin sensivity

9 8 7 6 5 4 90 100 110 120 130 140 150 160 170 180

Ideal body weight (%)

Genetic Factors in Type 2 Diabetes

The sulfonylurea Receptor (ABCC8):
Chromosome 11. KATP channels is found in the pancreas.
Chromosome 11
11P15 11P14 11P13 11P12 11P11

17400k

17410k

17420k

ABCC8

17430k

17440k

17450k

Activation of the KATP channel regulate the release of insulin. Mutation in ABCC8 can result in up-regulation of insulin secretion ( Familial persistent hyperinsulinemic hypoglycemia of infancy). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes. Sulphonylureas

KATP Channel close

K+

Insulin
Insuline secretion through exocytosis Ashcroft, Gribble, Diabetologia (1999) 42: 903-919

Who should not develop Diabetes

Age
Sex Ethnicity Family history Metabolic syndrome