genitic factor in dm

8/3/2019 Genitic Factor in DM

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GENETIC FACTORSIN

DIABETES MELLITUS


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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 European69% British Pakistani

Prevalence of congenital and genetic disorders:4.3% North European7.9% British Pakistani

0

20

40

60

80

North European British Pakistani

Corrected congenital malformation

Disability

Death1

month -5

years

Death


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IDDM 1

HLA alleles documented in the 1970s.

Locus contains many diabetes susceptibilitygenes.

The most important alleles are DQB1 & DRB1.

Sequences in DQB1 gene that code for anamino acid other than aspartic acid atposition 57 (non-ASP57) are highly associatedwith type 1 diabetes.

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

Chromosome 6Q p

DP DQ DR B C A

Class II Class III Class I

CLIIA2 DP DN DM LMP2 LMP7 DO DQ DR

B2 A2 B1 A1 A A B B B2A2B1A1 B1B2B3B9 A

Class II

Class III

CYP21 Hsp70 G7a TNF

C4BC4ABfC2 2 1Hom A B

Class IB C X E J A H G F


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Genetic Factors in Type 1Diabetes

18 regions of the genome have been linkedwith 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 1IDDM 2

MHCInsulin

611

IDDM 3

IDDM 4

IDDM 5

?

?

?

15

11

6

Weaker susceptibility loci:


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Diabetes susceptibility loci

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

Chromosome 2 Chromosome 5 Chromosome 6 Chromosome 10

IDDM10

IDDM17

IDDM1

IDDM15

IDDM5IDDM8

IDDM18

IDDM7IDDM12IDDM13

Chromosome 11 Chromosome 14 Chromosome 15 Chromosome 18

IDDM17

IDDM3

IDDM11

IDDM2

IDDM4


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Genetic Factors in Type 1 Diabetes

Empiric Risk of type 1 Diabetes

Relative with Modifying Risk ofType 1 Diabetes Factor Diabetes (%)

Identical twin 70Father 6Mother 2Sibling 5First degree relatives HLA DR3 & DR4 20

HLA DR3 or DR4 5HLA DR2 with DQB1*0502 5HLA DR2 with DQB1*0602


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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 diabetesby age 20 years

Age %

Siblings (No 1,430):Before age 5 years 11.75 9 years 3.610 14 years 2.3

Parents (No 2,419):Before age 5 years 5.95 9 years 3.710 14 years 3.7


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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.

4

5

6

7

8

9

10

11

12

90 100 110 120 130 140 150 160 170 180

Ideal body weight (%)

Insulin

sensivit

Impact of diabetogeneson obesity induced insulin

resistance


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Genetic Factors in Type 2Diabetes

The sulfonylurea Receptor (ABCC8):

Chromosome 11.

KATP channels is found in the pancreas.

Activation of the KATP channel regulate the release of insulin.

Mutation in ABCC8 can result in up-regulation of insulinsecretion ( Familial persistent hyperinsulinemic hypoglycemia ofinfancy).

Genetic variation in ABCC8 has also been implicated in theimpaired release of insulin that is seen in type 2 diabetes.

K+

Sulphonylureas

KATP Channel close

x

Ashcroft, Gribble, Diabetologia (1999) 42: 903-919

Insuline

secretion

through

exocytosis

Insulin

17400k

17410k

17420k

17430k

17440k

17450k

ABCC811P15

11P14

11P13

11P12

11P11

Chromosome 11


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Who should not develop Diabetes

Age

Sex

Ethnicity

Family history

Metabolic syndrome


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genitic factor in dm

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