GENETIC FACTORS IN DIABETES MELLITUS

Birmingham Study A random sample of 4886 birth. Comparison between the most valid data: 2432North European babies 956British 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

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. Protective HLA haplotypes is: DQA1*0102,DQB1*0602 Chromosome 6 Qp 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 I B C X E J A H G F

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) DesignationNatureChromosome IDDM 1 IDDM 2 MHC Insulin 6 11 IDDM 3 IDDM 4 IDDM 5 ?????? Weaker susceptibility loci:

Diabetes susceptibility loci 18 regions of the genome have been linked with influencing type 1 diabetes risk. Chromosome 2 Chromosome 5Chromosome 6Chromosome 10 IDDM10 IDDM17 IDDM1 IDDM15 IDDM5 IDDM8 IDDM18 IDDM7 IDDM12 IDDM13 Chromosome 11 Chromosome 14Chromosome 15Chromosome 18 IDDM17 IDDM3 IDDM11 IDDM2 IDDM4

Genetic Factors in Type 1 Diabetes Empiric Risk of type 1 Diabetes Relative with Modifying Risk of Type 1 Diabetes Factor Diabetes (%) Identical twin70 Father6 Mother2 Sibling5 First degree relativesHLA DR3 & DR420 HLA DR3 or DR45 HLA DR2 with DQB1*05025 HLA DR2 with DQB1*0602<0.2

Genetic Factors in Type 1 Diabetes The Bart’s 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 – 9 years – 14 years2.3 Parents (No 2,419): Before age 5 years5.9 5 – 9 years – 14 years3.7

Genetic Factors in Type 2 Diabetes Strong family history of diabetes add to other factor like obesity and it’s distribution. Ethnicity and family history show the genetic factor in type 2 diabetes. Controls Offspring of type 2 diabetes subjects Impact of diabetogenes on obesity induced insulin resistance

Genetic Factors in Type 2 Diabetes 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 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. K+K+ Sulphonylureas Dépolarisation K ATP Channel close x Ca 2+ Ca 2+ Influx Ashcroft, Gribble, Diabetologia (1999) 42: Insuline secretion through exocytosis Insulin 17400k 17410k 17420k 17430k 17440k 17450k ABCC8 11P15 11P14 11P13 11P12 11P11 Chromosome 11

Who should not develop Diabetes Age Sex Ethnicity Family history Metabolic syndrome