What is the role of genetics in diabetes mellitus?

Genetics in Diabetes Mellitus

Genetic factors play a crucial role in diabetes mellitus pathogenesis, with different genetic mechanisms underlying type 1 diabetes, type 2 diabetes, and monogenic forms of diabetes. 1

Type 1 Diabetes Genetics

HLA Associations

• Type 1 diabetes has a strong genetic component linked primarily to the HLA region on chromosome 6p21, accounting for 40-50% of genetic susceptibility 1, 2
• The major genetic determinants are polymorphisms in class II HLA genes encoding DQ and DR proteins 1
• Key high-risk haplotypes:
  • HLA-DQA103:01-B103:02 (DQ8) and HLA-DQA105:01-B102:01 (DQ2) 1
  • These haplotypes, alone or combined, account for up to 90% of children and young adults with type 1 diabetes 1
  • Highest risk is in heterozygotes with both DR3 and DR4 haplotypes (OR = 16.59) 2

Protective Alleles

• The HLA DQB1*06:02 allele provides strong protection against type 1 diabetes onset in children 1, 3
• The DRB115:01-DQA101:02-DQB1*06:02 haplotype confers significant protection (OR = 0.03) 2

Non-HLA Genetic Factors

• Multiple non-HLA loci contribute to type 1 diabetes risk with smaller effects 1, 4
• These include genes for:
  • Insulin (INS) on chromosome 11p15 5, 4
  • PTPN22 1, 4
  • CTLA-4 1, 4
  • IL2RA and IFIH1 4

Type 2 Diabetes Genetics

Genetic Architecture

• Type 2 diabetes has a higher familial risk than type 1, but only about 10% of contributing genes are currently known 5
• Multiple genetic factors with smaller individual effects contribute to disease risk 1
• Genome-wide association studies have identified more than 30 genetic risk factors 1
• HLA class II variations may also influence type 2 diabetes risk:
  • The DRB115:01~DQA101:02~DQB1*06:02 haplotype (protective in type 1) also reduces type 2 diabetes risk (OR 0.84) 6
  • The DRB107:01~DQA102:01~DQB1*03:03 haplotype increases risk in non-insulin-treated diabetes (OR 1.37) 6

Genes Associated with Type 2 Diabetes

• Insulin receptor gene on chromosome 19p13 5
• At least five glucose transporter genes 5
• Other potential contributors: glycogen synthase gene, glucokinase gene, and leptin gene 5

Monogenic Forms of Diabetes

MODY (Maturity-Onset Diabetes of the Young)

• Autosomal dominant inheritance pattern with specific mutations in several genes 1
• Key MODY types:
  • GCK-MODY: Mutations in glucokinase gene causing stable, non-progressive elevated fasting blood glucose 1
  • HNF1A-MODY: Progressive insulin secretory defect with presentation in adolescence or early adulthood; sensitive to sulfonylureas 1
  • HNF4A-MODY: Progressive insulin secretory defect; may have large birth weight and transient neonatal hypoglycemia 1

Neonatal Diabetes

• Diagnosed at <6 months of age 1
• Seven different genes with mutations may lead to transient or permanent diabetes 1
• Genetic analysis should be performed on all infants with diabetes diagnosed before 6 months 1

Clinical Applications of Genetic Testing

Recommendations for Type 1 Diabetes

• Routine determination of genetic markers such as HLA genes is not recommended for diagnosis or management of type 1 diabetes 1
• HLA typing has limited value in routine clinical diagnosis or classification 1
• Genetic risk scores may be useful for:
  • Disease prediction and progression monitoring 7
  • Discrimination between diabetes types in unclear cases 1, 7
  • Research purposes 1, 7

Recommendations for Type 2 Diabetes

• There is no role for routine genetic testing in people with type 2 diabetes 1
• Genetic studies should be confined to research settings and evaluation of specific syndromes 1

Recommendations for Monogenic Diabetes

• Genetic testing is valuable for:
  • Neonatal diabetes (all infants diagnosed <6 months) 1
  • MODY in young individuals with dominant family history of diabetes 1
  • Guiding treatment decisions (e.g., sulfonylureas for HNF1A-MODY) 1

Risk Prediction Using Genetics

• Children with high-risk HLA genotypes (DR3/4-DQ8 or DR4/DR4) who have a family history of type 1 diabetes have >20% risk for developing islet autoantibodies 4
• The same high-risk genotypes without family history carry approximately 5% risk 4
• Combining HLA and non-HLA polymorphisms in genetic risk scores has improved selection of individuals at risk for type 1 diabetes prevention trials 1

Pitfalls and Limitations

• HLA is necessary but not sufficient for type 1 diabetes development - high-risk haplotypes may be present in 30-40% of the general population 1
• HLA genes contribute to initial autoimmunity development but not to progression once autoimmunity has developed 1
• Genetic risk scores for type 2 diabetes have limited predictive value due to small individual effects of risk alleles 1
• Phenotype may not always correlate with genotype due to environmental factors and interactions among multiple genetic loci 1