What are the risk factors for type one diabetes?

Risk Factors for Type 1 Diabetes

Type 1 diabetes risk is primarily determined by genetic factors (particularly HLA genotypes contributing up to 50% of familial susceptibility), presence of islet autoantibodies, and family history, with specific HLA haplotypes conferring the highest risk when present in combination. 1

Genetic Risk Factors

HLA (Human Leukocyte Antigen) Genes - Primary Determinant

The HLA-DQ and HLA-DR genes on chromosome 6p21 account for 30-50% of genetic type 1 diabetes risk and are the most important genetic determinants. 1

Highest-risk HLA genotypes:

• Individuals heterozygous for HLA-DRB1*04:01-DQA1*03:01-DQB1*03:02 AND DRB1*03-DQA1*05:01-DQB1*02:01 (DR4-DQ8/DR3-DQ2) have the highest genetic susceptibility 1
• HLA-DR4/DR4 homozygotes also confer very high risk 2
• Specific DR4 subtypes matter: DRB1*04:01,04:04, and 04:07 are susceptible, while 04:03 and 04:06 are protective 1

Protective HLA genotypes:

• DRB1*15-DQA1*02:01-DQB1*06:02 haplotype strongly protects against type 1 diabetes at young ages 1
• DRB1*1501 and DQA1*0102-DQB1*0602 are protective 1

Non-HLA Genetic Factors

Multiple non-HLA genes contribute smaller but significant effects to type 1 diabetes risk: 1

• Insulin gene (INS) on chromosome 11p15: Variable nucleotide tandem repeat (VNTR) polymorphisms predict insulin autoantibody (IAA) as first-appearing autoantibody 1, 2
• PTPN22 gene on chromosome 1p13: Allelic odds ratio approximately 1.7 2, 3
• CTLA4 gene on chromosome 2q33: Allelic odds ratio approximately 1.2 2, 3
• IL2RA, IFIH1, and other loci identified through genome-wide association studies 1, 2

Combining HLA and non-HLA polymorphisms in genetic risk scores improves risk prediction beyond HLA typing alone. 1

Immunologic Risk Factors - Islet Autoantibodies

The presence and number of islet autoantibodies is the strongest predictor of progression to clinical type 1 diabetes: 1, 4

Specific Autoantibodies

• Insulin autoantibodies (IAA) 1
• Glutamic acid decarboxylase antibodies (GADA/GAD65) 1, 4
• Insulinoma-associated antigen 2 antibodies (IA-2A) 1
• Zinc transporter 8 antibodies (ZnT8A) 1

Risk Stratification by Autoantibody Number

The number of positive autoantibodies dramatically affects diabetes risk: 1, 4

• Single persistent autoantibody: 15% risk of diabetes within 10 years 1, 4
• Two or more autoantibodies: 70% risk of diabetes within 10 years 1, 4
• At Stage 1 (multiple autoantibodies with normoglycemia): 44% 5-year risk overall 1
• At Stage 2 (multiple autoantibodies with dysglycemia): 60% risk by 2 years and 75% risk within 5 years 1

Family History and Familial Risk

Family history significantly increases type 1 diabetes risk, though 90% of individuals who develop type 1 diabetes have no known affected relative: 1

Risk in Siblings Based on HLA Sharing

The degree of HLA haplotype sharing with an affected sibling determines risk: 1

• HLA-identical siblings: 1 in 4 (25%) risk 1
• One shared HLA haplotype: 1 in 12 (8.3%) risk 1
• No shared HLA haplotype: 1 in 100 (1%) risk 1

General Familial Risk

• First-degree relatives have approximately 5% risk, which is 15-fold higher than general population 4
• Monozygotic twins have higher risk than HLA-identical siblings, suggesting non-HLA genetic and possibly environmental factors 5

Environmental and Other Risk Factors

Age-Related Factors

Type 1 diabetes can occur at any age, though presentation patterns vary: 1

• Most common in childhood and adolescence, but can occur even in 8th and 9th decades 1
• Children and adolescents often present with DKA as first manifestation (25-50% of new diagnoses) 1

Obesity

Obesity does not preclude type 1 diabetes diagnosis and may be increasingly common in those who develop type 1 diabetes 1

Associated Autoimmune Conditions

Individuals with type 1 diabetes are prone to other autoimmune disorders, suggesting shared autoimmune susceptibility: 1

• Hashimoto thyroiditis 1
• Graves disease 1
• Celiac disease 1
• Addison disease 1
• Vitiligo, autoimmune hepatitis, myasthenia gravis, pernicious anemia 1

Medication-Induced Risk

Immune checkpoint inhibitors (particularly PD-1/PD-L1 pathway blockers) can trigger type 1 diabetes in approximately 1% of treated individuals, most commonly in those with high-risk HLA-DR4 1

Viral Triggers

Certain viruses have been associated with type 1 diabetes development: 1

• Enteroviruses such as Coxsackievirus B 1
• SARS-CoV-2 (COVID-19) associated with increased cases of new-onset diabetes and DKA 1

Clinical Application for Risk Assessment

For newborn screening or general population risk assessment: 1

• HLA-DR-DQ typing plus INS gene typing predicts type 1 diabetes risk better than 1 in 10 in general population 1
• Children with DR3/4-DQ8 or DR4/DR4 genotypes with family history have >1 in 5 risk for developing islet autoantibodies during childhood 2
• Same HLA-risk genotypes without family history have approximately 1 in 20 risk 2

For first-degree relatives of affected individuals: 1, 4

• Consider screening for islet autoantibodies (though not routinely recommended for general population) 1, 4
• Multiple positive autoantibodies indicate need for close monitoring and consideration for prevention trials 1