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A Review of Genetic Risks in Type 1 Diabetes

Aug 24, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Onyi Ibeji, PharmD. Candidate, LECOM School of Pharmacy

Does your ancestral origin determine your risk of developing type 1 diabetes? Study examines genetic risks in type 1 for differing populations.

Type 1 diabetes is due to the immunological destruction of beta cells of the pancreas. Type 1 diabetes itself is not necessarily inherited, but rather it is the genetic predisposition or tendency toward developing type 1 diabetes that is inherited. Genetic predisposition combined with immunologic and possibly environmental factors contribute to the destruction of beta cells, and they are considered the major risk factors for developing the disease. 

People with certain (HLA) human leukocyte antigen types like DR3 or DR4 have an increased genetic tendency of developing type 1 diabetes, and about 95% of patients with type 1 diabetes show these specific HLA types. Caucasians of northern European ancestry are known to be the most at-risk population in developing this disease, but recent data have shown that in the U.S, people of African and Hispanic ancestry show the most increasing rate of type 1 diabetes, and this means that most or all ethnic groups are vulnerable. This study was focused on performing genetic analyses of type 1 diabetes risk in the African-ancestry population, and developing type 1 diabetes genetic risk score with a comparison to the European-ancestry genetic risk score. A genetic risk score is used to predict traits when considering variation in multiple genetic variants.

The researchers of this study collected DNA samples and data of subjects of African ancestry as determined by Type 1 Diabetes Genetics Consortium (T1DGC),  and from various sources like SEARCH for Diabetes in Youth study, Genetics of Kidneys in Diabetes (GoKinD) study, the Barbara Davis Center (BDC), Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) etc. All the DNA samples collected received approval and informed consent. ImmunoChip (Illumina) was then used for genotyping and the recommended procedures were followed accordingly. Imputation of classical human leukocyte antigen alleles was based on the T1DGC single nucleotide polymorphism (SNP) reference panel that included 5,196 unrelated subjects of diverse ancestry (4,323 European, 251 African, 608 Asian, and 14 “other”) with both ImmunoChip and classical human leukocyte antigen genotypes. SNPs associated with type 1 diabetes risk were the basis for the African-ancestry genetic risk score, which was computed as the weighted sum of allele counts.

Analysis was eventually done using ImmunoChip SNPs in 3,949 African-ancestry subjects, of whom 1,021 had type 1 diabetes, with 2,928 in the control group. Comparisons made between the European-ancestry SNPs and the African-ancestry SNPs showed that the most important SNP in the African-ancestry participants is different from that of the European-ancestry participants. Despite this observed difference, a subgroup of the European-ancestry type 1 diabetes reliable SNPs also showed strong evidence of association in the African-ancestry population. SNP rs3842727 is the most associated SNP in African ancestry, which is highly correlated with rs689 in both European-ancestry and African-ancestry participants. Different HLA associations with African-ancestry type 1 diabetes were identified and they include various HLA alleles, HLA haplotypes. New significant associations for HLA-A, HLA-B, and HLA-C alleles with type 1 diabetes in African-ancestry populations were also identified. HLAB*57:03 is an African-specific allele and it was found to be protective against risk of type 1 diabetes.  It was also noted that type 1 diabetes genetic risk score in African-ancestry populations reflected an overlap with that of European-ancestry population.

The study suggests that type 1 diabetes genetic risk score could provide more predictive power to help in the disease risk identification, and this is advantageous since it includes SNPs that categorize other significant HLA risk alleles, and non-HLA SNPs. The increased ability to identify individuals at increased risk makes it easier for earlier diagnosis, patient education and better management of type 1 diabetes, especially in at-risk children. Historically, children of European ancestry are known to be at higher risk of developing this disease, but recent studies are showing that people of other ancestries are having type 1 diabetes at an increasing rate.

 

Practice Pearls:

  • Using a genetic risk score to make predictions for individuals at risk of type 1 diabetes may improve disease management and outcomes.
  • Children from ancestral backgrounds other than those from European ancestry are also predisposed to developing type 1 diabetes.
  • Early diagnoses and patient education are still very important in type 1 diabetes management and outcomes.

 

Reference for “A Review of Genetic Risks in Type 1 Diabetes”:

Onengut-Gumuscu, Chen, Robertson, et al. “Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score” Diabetes Care 2019;42:406–415 | https://doi.org/10.2337/dc18-1727

 

Onyi Ibeji, PharmD. Candidate, LECOM School of Pharmacy