Can We Use Improved Genetic Risk Scores to Predict Diabetes?

More accurate genes to screen for type 1 diabetes in both newborns and adults identified.

Type 1 diabetes (T1D) is an autoimmune genetic disease in which pancreatic beta cells are destroyed by antibodies. Since this disorder is genetic, it can become active at any age, which is why it is important to detect it early on to prevent complications and lessen medical costs. When it comes to Human Leukocyte Antigen (HLA) and non-HLA genes relevant to type 1 diabetes, there is a lot of missing information. In addition, existing autoantibody “surveillance is expensive and difficult in young children.” This is troubling because type 1 diabetes is especially prominent in children, and autoantibody measurement in adult diabetes is not accurate enough to diagnose the specific kind of diabetes they have, which is necessary for appropriate treatment.

HLA (DR-DQ) loci as well as non–DR-DQ loci through other single nucleotide polymorphisms were studied more completely in this study in order to improve genetic risk scores for type 1 diabetes in infants. Variations in specific loci that are related to type 1 diabetes include: “HLA class 2 DR-DQ loci, the HLA class 1 region, and over 50 associated non-HLA single nucleotide polymorphisms (SNPs), including INS and PTNP22.” HLA DR-DQ genotyping by itself has weak diagnostic differentiation compared with a combination of multiple T1D risk alleles put into one integrated genetic risk score (GRS). The original T1D GRS, called T1D GRS1, was missing a lot of haplotypes important in predicting T1D.

Larger sets of reference data, like the 1000 Genomes Project, have allowed more sensitivity and specificity of type 1 diabetes-related HLA measurements and tagging. In the Type 1 Diabetes Genetics Consortium, a huge case-control data set, 6,481 intervention cases, in addition to 9,247 in the control group, were taken into this study. The HLA locus IDDM1 was looked at first. HLA T1D literature provided alleles that either protected people from or increased risk of T1D. About 164,000 relevant HLA and non-HLA variants were analyzed as new combinations in a risk score called T1D GRS2 for the white Caucasian volunteers whose ages ranged from less than 1 year to a maximum age of 16 years (with an average age of 7.75 years old). Interactions were analyzed between 136 possible DR-DQ haplotype pairings (haplogenotypes) with a cut-off point of P < 3.7 x 10^ -4.

Logistic regression was used with T1D as the outcome. Variants of interest were used as independent variables. Odds ratios were used to validate these. The study tested the ability of the GRS to discriminate case from control subjects via DeLong algorithm generated statistics. A chi-square test evaluated the power of the different GRSs.

Improved HLA and non-HLA loci were identified and coined into “T1D GRS2” as another genetic risk score for type 1 diabetes. “The T1D GRS2 used 67 single nucleotide polymorphisms (SNPs) and accounted for interactions between 18 HLA DR-DQ haplotype combinations. The T1D GRS2 was highly discriminative for all T1D (area under the curve [AUC] 0.92; P < 0.0001 vs. older scores) and even more discriminative for early-onset T1D (AUC 0.96). In simulated newborn screening, the T1D GRS2 was nearly twice as efficient as HLA genotyping alone and 50% better than current genetic scores in general population T1D prediction.” This newly discovered genetic risk score will help differentiate the type of diabetes that adults have, and also it will better screen newborn babies for type 1 diabetes.

Since this testing is more cost-effective as well, this improved single nucleotide polymorphisms genotyping for type 1 diabetes should be very useful externally (clinically and in further research).

Practice Pearls:

• Both HLA and non-HLA genes have been found to be linked to type 1 diabetes, but there were lots of alleles still needed for accurate genotyping and diagnosing.
• This study has identified additional loci and interactions between them as well. They have been grouped together into an improved genetic risk score named “T1D GRS2.”
• This new genetic risk scoring is both more specific and sensitive, as well as more cost-effective for everyone involved. Now infants and adults can be better and more widely screened for type 1 diabetes.

References:

Beaumont, Robin N.; Hagopian, William A.; Harrison, James W.; Jones, Samuel E.; Locke, Jonathan M.; Oram, Richard A.; Rich, Stephen S.; Schneider, Darius A.; Sharp, Seth A.; Tyrrell, Jess; Weedon, Michael N.; Wood, Andrew R. “Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis.” Diabetes Care. January 2019. https://care.diabetesjournals.org/content/early/2018/11/30/dc18-1785.full-text.pdf. 22 January 2019.

Annahita Forghan, Pharm.D. Candidate 2019, LECOM College of Pharmacy