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. 2014 Aug;15(5):355-62.
doi: 10.1111/pedi.12092. Epub 2013 Nov 8.

Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers

Andrea K Steck  1 , Fran Dong, Randall Wong, Alexandra Fouts, Edwin Liu, Jihane Romanos, Cisca Wijmenga, Jill M Norris, Marian J Rewers
Affiliations

Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers

Andrea K Steck et al. Pediatr Diabetes. 2014 Aug.

Abstract

Objective: The purpose of this study was to explore whether non-human leukocyte antigen (non-HLA) genetic markers can improve type 1 diabetes(T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes.

Methods: The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for the development of T1D and islet autoimmunity (IA)children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms (SNPs) and one microsatellite.

Results: In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA [hazard ratio(HR)=1.87, 1.55, and 1.54, respectively, all p ≤ 0.003], while GLIS3 and IL2RA showed borderline association with development of IA. INS,UBASH3A, and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44, and 1.47, respectively, all p ≤ 0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared with 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives.

Conclusion: Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction.

Keywords: islet autoimmunity; non-HLA genetic markers; prediction; type 1 diabetes.

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Figures

Figure 1
Figure 1. Progression to Islet Autoimmunity (IA) and Diabetes in DAISY NHW general population children (N=843)*: IA by genetic risk strata (1A), Diabetes by genetic risk strata (1B), IA by HLA-DR3/4 (1C) and Diabetes by HLA-DR3/4 (1D)
High risk: all subjects with UBASH3A AA in addition to HLA-DR3/4 as well as all subjects with PTPN22 TT; Low risk: all other genotypes Follow-up time was defined as the age of the child at the 1st of the 2 consecutive positive visits for affected children and age of the child at the last visit for unaffected children. Non DR3/4 refers to not having the highest risk HLA DR3/4,DQB1*0302 genotype. *15 subjects not included due to missing either UBASH3A or PTPN22 genotyping
Figure 2
Figure 2. Progression to Islet Autoimmunity (IA) and Diabetes in DAISY NHW first-degree relatives (N=816)*: IA by genetic risk strata (1A), Diabetes by genetic risk strata (1B), IA by HLA-DR3/4 (1C) and Diabetes by HLA-DR3/4 (1D)
High risk: all subjects with UBASH3A AA in addition to HLA-DR3/4 as well as all subjects with PTPN22 TT; Low risk: all other genotypes Follow-up time was defined as the age of the child at the 1st of the 2 consecutive positive visits for affected children and age of the child at the last visit for unaffected children. Non DR3/4 refers to not having the highest risk HLA DR3/4,DQB1*0302 genotype. *35 subjects not included due to missing either UBASH3A or PTPN22 genotyping
Figure 3
Figure 3. Non-HLA gene SNP-risk allele score distribution in DAISY general population and first-degree relatives
Distribution of risk allele scores derived from 9 (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350/CLEC16A, CTLA4, SH2B3, IL18RAP, IL10) type 1 diabetes susceptibility genes in nondiabetic autoantibody negative children (unfilled bars) compared to children who progressed to diabetes (filled bars) in DAISY N=1332 antibody negative children and N=37 children with type 1 diabetes (antibody positive subjects who have not developed diabetes and subjects missing data for one or more SNPs are not included)
Figure 4
Figure 4. Progression to Diabetes in DAISY general population children (left) and DAISY first-degree relatives (right)
SNP-risk allele score categories are low <5, intermediate 5-9 and high >9 Inter: intermediate N=726 general population children and N=687 first-degree relatives (subjects missing data for one or more SNPs were not included)
See this image and copyright information in PMC

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