Improving prediction of type 1 diabetes by testing non‐HLA genetic variants in addition to HLA markers. Issue 5 (8th November 2013)

• Record Type: Journal Article
• Authors: Steck, Andrea K; Dong, Fran; Wong, Randall; Fouts, Alexandra; Liu, Edwin; Romanos, Jihane; Wijmenga, Cisca; Norris, Jill M; Rewers, Marian J
• Is Part Of: Pediatric diabetes. Volume 15:Issue 5(2014:Aug.)
• Page Start: 355
• Page End: 362
• Publication Date: 2013-11-08
• Subjects: Diabetes in children -- Periodicals; 616.462
• DOI: 10.1111/pedi.12092
• Languages: English
• ISSNs: 1399-543X

Abstract

<abstract abstract-type="main" id="pedi12092-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pedi12092-sec-0001" sec-type="section"> <title>Objective</title> <p id="pedi12092-para-0001">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.</p> </sec> <sec id="pedi12092-sec-0002" sec-type="section"> <title>Methods</title> <p id="pedi12092-para-0002">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.</p> </sec> <sec id="pedi12092-sec-0003" sec-type="section"> <title>Results</title> <p id="pedi12092-para-0003">In multivariate analyses adjusting for family history and HLA‐DR3/4 genotype, <italic>PTPN22</italic> (rs2476601) and two <italic>UBASH3A</italic> (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. <italic>INS</italic>, <italic>UBASH3A</italic>, and <italic>IFIH1</italic> were significantly associated with progression from IA to diabetes (HR=1.65, 1.44, and 1.47, respectively, all p ≤ 0.04), while <italic>PTPN22</italic> and <italic>IL27</italic> showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with <italic>PTPN22</italic> rs2476601 TT or HLA‐DR3/4 and <italic>UBASH3A</italic> 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.</p> </sec> <sec id="pedi12092-sec-0004" sec-type="section"> <title>Conclusion</title> <p id="pedi12092-para-0004">Addition of <italic>PTPN22</italic> and <italic>UBASH3A</italic> SNPs to HLA‐DR, DQ genotyping can improve T1D risk prediction.</p> </sec> </abstract>