A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes

Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children

“…Risk scores were generated for non-HLA genotypes as previously described [17]. For each gene, a score of 2 was given if the child was homozygous for the allele predisposing to type 1 diabetes, 1 if the child was heterozygous and 0 if the child was homozygous for the nonsusceptible allele.…”

“…An additional 12 type 1 diabetes susceptibility gene single nucleotide polymorphisms (SNPs) were selected for typing on the basis of the genes that were reported to be susceptible in 2009 [16], the strength of their OR and the SNP-typing that has successfully been established in Munich: PTPN22 rs6679677, PTPN2 rs1893217, ERBB3 rs2292239, IL2 rs4505848, SH2B3 rs3184504, CTLA4 rs3087243, IFIH1 rs2111485, KIAA0350 (also known as CLEC16A) rs12935413, CD25 rs11594656, IL18RAP rs917997, IL10 rs3024505, and COBL rs4948088. Genotyping of these SNPs was performed with the MassARRAY system using iPLEX chemistry (Sequenom, San Diego, CA, USA), as previously described [17]. To control for reproducibility, 16% of samples were genotyped in duplicate with a discordance rate <0.5%.…”

“…The sum of the scores was assigned as the combined risk score for each child. Combined risk scores were generated for permutations of multiple non-HLA genes (n=2 a −1, where a is the number of genes in the analysis) as previously described [17] and compared between groups using the Mann-Whitney U test and twosample permutation test [18].…”

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…In addition, PTPN22 1858T has been shown to be a predictor of more rapid progression to T1D among islet autoantibody-positive at-risk relatives [33]. Modeling of known genetic factors has shown that combinations of genes which include PTPN22 can be used to predict both islet autoantibody and diabetes development [34,35]. Furthermore, the PTPN22 risk variant has been linked to the development of autoantibodies when combined with environmental triggers [36].…”

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

“…Most studies, including a meta-analysis, identified the strongest association with the single nucleotide polymorphism (SNP) rs2292239, located in intron 7 of ERBB3 (Barrett et al, 2009;Onengut-Gumuscu et al, 2015;Burton et al, 2007;Hakonarson et al, 2008;Todd et al, 2007;Keene et al, 2012). Genetic variations in ERBB3 have also been used in different model approaches to improve prediction of T1D (Winkler et al, 2012;Bonifacio et al, 2014), autoimmunity (T€ orn et al, 2015;Brorsson and Pociot, 2015) and disease progression (Achenbach et al, 2013;Andersen et al, 2013). Despite the convincing genetic association of the ERBB3 region with T1D the functional implication underlying this has not been explored in detail, although it has been suggested that their most likely mechanism for affecting disease risk would be through effects on gene expression (Keene et al, 2012).…”