Wenzlau et al. 10.1073/pnas.0705894104. |
Fig. 7. Relationship of ZnT8A levels to GADA, IA2A, and IAA. Assays with ZnT8 constructs were compared with GADA, IA2A, and IAA on the same new-onset T1D samples. Results of linear regression analyses are shown together with a quadrant showing negative and positive in each assay (left lower quadrant, double negative; upper right quadrant, double positive).
Fig. 8. Relationship of ZnT8A levels to age at diabetes onset. New-onset T1D subjects ranging from <1 yr to 18 yr old were grouped in 2-yr intervals to illustrate the level of Zn C-terminal autoreactivity. Prevalence of antibodies to ZnT C-terminal and N/C constructs in relation to one another and to GADA, IA2A, and IAA is shown for the samples in Fig. 5.
Fig. 9. Levels of ZnT8A in prediabetic subjects. ZnT8 C-terminal autoreactivity is shown for 27 prediabetic subjects followed to T1D onset grouped by age up to 4 yr and a 2-yr countdown to diagnosis ( Dx, Dx-1, and Dx-2).
Fig. 10. Individual progression of autoantibodies in prediabetic subjects. ZnT8 C-terminal levels are shown for 10 individuals who were followed from <1 yr to the onset of diabetes. ZnT8A and IAA are grouped (Upper) as are GADA and IA2A (Lower). Autoreactivity in each is indexed as the log10 SD score The area below 4 SD is shaded to denote the cutoff for statistical significance. For each individual, the relationship to the diabetic first-degree relative, gender, HLA-DR genotype, and age at diabetes onset (Dx) is recorded above each. Individuals from the newborn cohort (NEC) have no family history of T1D and were selected on the basis of HLA-DR genotype alone.
Table 1. Candidate autoantigens
Rank A | Gene | Unigene | Pancreas abundance per 106 clones | Pancreas specificity (% global) | Islet abundance (ln Affx signal) | Rank B |
1 | INS | Hs.89832 | 1,5426.0 | 98.6 | 14.93 | 1 |
2 | IAPP | Hs.142255 | 1,564.0 | 99.6 | 12.02 | 9 |
3 | SGNE1 (7B2) | Hs.156540 | 1,884.0 | 50.7 | 12.93 | 5 |
4 | SLC30A8 (ZNT8) | Hs.532270 | 830.0 | 81.7 | 8.74 | 29 |
5 | PSKN1 | Hs.522640 | 1,047.0 | 44.3 | 9.17 | 28 |
6 | GNAS | Hs.125898 | 4,600.0 | 9.4 | 13.70 | 3 |
7 | CPE | Hs.75360 | 1,811.0 | 19.0 | 12.62 | 6 |
8 | GAD2 (GAD65) | Hs.231829 | 356.0 | 75.9 | 4.95 | 50 |
9 | TM4SF4 | Hs.133527 | 565.0 | 43.3 | 10.27 | 19 |
10 | G6PC2 (IGRP) | Hs.283963 | 260.0 | 84.7 | 4.78 | 51 |
11 | CEL | Hs.533258 | 428.0 | 39.8 | 14.41 | 2 |
12 | NKX2.2 | Hs.516922 | 187.0 | 90.3 | 8.60 | 30 |
13 | CHGB | Hs.516874 | 791.0 | 15.1 | 11.81 | 11 |
14 | ERO1LB | Hs.558519 | 439.0 | 26.4 | 9.78 | 23 |
15 | PC2 | Hs.315186 | 434.0 | 23.6 | 7.06 | 44 |
16 | IPF1 (PDX1) | Hs.32938 | 91.0 | 100.0 | 2.74 | 62 |
17 | PAX6 | Hs.591993 | 292.0 | 28.9 | 10.11 | 20 |
18 | SCGN | Hs.116428 | 187.0 | 43.2 | 9.50 | 25 |
19 | INSM1 | Hs.89584 | 178.0 | 42.5 | 9.43 | 26 |
20 | PC1 | Hs.78977 | 224.0 | 29.6 | 10.40 | 18 |
21 | APLP1 | Hs.74565 | 328.0 | 15.5 | 7.26 | 43 |
22 | SCG3 | Hs.232618 | 210.0 | 24.0 | 9.26 | 27 |
23 | CFTR | Hs.489786 | 200.0 | 20.5 | 9.98 | 22 |
24 | SCG2 | Hs.516726 | 278.0 | 13.8 | 11.59 | 12 |
25 | KRT17 | Hs.2785 | 2,276.0 | 1.7 | 10.90 | 16 |
26 | PTPRN (IA2) | Hs.89655 | 150.0 | 18.1 | 8.02 | 39 |
27 | PPPIR1A | Hs.505662 | 141.0 | 19.3 | 8.08 | 38 |
28 | CRB3 | Hs.150319 | 104.0 | 26.1 | 7.47 | 42 |
29 | ATP2A3 | Hs.513870 | 269.0 | 9.3 | 3.61 | 58 |
30 | ChGA | Hs.150793 | 292.0 | 8.3 | 11.83 | 10 |
31 | KCNMB2 | Hs.478368 | 123.0 | 14.2 | 5.34 | 48 |
32 | REG3G | Hs.447084 | 73.0 | 23.7 | 10.80 | 17 |
33 | SEZ6L2 | Hs.6314 | 136.0 | 10.5 | 5.32 | 49 |
34 | HSP90AB1 | Hs.509736 | 898.0 | 1.4 | 12.99 | 4 |
35 | FXYD2 | Hs.413137 | 54.0 | 21.6 | 8.33 | 32 |
36 | PTPRN2 (IA2ß) | Hs.490789 | 182.0 | 6.0 | 6.08 | 46 |
37 | CLU | Hs.436657 | 512.0 | 1.9 | 12.19 | 8 |
38 | REG3A | Hs.567312 | 178.0 | 4.2 | 12.42 | 7 |
39 | SYT13 | Hs.436643 | 68.0 | 9.2 | 8.22 | 36 |
40 | HMGN3 | Hs.77558 | 128.0 | 3.9 | 11.28 | 13 |
41 | ICA1 (ICA69) | Hs.487561 | 86.0 | 5.7 | 7.87 | 40 |
42 | SNAP25 | Hs.167317 | 160.0 | 3.0 | 8.35 | 31 |
43 | TMEM54 | Hs.534521 | 50.0 | 7.3 | 8.32 | 33 |
44 | TOB1 | Hs.531550 | 82.0 | 3.7 | 10.07 | 21 |
45 | ENO2 | Hs.511915 | 109.0 | 2.4 | 11.26 | 15 |
46 | IMO38 (MRPS31) | Hs.154655 | 73.0 | 3.4 | 8.18 | 37 |
47 | SORL1 | Hs.368592 | 95.0 | 2.5 | 9.70 | 24 |
48 | CNTN1 | Hs.567249 | 41.0 | 4.8 | 5.94 | 47 |
49 | NPY | Hs.1832 | 27.0 | 6.7 | 4.35 | 55 |
50 | TTFG3 | Hs.82961 | 45.0 | 4.0 | 4.08 | 56 |
51 | LYPD5 | Hs.44289 | 31.0 | 5.8 | 1.91 | 68 |
52 | EPHB3 | Hs.26988 | 27.0 | 5.5 | 2.23 | 67 |
53 | RAMP2 | Hs.514193 | 18.0 | 7.0 | 2.47 | 64 |
54 | INPP5E | Hs.120998 | 27.0 | 4.5 | 7.52 | 41 |
55 | SYP | Hs.75667 | 27.0 | 4.0 | 4.59 | 52 |
56 | HPN | Hs.182385 | 31.0 | 3.3 | 8.26 | 34 |
57 | GLIPR1 | Hs.591034 | 36.0 | 1.8 | 8.25 | 35 |
58 | PRPH | Hs.37044 | 27.0 | 2.1 | 4.46 | 54 |
59 | XPO4 | Hs.507452 | 27.0 | 2.1 | 2.35 | 65 |
60 | WBSCR14 (MLXIPL) | Hs.520446 | 18.0 | 2.7 | 3.68 | 57 |
61 | GJA4 | Hs.296310 | 18.0 | 2.5 | 3.46 | 59 |
62 | CEACAM1 | Hs.512682 | 27.0 | 1.6 | 4.50 | 53 |
63 | SOX17 | Hs.98367 | 13.0 | 2.6 | 2.50 | 63 |
64 | IGF1 | Hs.160562 | 27.0 | 1.1 | 2.34 | 66 |
65 | SOX13 | Hs.201671 | 13.0 | 1.1 | 3.05 | 61 |
66 | SYTL4 | Hs.522054 | 9.0 | 0.7 | 6.80 | 45 |
67 | PROM 1 | Hs.479220 | 9.0 | 0.3 | 11.27 | 14 |
68 | GAD1 (GAD67) | Hs.420036 | 4.0 | 0.5 | 3.28 | 60 |
This list was compiled by multidimensional analysis of microarray data initially using the human Novartis Gene Atlas V2 as a source of information on islet specificity of gene expression in man. This data was complemented from Affymetrix HGI133 Plus 2.0 analyses of human fetal pancreas. Islet cell type specificity was deduced from Affymetrix MOE430 microarrays of pancreatic endocrine tumor and ductal cell lines compared with islets and sorted b-cells. In the final analysis, pancreas specificity was evaluated from Unigene expression profiles of each gene of interest and islet abundance from microarray results. In Rank A, genes are listed in descending order according to the index (pancreas abundance ´ pancreas specificity) derived from the Unigene expression profiles. Normalized islet microarray data is expressed on a ln2 scale and descending rank shown as Rank B. Known autoantigens are in bold type, and the candidate under study is boxed.