Altered Immune Regulation in Type 1 Diabetes

Table 1

T1DM-associated non-MHC risk polymorphisms (SNPs) with an odds ratio above 1.4 and the reported/mapped candidate genes in GWAStudies ranked by the highest corresponding odds ratio (OR) values in addition to the candidate genes (CTLA4, IFIH1, IL2, and PTPN2) that due to their immunological functions have been discussed in detail in the text.

Region

SNPs

Reported gene(s)

Mapped gene

Odds; ratio

Risk allele frequency

𝑃 value

Gene product function [42]

Context

Initial sample size

Replication sample size

Platform (SNPs passing QC)

References

1p13.2

rs6679677

PHTF1, PTPN22

PHTF1-RSBN1

1,89

0,1

1𝐸−40

PHTF1: transcription factor; RSBN1: not fully characterized

Intergenic

1,963 cases, 2,938 cntrl

2997 trios, 4,000 cases, 5,000 cntrl

See [15]

[10]

rs2476601

PTPN22

PTPN22

NR

NR

9𝐸−85

Lymphoid-specific intracellular phosphatase, a negative regulator of many signal transduction pathways

Missense

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

1,8

0,09

1𝐸−07

Missense

467 trios, 561 cases, 1,143 cntrl

2,350 individuals in 549 families; 390 trios

Illumina (543,071)

[16]

1,98

0,09

2𝐸−80

Missense

1,963 cases, 2,938 cntrl

2997 trios, 4,000 cases, 5,000 cntrl

See [15]

[10]

rs6679677

PHTF1-RSBN1

NR

NR

1𝐸−40

Intergenic

3,561 cases, 4,646 cntrl

6,225 cases, 6,946 cntrl, 3,064 trios

Affymetrix (up to 335,565)

[14]

1,82

0,1

5𝐸−26

Intergenic

1,963 cases, 2,938 cntrl

See [10]

Affymetrix (469,557)

[15]

11p15.5

rs1004446

INS

IGF2; IGF2-AS; INS-IGF2

1,61

0,65

4𝐸−09

Insulin hormone, IGF-2 growth factor

Intron

467 trios, 561 cases, 1,143 cntrl

2,350 individuals in 549 families; 390 trios

Illumina (543,071)

[16]

rs3741208

IGF2; IGF2-AS; INS-IGF2

1,25

0,38

2𝐸−07

Intron; ncRNA

1,963 cases, 2,938 cntrl

2997 trios, 4,000 cases, 5,000 cntrl

See [15]

[10]

rs7111341

MIR4686-ASCL2

NR

NR

4𝐸−48

MIR4686: micro-RNA; ASCL2: a helix-loop-helix transcription factor involved in the determination of the neuronal precursors in the central and peripheral nervous system

Intergenic

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

10p15.1

rs61839660

IL2RA

IL2RA

1,6

NR

5𝐸−09

IL2RA: as homodimer, a low-affinity receptor of IL-2; RPL32P23: pseudogene; RBM17: an RNA-binding protein, part of the spliceosome complex

Intron

16,179 Eu individuals

NR

NR (6,233,112) (imputed)

[12]

rs12251307

RPL32P23-RBM17

NR

NR

1𝐸−13

Intergenic

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

NR

NR

2𝐸−06

Intergenic

3,561 cases, 4,646 cntrl

6,225 cases,6,946 cntrl, 3,064 trios

Affymetrix (up to 335,565)

[14]

12p13.31

rs3764021

NR

CLEC2D

1,57

0,47

5𝐸−08

C-type lectin, a member of the natural killer cell receptor family, inhibits osteoclast formation

Cds-synon

1,963 cases, 2,938 cntrl

See [10]

Affymetrix (469,557)

[15]

16p13.13

rs2903692

KIAA0350

CLEC16A

1,54

0,62

7𝐸−11

Member of the C-type lectin domain containing family

Intron

467 trios, 561 cases, 1,143 cntrl

2,350 individuals in 549 families; 390 trios

Illumina (543,071)

[16]

rs12708716

1,19

0,65

5𝐸−07

Intron

1,963 cases, 2,938 cntrl

See [10]

Affymetrix (469,557)

[15]

1,23

0,68

3𝐸−18

Intron

1,963 cases, 2,938 cntrl

2997 trios, 4,000 cases, 5,000 cntrl

See [15]

[10]

12p13.31

rs11052552

NR

NPM1P7-CLECL1

1,49

0,49

7𝐸−07

NPM1P7: pseudogene CLECL1: transmembrane, C-type lectin-like protein highly expressed on dendritic and B cells, may act as a T-cell costimulatory molecule

Intergenic

1,963 cases, 2,938 cntrl

See [10]

Affymetrix (469,557)

[15]

12q24.12

rs1265564

CUX2

CUX2

1,45

NR

1𝐸−16

A protein that contains three CUT domains and a homeodomain; both domains are DNA-binding motifs

Intron

16,179 eu individuals

NR

NR (6,233,112) (imputed)

[12]

13q22.2

rs539514

LMO7

LMO7

1,43

0,5

6𝐸−11

May be involved in protein-protein interactions

Intron

9,934 eu cases, 16,956 eu cntrl

1,120 eu affected trios

Affymetrix and illumina (~2.54 million) (imputed)

[17]

2q33.2

rs3087243

CTLA4

CTLA4

NR

NR

1𝐸−15

Transmits an inhibitory signal to T-cells

NearGene-3

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

NR

NR

8𝐸−11

NearGene-3

3,561 cases, 4,646 cntrl

6,225 cases, 6,946 cntrl, 3,064 trios

Affymetrix (up to 335,565)

[14]

2q24.2

rs1990760

IFIH1

IFIH1

NR

NR

7𝐸−11

Acts as a cytoplasmic sensor of viral nucleic acids

Missense

7,514 cases, 9,045 controls

4,267 cases, 4,670 controls, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

1,18

0,6

2𝐸−11

Missense

1,963 cases, 2,938 controls

2997 trios, 4,000 cases, 5,000 controls

See [15]

[10]

4q27

rs4505848

IL2

KIAA1109

NR

NR

5𝐸−13

KIAA1109: thought to function in the regulation of epithelial growth and differentiation and in tumor development

Intron

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

rs2069762

IL2

IL2

0,889

NR

NR

Cytokine, key activator of T-cells

Intron

8506 T1DM samples

Affymetrix and illumina (841,622) (imputed)

[29]

18p11.21

rs1893217

PTPN2

PTPN2

NR

NR

4𝐸−15

Member of the protein tyrosine phosphatase (PTP) family. Reported to have inhibitory role in beta-cell apoptosis

Intron

7,514 cases, 9,045 cntrl

4,267 cases, 4,670 cntrl, 4,342 trios

Affymetrix and illumina (841,622) (imputed)

[13]

rs2542151

PSMG2-PTPN2

NR

NR

9𝐸−08

PSMG2: proteasome assembly chaperone

Intergenic

3,561 cases, 4,646 cntrl

6,225 cases, 6,946 cntrl, 3,064 trios

Affymetrix (up to 335,565)

[14]

1,3

0,16

1𝐸−14

Intergenic

1,963 cases, 2,938 cntrl

2997 trios, 4,000 cases, 5,000 cntrl

See [15]

[10]