Table 1.
SNPs Modulating Cytokines in Response to C. albicans Show Strong association with Susceptibility (P < 9.99 × 10–5).
| P value | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Chr | SNP | Susceptibility | cQTL | OR | Cytokine | Stimulant | Cell system | Time | Gene(s) | |
| 1 | rs11588087 | 4.34 × 10–6 | 0.014 | 3.07 | IL-1β | Yeast | PBMCs | 24h | GLUL(a), RGS16(a) | |
| 2 | rs34089869 | 4.26 × 10–5 | 0.019 |
0.35 IFNγ |
Yeast | PBMCs | 7days | |||
| 2 | rs62159917 | 3.74 × 10–5 | 0.049 | 0.36 | TNF-α | Yeast | Macrophages | 24h | ||
| 3 | rs12493413 | 3.54 × 10–5 | 0.021 | 0.49 | IL-22 | Hyphae | PBMCs | 7days | ARL8B(a), BHLHE40 (a), SUMF1(g) | |
| 3 | rs9879846 | 4.79 × 10–5 | 0.036 | 0.44 | IFNγ | Yeast | Whole blood | 48h | C3orf14(a,c) | |
| 5 | rs78969277 | 4.69 × 10–5 | 0.026 | 3.29 | TNF-α | Yeast | Macrophages | 24h | ADAM19(a,b), HAVCR2(a), NIPAL4(a), ITK(c) | |
| 5 | rs4895365 | 6.94 × 10–5 | 0.019 | 0.46 | IL-1β | Hyphae | PBMCs | 24h | HSD17B4(c,g), TNFAIP8(b,g), DMXL1(c) | |
| 5 | rs6872016 | 4.76 × 10–5 | 0.015 | 0.39 | IL-1β | Yeast | Whole blood | 48h | ||
| 6 | rs11155859 | 1.06 × 10–5 | 0.044 | 0.48 | IFNγ | Yeast | PBMCs | 7days | SYNE1(c) | |
| 6 | rs11155859 | 1.06 × 10-5 | 0.031 | 0.48 | IL-6 | Yeast | Macrophages | 24h | SYNE1(c) | |
| 6 | rs11155859 | 1.06 × 10-5 | 0.048 | 0.48 | IL-6 | Yeast | Whole blood | 48h | SYNE1(c) | |
| 7 | rs3807184 | 7.63 × 10–5 | 0.013 | 0.45 | IL-17 | Hyphae | PBMCs | 7days | NME8(a,c,e), EPDR1(b,c,d),GPR141(c),TXNDC3(c), STARD3NL(g) | |
| 7 | rs3807184 | 7.63 × 10–5 | 0.036 | 0.45 | IL-22 | Hyphae | PBMCs | 7days | NME8(a,c,e), EPDR1(b,c,d),GPR141(c),TXNDC3(c), STARD3NL(g) | |
| 8 | rs2725008 | 6.17 × 10–5 | 0.015 | 0.43 | IL-6 | Yeast | Macrophages | 24h | ||
| 8 | rs2725008 | 6.17 × 10–5 | 0.015 | 0.43 | TNF-α | Yeast | Macrophages | 24h | ||
| 10 | rs10884489 | 1.02 × 10–5 | 0.032 | 0.48 | TNF-α | Yeast | Macrophages | 24h | ||
| 11 | rs1945666 | 7.37 × 10–5 | 0.038 | 1.99 | IL-17 | Yeast | PBMCs | 7days | ||
| 11 | rs1945666 | 7.37 × 10–5 | 0.038 | 1.99 | TNF-α | Yeast | Macrophages | 24h | ||
| 12 | rs7306373 | 1.33 × 10–5 | 0.034 | 0.47 | IFNγ | Hyphae | PBMCs | 7days | CPM(a,b), LYZ(a,b) | |
| 13 | rs9530375 | 5.45 × 10–5 | 0.049 | 2.329 | IFNγ | Yeas | PBMCs | 7days | PLEKHA1(d) | |
| 13 | rs7322708 | 2.08 × 10–5 | 0.026 | 2.34 | IL-22 | Hyphae | PBMCs | 7days | CMIP(d),HSPA9(d), PLEKHA1(d), PPP1R8(d) | |
| 13 | rs6563046 | 4.35 × 10–6 | 0.001 | 2.12 | IL-6 | Yeast | Macrophages | 24h | RNF219(c) | |
| 13 | rs6563046 | 4.35 × 10–6 | 0.002 | 2.12 | TNF-α | Yeast | Macrophages | 24h | RNF219(c) | |
| 13 | rs7337751 | 7.61 × 10–5 | 0.017 | 2.05 | TNF-α | Yeast | Macrophages | 24h | ||
| 14 | rs71423384 | 1.29 × 10–5 | 0.041 | 0.39 | IL-1β | Hyphae | PBMCs | 24h | SLC8A3(a), KIAA0247, SLC10A1(g) | |
| 15 | rs12593397 | 3.02 × 10–5 | 0.037 | 0.51 | IFNy | Yeast | Whole blood | 48h | EHD4(b,c,d), JMJD7-PLA2G4B(c,g),RPAP1(c), PLA2G4B(c,g), SPTBN5(c), RP11-23P13.6(c), RP11-107F6.3(c), JMJD7(c), MAPKBP1(c), MGA(c), CTD-2382E5.3(c), PLA2G4D(g), PLA2G4E(g), PLA2G4F(g) | |
| 16 | rs2189521 | 9.14 × 10–5 | 0.048 | 0.52 | IL-1β | Yeast | PBMCs | 24h | GTF3C1(c), IL21R(c) | |
| 16 | rs4785438 | 8.50 × 10–5 | 0.039 | 0.53 | IL-1β | Yeast | Whole blood | 48h | CARD15(c), NOD2(a,c,d), CYLD(c), NKD1(c), RP11-401P9.4(c), RP11-327F22.6(c) | |
| 17 | rs3027232 | 9.27 × 10–5 | 0.019 | 0.47 | IL-17 | Yeast | PBMC | 7days |
C17orf44(c), TMEM107(c), TMEM88(b), ALOX15B(a,g), ALOXE3(a,f,g), LINC00324(c), ALOX12B(g) |
|
| 17 | rs3027232 | 9.27 × 10–5 | 0.009 | 0.47 | IL-22 | Yeast | PBMCs | 7days |
C17orf44(c), TMEM107(c), TMEM88(b), ALOX15B(a,g), ALOXE3(a,f,g), LINC00324(c), ALOX12B(g) |
|
| 17 | rs3027232 | 9.27 × 10–5 | 0.005 | 0.47 | IFNy | Yeast | Whole blood | 48h | C17orf44(c), TMEM107(c), TMEM88(b), ALOX15B(a,g), ALOXE3(a,f,g), LINC00324(c), ALOX12B(g) | |
| 17 | rs3027232 | 9.27 × 10–5 | 0.046 | 0.47 | IL-1β | Yeast | Whole blood | 48h | C17orf44(c), TMEM107(c), TMEM88(b), ALOX15B(ag), ALOXE3(a,f,g), LINC00324(c), ALOX12B(g) | |
| 17 | rs3027232 | 9.27 × 10–5 | 0.036 | 0.47 | IL-6 | Yeast | Whole blood | 48h | C17orf44(c), TMEM107(c), TMEM88(b), ALOX15B(a,g), ALOXE3(a,f,g), LINC00324(c), ALOX12B(g) | |
| 18 | rs72987764 | 3.01 × 10–6 | 0.042 | 0.38 | IL-17 | Yeast | PBMCs | 7days | ||
| 18 | rs72987756 | 2.65 × 10–5 | 0.04 | 0.449 | IL-6 | Yeast | Macrophages | 24h | ||
| 18 | rs72987756 | 2.65 × 10–5 | 0.03 | 0.449 | TNF-α | Yeast | Macrophages | 24h | ||
| 22 | rs113413 | 8.04 × 10–5 | 0.029 | 2.03 | IL-17 | Hyphae | PBMC | 7days | AP000350.4(c), AP000350.5(c), AP000350.6(c),AP000351.10 (c), DDT(c,d), DDTL(c),GSTT1(c,d),KB-226F1.1(c),KB-226F1.2(c), MIF(d), GGT5(a,g), DDT22(c), UPB1(c), |
Abbreviations: Chr, chromosome; cQTL, cytokine quantitative trait loci; IFN, interferon; IL, interleukin; OR, odds ratio; PBMCs, peripheral blood mononuclear cells; SNP, single-nucleotide polymorphisms; TNF, tumor necrosis factor.
a Differentially-expressed genes after 24-hour Candida stimulation.
b Differentially-expressed genes after 4-hour Candida stimulation.
c Candidemia-associated SNPs or proxies (r2 > 0.8) showed an eQTL effect in whole blood based on publicly available eQTL datasets [18,47,48].
d Candidemia-associated SNPs or proxies (r2 > 0.8) showed an eQTL effect in monocytes [46,49].
e Candidemia-associated SNP in strong LD (r2 > 0.8) with a synonymous variant.
f Candidemia-associated SNP is a missense variant.
g Gene is involved in lipid metabolism (Reactome).