Supplementary Table
Supplementary Table 1. Descriptive and regression analysis of plasma levels for patients with COVID-19, when comparing non-critical (n=264) and critical (n=162) cases.
Unadjusted Analysis Adjusted Analysis
Non-Critical
Mean (SD) Critical
Mean (SD) Z-statistic p-value T-statistic p-value IP-10
(pg/ml) 34.54 (106.37) 134.84 (290.38) -8.693 <0.001 6.056 <0.001 MCP-1
(pg/ml) 781.47 (607.26) 1202.73 (1580.35) -1.012 0.311 0.821 0.412 IL-1b
(pg/ml) 25.17 (165.80) 76.43 (342.46) -0.739 0.460 -0.061 0.952 IFN
(pg/ml) 60.99 (436.57) 90.67 (548.54) -0.162 0.871 3.233 0.001 MCP-3
(pg/ml) 3.21 (24.92) 8.94 (36.76) -9.215 <0.001 1.834 0.068 MIP-1a
(pg/ml) 99.13 (543.44) 98.97 (326.96) -2.567 0.010 1.905 0.057 TNF-a
(pg/ml) 9.32 (54.71) 17.18 (91.57) -2.981 0.003 0.164 0.685
IL-6
(pg/ml) 94.22 (515.21) 365.95 (1161.86) -8.774 <0.001 6.660 <0.001 CXCL-16
(pg/ml) 11595.21 (4748.36) 18835.46
(11506.73) -5.615 <0.001 3.922 <0.001
Mann-Whitney U-test of significance (two-sided) was used to measure the distribution of ranks between non- critical and critical cases; z-statistic and p-value of the non-parametric test is noted.
Multiple Linear Regression Model (dependent variable: plasma marker as continuous variable that were subjected to log-transformation and standardizing; independent variable: non-critical vs critical) was used for the models, presented as T-statistic and adjusted for age and gender.
Supplementary Table 2. Adjusted effect size and p-value of the genetic variant involved in the cytokine, between non-critical (n=453) and critical (n=193) COVID-19 cases.
Cytokine Gene Name
(Cytoband) Number
of SNPs Significant
SNPs (rs-ID) Minor
Allele Adjusted Odds
Ratio*
Adjusted p-value
IP-10 (pg/ml) CXCL10 (4q21.1)
9 NA
NA NA
NA
MCP-1 (pg/ml) CCL2 (17q12)
4 NA
NA NA
NA
IL-1b (pg/ml) IL1 (2q14.1)
14 NA
NA NA
NA
IL-6 (pg/ml) IL6 (7p15.3)
14 rs1554606
rs2069845 rs2069832 rs1474347 rs1474348 G
A G A G 0.67 (0.66, 0.68)
0.67 (0.66, 0.68) 0.69 (0.68, 0.70) 0.69 (0.68, 0.70) 0.69 (0.68, 0.70) 0.017
0.017 0.025 0.025 0.029
IFN (pg/ml) IFNG (12q15)
8 rs2069718
rs2430561 rs35314021 G
A A 0.63 (0.62, 0.64)
0.65 (0.64, 0.66) 0.66 (0.65, 0.66) 0.002
0.003 0.004
MCP-3 (pg/ml) CCL7 (17q12)
3 NA
NA NA
NA
TNF-a (pg/ml) TNF (6p21.33)
11 NA
NA NA
NA
MIP-1a (pg/ml) MIP (12q13.3)
rs799187 7 rs1082214 A
T 1.69 (1.66, 1.72)
1.69 (1.66, 1.72) 0.034
0.034
CXCL-16 (pg/ml) CXCL16 (17p13.2)
24 rs8071286
rs34680313 rs1131456 A
A T 1.42 (1.41, 1.43)
1.39 (1.38, 1.41) 1.36 (1.35, 1.38) 0.018
0.026 0.037
*Adjusted for age, sex, and PCA
Only SNPs that were significant, after adjustment, as listed in this table. The remaining adjusted and unadjusted SNPs are located in Supplementary Table 4. For genes that had no significant SNPs, NA (Not Applicable) was stated.
Supplementary Table 3. The association of genetic variants with serum levels in COVID-19 patients in non-critical (n=264) vs. critical (n=162) cases.
SNP (rs-ID) Genotype Classification Group Genotype (%) Plasma level# p-value*
IL-6
rs1554606
TT Non-Critical
Critical 108 (41.2%)
88 (54.0%) 58.83 (192.48)
220.68 (541.79) <0.001
TG Non-Critical
Critical 135 (51.5%)
67 (41.1%) 113.69 (669.76)
532.52 (1642.56) <0.001
GG Non-Critical
Critical 19 (7.3%)
8 (4.9%) 157.03 (524.17)
569.01 (1255.66) 0.147
rs2069845
GG Non-Critical
Critical 108 (41.2%)
88 (54.0%) 58.83 (192.48)
220.68 (541.79) <0.001
GA Non-Critical
Critical
135 (51.5%) 67 (41.1%)
113.69 (669.76)
532.52 (1642.56) <0.001
AA Non-Critical
Critical 19 (7.3%)
8 (4.9%) 157.03 (524.17)
569.01 (1255.66) 0.147
rs2069832
AA Non-Critical
Critical 92 (35.1%)
82 (50.3%) 63.77 (206.33)
229.02 (558.48) <0.001
AG Non-Critical
Critical 147 (56.1%)
70 (42.9%) 107.42 (642.38)
514.92 (1609.44) <0.001
GG Non-Critical
Critical 23 (8.8%)
11 (6.7%) 131.64 (477.51)
438.81 (1074.56) 0.063
rs1474347
CC Non-Critical
Critical 93 (35.5%)
82 (50.3%) 63.09 (205.28)
229.02 (558.48) <0.001
CA Non-Critical
Critical 146 (55.7%)
71 (43.6%) 108.15 (644.53)
509.29 (1598.60) <0.001
AA Non-Critical
Critical 23 (8.8%)
10 (6.1%) 131.64 (477.51)
471.16 (1127.03) 0.114
rs1474348
CC Non-Critical
Critical 93 (35.5%)
82 (50.3%) 63.09 (205.28)
229.02 (558.48) <0.001
CG Non-Critical
Critical 146 (55.7%)
70 (42.9%) 108.15 (644.53)
514.92 (1609.44) <0.001
GG Non-Critical
Critical
23 (8.8%) 11 (6.7%)
131.64 (477.51)
438.82 (1074.57) 0.065 IFN
rs2069718
AA Non-Critical
Critical
80 (30.5%) 61 (37.6%)
116.55 (749.25)
19.75 (61.11) 0.304
GA Non-Critical
Critical 128 (48.8%)
70 (43.4%) 35.15 (176.58)
63.37 (423.87) 0.649
GG Non-Critical
Critical 54 (20.6%)
31 (19.1%) 39.94 (142.77)
291.88 (1067.86) 0.114
rs2430561
TT Non-Critical
Critical 100 (38.2
75 (46.3 95.05 (670.77)
17.79 (55.73) 0.336
TA Non-Critical
Critical 120 (45.8
66 (40.7 36.53 (182.18)
65.65 (436.57 0.571
AA Non-Critical
Critical 42 (16.0
21 (12.9 49.78 (160.83)
429.59 (1284.03) 0.831
rs35314021
GG Non-Critical
Critical 100 (38.2%)
74 (45.6%) 95.05 (670.77)
18.03 (56.07) 0.278
GA Non-Critical
Critical 120 (45.8%)
66 (40.7%) 36.54 (182.18)
65.65 (436.57) 0.571
AA Non-Critical
Critical 42 (16.0%)
22 (13.5%) 49.78 (160.83)
410.06 (1256.43) 0.658
3
CXCL-16
rs8071286
GG Non-Critical
Critical 77 (30.0%)
43 (26.4%) 12887.99 (5859.42)
18055.16 (9233.45) <0.001
GA Non-Critical
Critical 122 (47.7%)
80 (49.1%) 12890.81 (8465.89)
15785.05 (9971.78) <0.001
AA Non-Critical
Critical 57 (22.3%)
40 (24.5%) 13398.94 (9016.73)
16583.59 (9604.62) 0.008
rs34680313
GG Non-Critical
Critical 117 (64.3%)
65 (39.8%) 12936.08 (6107.67)
16867.03 (8750.73) <0.001
GA Non-Critical
Critical 115 (60.2%)
76 (46.6%) 12365.11 (8216.16)
16413.96 (10925.29) <0.001
AA Non-Critical
Critical 24 (52.2%)
22 (13.6%) 16386.84 (12337.52)
16304.58 (7916.21) 0.272
rs1131456
CC Non-Critical
Critical 117 (64.3%)
65 (39.8%) 12927.73 (6113.65)
16887.82 (8748.52) <0.001
CT Non-Critical
Critical 115 (60.2%)
76 (46.6%) 12373.60 (8212.22)
16415.14 (10920.01) <0.001
TT Non-Critical
Critical
24 (52.2%) 22 (13.6%)
16386.84 (12337.52)
16239.11 (7944.64) 0.281
# Concentration unit (pg/ul) for IL-6 and IFN, pg/ml for CXCL16
* All cytokine data were compared by two-tailed unpaired Mann-Whitney U-test
Supplementary Table 4. Unadjusted and Adjusted effect size and p-value of the following genes:
CCR1, CCR2, CCR3, CCR5, CD46, CXCL16, CXCR6, DPP9, FYCO1, IFNAR2, IFNG, IL1, IL6, LIMD1, LRRC2, LZTFL1, OAS1, OAS2, OAS3, SLC6A2, SLC6A20, VSTM2A, XCR1, TNF-A, MIP, CXCL10, CCL7, CCL2, CCR9, CD40, FCGR2, IL17, PEDS1. Two candidate gene association tests were conducted that included unadjusted analysis (correction for population stratification using the top ten eigenvectors) and adjustment analysis (correction for population stratification using the top ten eigenvectors, age, and gender). Association was measured using logistic regression, assuming additive allelic effects.
