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The association of genetic factors with serum calretinin levels in asbestos-related diseases

Cita Zupanc
Cita Zupanc
, 
Alenka Franko
Alenka Franko
, 
Danijela Strbac
Danijela Strbac
, 
Viljem Kovac
Viljem Kovac
, 
Vita Dolzan
Vita Dolzan
 y 
Katja Goricar
Katja Goricar
   | 30 nov 2023
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Article Category: Research Article
Publicado en línea: 30 nov 2023
Páginas: 473 - 486
Recibido: 19 oct 2023
Aceptado: 31 oct 2023
DOI: https://doi.org/10.2478/raon-2023-0061
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© 2023 Cita Zupanc et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

Association of selected single nucleotide polymorphisms (SNPs) with serum calretinin concentration: CALB2 rs889704 (A), E2F2 rs2075995 (B), MIR335 rs3807348 (C), NRF1 rs13241028 (D).
Association of selected single nucleotide polymorphisms (SNPs) with serum calretinin concentration: CALB2 rs889704 (A), E2F2 rs2075995 (B), MIR335 rs3807348 (C), NRF1 rs13241028 (D).

Association of investigated single nucleotide polymorphisms (SNPs) with malignant mesothelioma (MM) susceptibility

SNP Genotype Subjects without MM (N = 616) N (%) MM patients (N = 288) N (%) OR (95% CI) P OR (95% CI)adj Padj
CALB2 rs1862818 CC 340 (55.2) 139 (48.3) Reference Reference
CT 226 (36.7) 120 (41.7) 1.30 (0.97–1.75) 0.084 1.35 (0.97–1.87) 0.073
TT 50 (8.1) 29 (10.1) 1.42 (0.86–2.34) 0.169 1.34 (0.77–2.32) 0.299
CT+TT 276 (44.8) 149 (51.7) 1.32 (1.00–1.75) 0.052 1.35 (0.99–1.83) 0.059
CALB2 rs889704 CC 485 (78.9) [1] 223 (77.4) Reference Reference
CA 121 (19.7) 61 (21.2) 1.10 (0.78–1.55) 0.602 1.03 (0.70–1.51) 0.899
AA 9 (1.5) 4 (1.4) 0.97 (0.29–3.17) 0.955 0.55 (0.15–1.94) 0.349
CA+AA 130 (21.1) 65 (22.6) 1.09 (0.78–1.52) 0.626 0.98 (0.67–1.42) 0.912
CALB2 rs8063760 CC 352 (57.3) [2] 175 (60.8) Reference Reference
CT 222 (36.2) 97 (33.7) 0.88 (0.65–1.19) 0.398 0.91 (0.66–1.26) 0.576
TT 40 (6.5) 16 (5.6) 0.80 (0.44–1.48) 0.483 0.82 (0.42–1.60) 0.554
CT+TT 262 (42.7) 113 (39.2) 0.87 (0.65–1.15) 0.329 0.90 (0.65–1.23) 0.493
E2F2 rs2075995 CC 117 (19.0) 70 (24.3) Reference Reference
CA 319 (51.8) 149 (51.7) 0.78 (0.55–1.11) 0.171 0.83 (0.56–1.23) 0.349
AA 180 (29.2) 69 (24.0) 0.64 (0.43–0.96) 0.032 0.68 (0.44–1.07) 0.093
CA+AA 499 (81.0) 218 (75.7) 0.73 (0.52–1.02) 0.067 0.78 (0.53–1.13) 0.182
MIR335 rs3807348 GG 158 (25.8) [3] 70 (24.3) Reference Reference
GA 307 (50.1) 139 (48.3) 1.02 (0.72–1.44) 0.902 1.00 (0.68–1.46) 0.98
AA 148 (24.1) 79 (27.4) 1.20 (0.81–1.78) 0.352 1.22 (0.79–1.87) 0.376
GA+AA 455 (74.2) 218 (75.7) 1.08 (0.78–1.50) 0.636 1.07 (0.75–1.52) 0.724
NRF1 rs13241028 TT 374 (60.7) 173 (60.1) Reference Reference
TC 210 (34.1) 103 (35.8) 1.06 (0.79–1.43) 0.699 1.08 (0.78–1.50) 0.636
CC 32 (5.2) 12 (4.2) 0.81 (0.41–1.61) 0.550 0.92 (0.44–1.93) 0.823
TC+CC 242 (39.3) 115 (39.9) 1.03 (0.77–1.37) 0.853 1.06 (0.78–1.45) 0.711
SEPTIN7 rs3801339 TT 109 (17.7) 55 (19.1) Reference Reference
TC 266 (43.2) 135 (46.9) 1.01 (0.68–1.48) 0.976 1.05 (0.69–1.61) 0.815
CC 241 (39.1) 98 (34.0) 0.81 (0.54–1.20) 0.291 0.76 (0.49–1.18) 0.218
TC+CC 507 (82.3) 233 (80.9) 0.91 (0.64–1.30) 0.610 0.91 (0.61–1.35) 0.627

Receiver operating characteristic (ROC) curve analysis according to individual genotypes for selected single nucleotide polymorphisms: comparison of malignant mesothelioma (MM) patients with all other subjects

SNP Genotype AUC (95% CI) P Calretinin cut-off (ng/ml)1 Sensitivity Specificity
Overall analysis in the whole group / 0.825 (0.781–0.868) < 0.001 0.32 0.681 0.887
CALB2 rs889704 CC 0.831 (0.782–0.880) < 0.001 0.32 0.695 0.876
CA 0.779 (0.667–0.891) < 0.001 0.31 0.607 0.935
AA2 0.958 (0.837–1.000) 0.019 0.21 1.000 0.833
CA+AA 0.801 (0.702–0.901) < 0.001 0.31 0.625 0.940
E2F2 rs2075995 CC 0.906 (0.845–0.968) < 0.001 0.26 0.810 0.903
CA 0.803 (0.736–0.869) < 0.001 0.32 0.671 0.888
AA 0.781 (0.686–0.876) < 0.001 0.33 0.615 0.877
CA+AA 0.797 (0.742–0.851) < 0.001 0.32 0.653 0.881
MIR335 rs3807348 GG 0.853 (0.766–0.940) < 0.001 0.29 0.757 0.872
GA 0.803 (0.739–0.867) < 0.001 0.32 0.643 0.892
AA 0.845 (0.765–0.925) < 0.001 0.35 0.738 0.881
GA+AA 0.815 (0.764–0.866) < 0.001 0.32 0.675 0.881
NRF1 rs13241028 TT 0.812 (0.754–0.871) < 0.001 0.32 0.693 0.884
TC 0.868 (0.804–0.931) < 0.001 0.23 0.818 0.798
CC3 0.664 (0.406–0.922) 0.203 0.18 0.714 0.700
TC+CC 0.842 (0.777–0.907) < 0.001 0.23 0.790 0.785

Clinical characteristics of the subjects included in the study

Characteristic Category/unit No disease (N = 83) Pleural plaques (N = 380) Asbestosis (N = 153) MM (N = 288) P
Sex Male, N (%) 61 (73.5) 262 (68.9) 119 (77.8) 213 (74.0) 0.1801
Female, N (%) 22 (26.5) 118 (31.1) 34 (22.2) 75 (26.0)
Age Median (25%–75%) 53.4 (48.5–59.2) 54.8 (48.8–62.7) 59.4 (51.3–66.1) 66.0 (59–73) < 0.0012
Smoking No, N (%) 46 (55.4) 187 (49.2) 74 (48.4) 158 (56.4) [8] 0.2051
Yes, N (%) 37 (44.6) 193 (50.8) 79 (51.6) 122 (43.6)

Association of selected SNPs with serum calretinin concentration

SNP Genotype All subjects Subjects without MM MM patients
Calretinin (ng/ml) Median (25–75%) Padd Pdom Calretinin (ng/ml) Median (25–75%) Padd Pdom Calretinin (ng/ml) Median (25–75%) Padd Pdom
CALB2 rs1862818 CC 0.18 (0.11–0.34) 0.622 0.422 0.15 (0.09–0.22) 0.751 0.865 0.64 (0.22–1.45) 0.952 0.802
CT 0.19 (0.11–0.41) 0.16 (0.09–0.24) 0.51 (0.23–1.41)
TT 0.18 (0.10–0.37) 0.13 (0.08–0.20) 0.38 (0.21–3.57)
CT+TT 0.19 (0.11–0.40) 0.15 (0.09–0.24) 0.48 (0.23–1.43)
CALB2 rs889704 CC 0.19 (0.11–0.37) 0.099 0.036 0.15 (0.10–0.23) 0.130 0.069 0.52 (0.25–1.43) 0.508 0.441
CA 0.17 (0.08–0.27) 0.16 (0.08–0.21) 0.44 (0.14–1.35)
AA 0.21 (0.05–0.77) 0.10 (0.02–0.21) 1.07 (0.28–1.84)
CA+AA 0.17 (0.08–0.28) 0.14 (0.07–0.21) 0.50 (0.15–1.51)
CALB2 rs8063760 CC 0.18 (0.11–0.38) 0.955 0.770 0.14 (0.09–0.22) 0.382 0.647 0.53 (0.24–1.44) 0.326 0.768
CT 0.18 (0.12–0.32) 0.16 (0.1–0.24) 0.44 (0.19–1.30)
TT 0.21 (0.06–0.51) 0.12 (0.05–0.22) 0.86 (0.50–2.30)
CT+TT 0.19 (0.11–0.34) 0.16 (0.09–0.24) 0.51 (0.21–1.43)
E2F2 rs2075995 CC 0.19 (0.10–0.46) 0.512 0.481 0.14 (0.08–0.2) 0.161 0.059 0.72 (0.33–1.45) 0.189 0.117
CA 0.18 (0.12–0.34) 0.16 (0.1–0.23) 0.53 (0.20–1.48)
AA 0.18 (0.10–0.33) 0.14 (0.09–0.24) 0.40 (0.18–0.90)
CA+AA 0.18 (0.11–0.34) 0.15 (0.1–0.23) 0.48 (0.20–1.44)
MIR335 rs3807348 GG 0.18 (0.09–0.34) 0.057 0.151 0.14 (0.08–0.2) 0.027 0.081 0.44 (0.26–1.43) 0.400 0.978
GA 0.18 (0.11–0.34) 0.14 (0.09–0.22) AA vs. GG P = 0.029 0.50 (0.18–1.16)
AA 0.21 (0.13–0.39) 0.18 (0.11–0.26) 0.65 (0.27–1.80)
GA+AA 0.19 (0.11–0.37) 0.15 (0.1–0.23) 0.52 (0.22–1.44)
NRF1 rs13241028 TT 0.19 (0.12–0.36) 0.272 0.144 0.16 (0.1–0.23) 0.096 0.034 0.52 (0.21–1.15) 0.381 0.672
TC 0.18 (0.10–0.33) 0.14 (0.08–0.21) 0.64 (0.25–1.67)
CC 0.17 (0.07–0.36) 0.15 (0.07–0.3) 0.24 (0.07–1.18)
TC+CC 0.18 (0.09–0.34) 0.14 (0.08–0.21) 0.46 (0.24–1.53)
SEPTIN7 rs3801339 TT 0.18 (0.11–0.34) 0.403 0.419 0.14 (0.09–0.2) 0.424 0.288 0.35 (0.17–1.05) 0.079 0.080
TC 0.18 (0.11–0.33) 0.15 (0.09–0.22) 0.51 (0.21–1.23)
CC 0.20 (0.11–0.45) 0.16 (0.09–0.25) 0.72 (0.38–1.48)
TC+CC 0.19 (0.11–0.37) 0.15 (0.09–0.23) 0.64 (0.26–1.45)

Association of CALB2 haplotypes with malignant mesothelioma (MM) susceptibility and serum calretinin concentration

Haplotype Subjects without MM Predicted frequency MM patients Predicted frequency OR (95% CI) P OR (95% CI)adj Padj Serum calretinin concentration P
CCC 0.457 0.431 Reference Reference
TCC 0.245 0.294 1.26 (0.0–991.60) 0.061 1.26 (0.97–1.64) 0.084 0.272
CCT 0.176 0.147 0.88 (0.65–1.20) 0.415 0.94 (0.66–1.34) 0.731 0.125
CAT 0.058 0.066 1.21 (0.77–1.89) 0.408 1.08 (0.64–1.81) 0.782 0.731
CAC 0.045 0.047 1.11 (0.64–1.91) 0.713 0.99 (0.55–1.79) 0.974 0.852

Genotype frequencies of investigated single nucleotide polymorphisms (SNPs) in the whole study group, their variant allele frequency (VAF) and agreement with Hardy-Weinberg equilibrium (HWE) in subjects without any asbestos-related disease (controls)

Gene SNP Nucleotide or amino acid change Predicted function Genotype N (%) VAF (controls) pHWE (controls)
CALB2 rs1862818 c.-828C>T May influence transcription factor binding, may alter chromatin states and regulatory motifs CC 479 (53.0) 0.27 0.617
CT 346 (38.3)
TT 79 (8.7)
CALB2 rs889704 c.-634C>A May influence transcription factor binding, may alter chromatin states and regulatory motifs CC 708 (78.4) [1] 0.14 0.814
CA 182 (20.2)
AA 13 (1.4)
CALB2 rs8063760 c.*138T>C May influence miRNA binding, may alter regulatory motifs CC 527 (58.4) [2] 0.23 0.322
CT 319 (35.4)
TT 56 (6.2)
E2F2 rs2075995 c.678C>A, p.Gln226His Nonsynonymous, may influence splicing CC 187 (20.7) 0.61 0.209
CA 468 (51.8)
AA 249 (27.5)
MIR335 rs3807348 g.130496266G>A Downstream transcript variant, may influence transcription factor binding GG 228 (25.3) [3] 0.49 0.376
GA 446 (49.5)
AA 227 (25.2)
NRF1 rs13241028 c.*1321T>C May influence miRNA binding TT 547 (60.5) 0.22 0.061
TC 313 (34.6)
CC 44 (4.9)
SEPTIN7 rs3801339 c.1168-4451T>C Genic downstream transcript variant1 TT 164 (18.1) 0.63 0.187
TC 401 (44.4)
CC 339 (37.5)
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