GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant
Abstract
:1. Introduction
2. Results
2.1. Patient Characteristics
2.2. The TT Genotype of GNB3 Is Associated with a Higher Risk of Myocardial Infarction after Renal Transplant
2.3. The TT Genotype of GNB3 Is an Independent Risk Factor for the Occurrence of Acute PAOD after Renal Transplant
2.4. The TT Genotype of GNB3 Is Not Associated with Allograft Failure or Rejection after Renal Transplant
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. HLA Typing of Recipients and Donors
4.3. HLA Antibody Detection and Specification
4.4. GNB3 rs5443 Genotyping
4.5. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ABMR | antibody-mediated rejection |
ADA | American Diabetes Association |
Anti-HLA | anti–human leukocyte antigen |
ATG | anti-thymocyte globulin |
BKV | BK virus |
CAD | coronary artery disease |
cAMP | Adenosine 3′5′ Cyclic Monophosphate |
CDC | complement-dependent cytotoxicity |
CI | confidence interval |
CKD-EPI | Chronic Kidney Disease Epidemiology Collaboration |
CMV | cytomegalovirus |
D | donor |
DDG | Deutsche Diabetes-Gesellschaft |
DNA | Deoxyribonucleic Acid |
DSA | donor-specific antibody |
DTT | dithiothreitol |
EBV | Epstein-Barr virus |
ECG | electrocardiogram |
EDTA | ethylenediaminetetraacetic acid |
eGFR | estimated glomerular filtration rate |
ESRD | end-stage renal disease |
GDP | Guanosine diphosphate |
GNB3 | guanine nucleotide-binding protein subunit β3 |
GTP | Guanosine triphosphate |
Gβ3s | truncated Gβ3 molecule |
HEV | hepatitis E virus |
HLA | human leukocyte antigen |
HWE | Hardy–Weinberg equilibrium |
IgG | immunoglobulin G |
IL-2 | interleukin-2 |
MFI | mean fluorescence intensity |
MI | myocardial infarction |
MM | mismatch |
MMF | mycophenolate mofetil |
MPA | mycophenolic acid |
mTOR | mammalian target of rapamycin |
OR | odds ratio |
PAOD | peripheral artery occlusive disease |
PCR | polymerase chain reaction |
PRA | panel-reactive antibodies |
PTLD | post-transplant lymphoproliferative disorder; |
R | recipient |
RFLP | restriction fragment length polymorphism |
SAB | single antigen bead |
Tx | transplantation |
VZV | Varicella-Zoster virus |
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All Patients n = 436 | GNB3 TT n = 43 | GNB3 CC/CT n = 393 | χ2 | OR (CI 95%) | p Value | |
---|---|---|---|---|---|---|
Recipients | ||||||
Age in years, median (range) | 53 (18–81) | 56 (18–71) | 53 (18–81) | 0.27 | ||
Women, n (%) | 183 (42) | 13 (30) | 170 (43) | 2.70 | 0.57 (0.28–1.1) | 0.10 |
Previous transplants, n (%) | 52 (12) | 5 (12) | 47 (12) | 0.004 | 0.97 (0.4–2.51) | 0.95 |
CMV status positive, n (%) | 270 (62) | 30 (70) | 240 (61) | 1.24 | 1.47 (0.76–2.99) | 0.26 |
CMV high risk (D+/R−), n (%) | 75 (17) | 5 (12) | 70 (18) | 1.04 | 0.61 (0.25–1.52) | 0.31 |
PRA, n (%) | 37 (8) | 3 (7) | 34 (9) | 0.14 | 0.79 (0.25–2.56) | 0.71 |
Preformed anti-HLA antibodies, n (%) | 163 (37) | 15 (35 | 148 (38) | 0.13 | 0.89 (0.47–1.69) | 0.72 |
Class I, n (%) | 89 (20) | 7 (16) | 82 (21) | 0.50 | 0.74 (0.3–1.68) | 0.48 |
Class II, n (%) | 27 (6) | 4 (9) | 23 (6) | 0.79 | 1.65 (0.59–4.91) | 0.37 |
Class I and II, n (%) | 47 (11) | 4 (9) | 43 (11) | 0.11 | 0.83 (0.31–2.25) | 0.74 |
Preformed anti-HLA DSA, n (%) | 38 (9) | 3 (7) | 35 (9) | 0.18 | 0.77 (0.24–2.47) | 0.67 |
Rest diuresis in ml, median (range) | 500 (0–3000) | 500 (0–2500) | 500 (0–3000) | 0.36 | ||
Delayed graft function, n (%) | 99 (23) | 9 (21) | 90 (23) | 0.09 | 0.89 (0.41–1.85) | 0.77 |
Cold ischemia time in minutes, median (range) | 660 (58–1869) | 507 (98–1177) | 665 (58–1869) | 0.84 | ||
Warm ischemia time in minutes, median (range) | 26 (11–82) | 27 (11–50) | 26 (11–82) | 0.85 | ||
Coronary artery disease pretransplant, n (%) | 93 (21) | 12 (28) | 81 (21) | 1.23 | 1.49 (0.75–3.03) | 0.27 |
Chronic PAOD, n (%) | 58 (13) | 9 (21) | 49 (12) | 2.41 | 1.86 (0.82–4.1) | 0.12 |
Diabetes mellitus pretransplant, n (%) | 68 (16) | 9 (21) | 59 (15) | 1.03 | 1.50 (0.67–3.21) | 0.31 |
Diabetes mellitus type I pretransplant, n (%) | 18 (4) | 3 (7) | 15 (4) | 0.98 | 1.89 (0.56–6.64) | 0.32 |
Diabetes mellitus type II pretransplant, n (%) | 48 (11) | 5 (12) | 43 (11) | 0.02 | 1.07 (0.44–2.8) | 0.89 |
Diabetes mellitus type III pretransplant, n (%) | 2 (1) | 1 (2) | 1 (1) | 3.64 | 9.33 (0.48–177.6) | 0.06 |
Donors | ||||||
Deceased, n (%) | 313 (72) | 27 (63) | 286 (73) | 1.91 | 0.63 (0.33–1.26) | 0.17 |
Age in years, median (range) | 52 (0–82) | 52 (22–76) | 52 (0–82) | 0.58 | ||
Female, n (%) | 203 (47) | 21 (49) | 182 (46) | 0.10 | 1.11 (0.58–2.09) | 0.75 |
CMV status, +/−, n (%) | 245 (56) | 24 (56) | 221 (56) | 0.003 | 0.98 (0.53–1.8) | 0.96 |
ABO-incompatible transplant, n (%) | 33 (8) | 6 (14) | 27 (7) | 2.78 | 2.20 (0.88–5.72) | 0.10 |
Immunosuppression at time of transplant | ||||||
IL-2 receptor antagonist, n (%) | 405 (93) | 36 (84) | 369 (94) | 6.07 | 0.33 (0.13–0.87) | 0.01 |
ATG, n (%) | 23 (5) | 5 (12) | 18 (5) | 3.85 | 2.74 (1.06–7.86) | 0.05 |
Calcineurin inhibitor, n (%) | 436 (100) | 43 (100) | 393 (100) | |||
Tacrolimus, n (%) | 402 (92) | 41 (95) | 361 (92) | 0.66 | 1.82 (0.48–7.94) | 0.42 |
Tacrolimus extended-release formulation, n (%) | 26 (6) | 5 (12) | 21 (5) | 2.73 | 2.33 (0.91–6.39) | 0.10 |
Cyclosporine A, n (%) | 34 (8) | 2 (5) | 32 (8) | 0.66 | 0.55 (0.13–2.08) | 0.42 |
mTOR inhibitor, n (%) | 73 (17) | 7 (16) | 66 (17) | 0.007 | 0.96 (0.39–2.23) | 0.93 |
MMF/MPA, n (%) | 362 (83) | 36 (84) | 326 (83) | 0.02 | 1.06 (0.46–2.6) | 0.90 |
Steroids, n (%) | 436 (100) | 43 (100) | 393 (100) | |||
Rituximab, n (%) | 5 (1) | 2 (5) | 3 (1) | 5.17 | 6.34 (1.09–31.54) | 0.02 |
Other, n (%) | 3 (1) | 0 | 3 (1) | 0.33 | 0 (0.0–10.64) | 0.57 |
HLA mismatches | ||||||
MM (A/B), n (%) | 362 (83) | 35 (81) | 327 (83) | 0.09 | 0.88 (0.4–1.89) | 0.76 |
HLA class I MM (A/B): 1–2, n (%) | 214 (49) | 16 (37) | 198 (50) | 2.69 | 0.58 (0.3–1.1) | 0.10 |
HLA class I MM (A/B): 3–4, n (%) | 148 (34) | 19 (44) | 129 (33) | 2.23 | 1.62 (0.88–3.05) | 0.14 |
MM (DR), n (%) | 312 (72) | 28 (65) | 284 (72) | 0.97 | 0.72 (0.37–1.36) | 0.32 |
HLA class II MM (DR): 1, n (%) | 206 (47) | 16 (37) | 190 (48) | 1.93 | 0.63 (0.32–1.19) | 0.16 |
HLA class II MM (DR): 2, n (%) | 106 (24) | 12 (28) | 94 (24) | 0.34 | 1.23 (0.63–2.49) | 0.56 |
Causes of renal failure | ||||||
1. Diabetic glomerulosclerosis, n (%) | 41 (9) | 8 (19) | 33 (8) | 4.74 | 2.49 (1.13–5.6) | 0.03 |
due to diabetes mellitus type II, n (%) | 23 (5) | 5 (12) | 18 (5) | 3.85 | 2.74 (1.06–7.86) | 0.05 |
due to diabetes mellitus type I, n (%) | 18 (4) | 3 (7) | 15 (4) | 0.98 | 1.89 (0.56–6.64) | 0.32 |
2. Chronic glomerulonephritis, n (%) | 117 (27) | 10 (23) | 107 (27) | 0.31 | 0.81 (0.4–1.71) | 0.58 |
3. Nephrosclerosis, n (%) | 58 (13) | 8 (19) | 50 (13) | 1.16 | 1.57 (0.73–3.55) | 0.28 |
4. Polycystic kidney disease, n (%) | 66 (15) | 5 (12) | 61 (15) | 0.46 | 0.72 (0.3–1.81) | 0.50 |
5. Tubulointerstitial nephritis, n (%) | 15 (3) | 0 | 15 (4) | 1.70 | 0 (0.0–2.28) | 0.19 |
6. Congenital anomalies, n (%) | 39 (9) | 6 (14) | 33 (8) | 1.47 | 1.77 (0.73–4.43) | 0.23 |
7. Autoimmune disease, n (%) | 18 (4) | 0 | 18 (5) | 2.05 | 0 (0.0–1.82) | 0.15 |
8. Amyloidosis, n (%) | 4 (1) | 0 | 4 (1) | 0.44 | 0 (0.0–9.44) | 0.51 |
9. Reflux nephropathy/recurrent pyelonephritis, n (%) | 21 (5) | 3 (7) | 18 (5) | 0.49 | 1.56 (0.47–5.19) | 0.49 |
10. HUS, n (%) | 8 (2) | 0 | 8 (2) | 0.89 | 0 (0.0–4.23) | 0.35 |
11. Other, n (%) | 49 (11) | 4 (9) | 45 (12) | 0.18 | 0.79 (0.29–2.13) | 0.67 |
All Patients n = 436 | GNB3 TT n = 43 | GNB3 CC/CT n = 393 | χ2 | OR (CI 95%) | p Value | |
---|---|---|---|---|---|---|
Acute cardiovascular events after transplant | ||||||
Death due to cardiovascular event, n (%) | 11 (3) | 4 (9) | 7 (2) | 8.92 | 5.66 (1.78–18.83) | 0.003 |
Myocardial infarction, n (%) | 35 (8) | 8 (19) | 27 (7) | 7.23 | 3.1 (1.37–7.23) | 0.007 |
Stroke, n (%) | 13 (3) | 1 (2) | 12 (3) | 0.07 | 0.76 (0.07–4.32) | 0.79 |
Acute PAOD, n (%) | 28 (6) | 7 (16) | 21 (5) | 7.71 | 3.44 (1.33–8.24) | 0.006 |
Posttransplant diabetes mellitus, n (%) | 75 (17) | 3 (7) | 72 (18) | 3.50 | 0.33 (0.11–1.01) | 0.06 |
Allograft outcome | ||||||
Cellular rejection, n (%) | 81 (19) | 7 (16) | 74 (19) | 0.17 | 0.84 (0.34–1.93) | 0.68 |
Borderline rejection, n (%) | 77 (18) | 2 (5) | 75 (19) | 5.55 | 0.21 (0.05–0.8) | 0.02 |
Cellular and borderline rejection, n (%) | 137 (31) | 9 (21) | 128 (33) | 2.44 | 0.55 (0.25–1.18) | 0.12 |
ABMR with DSAs, n (%) | 28 (6) | 0 (0) | 28 (7) | 3.27 | 0 (0.0–1.07) | 0.07 |
All ABMR, n (%) | 56 (13) | 2 (5) | 54 (14) | 2.86 | 0.31 (0.07–1.21) | 0.09 |
All rejections, n (%) | 155 (36) | 10 (23) | 145 (37) | 3.15 | 0.52 (0.26–1.08) | 0.08 |
Multiple cellular/borderline rejections, n (%) | 29 (7) | 1 (2) | 28 (7) | 1.44 | 0.31 (0.03–1.73) | 0.23 |
Transplant failure, n (%) | 52 (12) | 5 (12) | 47 (12) | 0.004 | 0.97 (0.4–2.51) | 0.95 |
Decrease in eGFR, n (%) | 84 (19) | 6 (14) | 78 (20) | 0.87 | 0.65 (0.28–1.6) | 0.35 |
de novo anti-HLA antibodies, n (%) | 117 (27) | 13 (30) | 104 (26) | 0.28 | 1.2 (0.59–2.38) | 0.60 |
Class I, n (%) | 42 (10) | 4 (9) | 38 (10) | 0.006 | 0.96 (0.35–2.62) | 0.94 |
Class II, n (%) | 42 (10) | 6 (14) | 36 (9) | 1.02 | 1.61 (0.66–3.97) | 0.31 |
Class I and II, n (%) | 33 (8) | 3 (7) | 30 (8) | 0.02 | 0.91 (0.28–2.99) | 0.88 |
de novo anti HLA DSA, n (%) | 51 (12) | 4 (9) | 47 (12) | 0.26 | 0.76 (0.28–2.02) | 0.61 |
Class I, n (%) | 17 (4) | 1 (2) | 16 (4) | 0.32 | 0.56 (0.05–3.47) | 0.57 |
Class II, n (%) | 24 (6) | 2 (5) | 22 (6) | 0.07 | 0.82 (0.19–3.31) | 0.80 |
Class I and II, n (%) | 10 (2) | 1 (2) | 9 (2) | 0.0002 | 1.01 (0.09–6.49) | 0.99 |
Infections | ||||||
CMV infection, n (%) | 162 (37) | 11 (26) | 151 (38) | 2.74 | 0.55 (0.27–1.12) | 0.10 |
CMV disease, n (%) | 34 (8) | 4 (9) | 30 (8) | 0.15 | 1.24 (0.45–3.51) | 0.70 |
BKV viremia, n (%) | 101 (23) | 13 (30) | 88 (22) | 1.34 | 1.5 (0.72–2.99) | 0.25 |
BKV nephropathy, n (%) | 30 (7) | 3 (7) | 27 (7) | 0.001 | 1.02 (0.31–3.1) | 0.98 |
HEV infection, n (%) | 11 (3) | 1 (2) | 10 (3) | 0.008 | 0.91 (0.08–5.56) | 0.93 |
EBV reactivation, n (%) | 84 (19) | 11 (26) | 73 (19) | 1.22 | 1.51 (0.71–3.16) | 0.27 |
Influenza A and B infections, n (%) | 19 (4) | 0 (0) | 19 (5) | 2.17 | 0 (0.0–1.7) | 0.14 |
Norovirus infection, n (%) | 9 (2) | 2 (5) | 7 (2) | 1.58 | 2.69 (0.55–12.76) | 0.21 |
HSV infection, n (%) | 6 (1) | 0 (0) | 6 (2) | 0.67 | 0 (0.0–6.65) | 0.41 |
VZV/Zoster infection, n (%) | 11 (3) | 0 (0) | 11 (3) | 1.24 | 0 (0.0–3.43) | 0.27 |
Pyelonephritis, n (%) | 122 (28) | 10 (23) | 112 (28) | 0.53 | 0.76 (0.37–1.6) | 0.47 |
More than 1 episode, n (%) | 64 (15) | 4 (9) | 60 (15) | 1.10 | 0.57 (0.21–1.61) | 0.29 |
Pneumonia, n (%) | 62 (14) | 6 (14) | 56 (14) | 0.003 | 0.98 (0.42–2.29) | 0.96 |
More than 1 episode, n (%) | 21 (5) | 2 (5) | 19 (5) | 0.003 | 0.96 (0.21–4.0) | 0.96 |
Sepsis, n (%) | 85 (19) | 7 (16) | 78 (20) | 0.31 | 0.79 (0.32–1.8) | 0.58 |
More than 1 episode, n (%) | 21 (5) | 3 (7) | 18 (5) | 0.49 | 1.56 (0.47–5.19) | 0.49 |
Malignant tumors | ||||||
Solid malignant tumor, n (%) | 47 (11) | 6 (14) | 41 (10) | 0.50 | 1.39 (0.58–3.38) | 0.48 |
Squamous cell carcinoma, n (%) | 52 (12) | 4 (9) | 48 (12) | 0.31 | 0.74 (0.27–1.97) | 0.58 |
PTLD, n (%) | 2 (1) | 0 (0) | 2 (1) | 0.22 | 0 (0.0–19.89) | 0.64 |
Myocardial Infarction n = 35 | Patients without Myocardial Infarction n = 401 | Univariate Relative Risk (95% CI) | p Value | Multivariate Relative Risk (95% CI) | p Value | |
---|---|---|---|---|---|---|
Variable | ||||||
Age in years, median (range) | 59 (29–71) | 52 (18–81) | 0.005 | 1.04 (1.01–1.08) | 0.01 | |
Women, n (%) | 11 (31) | 172 (43) | 0.73 (0.43–1.14) | 0.19 | ||
Diabetes mellitus pretransplant, n (%) | 11 (31) | 57 (14) | 2.21 (1.24–3.63) | 0.007 | 3.72 (1.71–8.09) | <0.001 |
Nephrosclerosis as cause of ESRD, n (%) | 5 (14) | 53 (13) | 1.08 (0.46–2.33) | 0.86 | ||
GNB3 TT genotype, n (%) | 8 (23) | 35 (9) | 2.62 (1.29–4.93) | 0.007 | 2.23 (0.95–5.24) | 0.065 |
Follow-up time, median (range) | 2113 (379–3474) | 2027 (6–3756) | 0.35 | |||
Time on dialysis, median (range) | 1445 (11–6822) | 1078 (0–12379) | 0.02 | 1.00 (1.00–1.00) | <0.001 | |
IL-2 receptor antagonist, n (%) | 33 (94) | 372 (93) | 1.02 (0.88–1.08) | 0.74 | ||
ATG, n (%) | 2 (6) | 21 (5) | 1.09 (0.29–3.82) | 0.9 | ||
Decrease in eGFR, n (%) | 7 (20) | 77 (19) | 1.04 (0.51–1.94) | 0.91 |
Acute PAOD n = 28 | Patients without Acute PAOD n = 408 | Univariate Relative Risk (95% CI) | p Value | Multivariate Relative Risk (95% CI) | p Value | |
---|---|---|---|---|---|---|
Variable | ||||||
Age in years, median (range) | 53 (32–70) | 53 (18–81) | 0.64 | |||
Women, n (%) | 9 (32) | 174 (43) | 0.75 (0.42–1.21) | 0.28 | ||
Diabetes mellitus pretransplant, n (%) | 13 (46) | 55 (13) | 3.44 (2.07–5.25) | <0.001 | 5.55 (2.59–11.91) | <0.001 |
Nephrosclerosis as cause of ESRD, n (%) | 4 (14) | 54 (13) | 1.08 (0.42–2.49) | 0.87 | ||
GNB3 TT genotype, n (%) | 7 (25) | 36 (9) | 2.83 (1.35–5.40) | 0.006 | 2.39 (1.00–5.72) | 0.05 |
Follow-up time in days, median (range) | 2154 (1153–3418) | 2027 (6–3756) | 0.12 | |||
Time on dialysis, median (range) | 1321 (152–5895) | 1109 (0–12379) | 0.19 | |||
IL-2 receptor antagonist, n (%) | 24 (86) | 381 (93) | 0.92 (0.73–1.02) | 0.13 | ||
ATG, n (%) | 2 (7) | 21 (5) | 1.39 (0.37–4.76) | 0.65 | ||
Decrease in eGFR, n (%) | 4 (14) | 80 (20) | 0.73 (0.29–1.65) | 0.49 |
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Peitz, T.; Möhlendick, B.; Siffert, W.; Heinemann, F.M.; Kribben, A.; Eisenberger, U.; Friebus-Kardash, J. GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant. Int. J. Mol. Sci. 2022, 23, 9783. https://doi.org/10.3390/ijms23179783
Peitz T, Möhlendick B, Siffert W, Heinemann FM, Kribben A, Eisenberger U, Friebus-Kardash J. GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant. International Journal of Molecular Sciences. 2022; 23(17):9783. https://doi.org/10.3390/ijms23179783
Chicago/Turabian StylePeitz, Tobias, Birte Möhlendick, Winfried Siffert, Falko Markus Heinemann, Andreas Kribben, Ute Eisenberger, and Justa Friebus-Kardash. 2022. "GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant" International Journal of Molecular Sciences 23, no. 17: 9783. https://doi.org/10.3390/ijms23179783