ArtIcle
Recipient But Not Donor Adiponectin Polymorphisms Are Associated With Early Posttransplant Hepatic Steatosis in Patients Transplanted for Non-Nonalcoholic Fatty Liver Disease Indications Binu V. John,1,* Taylor Aiken,2,* Ari Garber,3 Dawn Thomas,4 Rocio Lopez,5 Deepa Patil,4 Venkata Rajesh Konjeti,1 John J Fung,6 Arthur J. McCollough,3 Medhat Askar7 Abstract Objectives: De novo steatosis after liver transplant is common and can occur in up to one-third of patients who are transplanted for liver disease other than for nonalcoholic fatty liver disease. Genetic factors may influence posttransplant steatosis; in a posttransplant setting, donor or recipient genetic factors could also play roles. Genetic polymorphisms in the adiponectin gene have been associated with metabolic syndrome in the pretransplant setting. We aimed to assess the association between donor and recipient adiponectin polymorphisms and early posttransplant hepatic steatosis identified on liver biopsies. Materials and Methods: Clinical data were collected for 302 liver transplant patients who underwent protocol biopsies for hepatitis C. Of these, 111 patients had available biopsies and donor/recipient DNA. Patients with grade 1 steatosis or greater (35% of patients) were compared with patients without posttransplant steatosis with respect to clinical features and donor/recipient adiponectin polymorphism genotypes. Results: Patients who developed posttransplant steatosis and those without steatosis were similar with respect to individual components of metabolic syndrome. The adiponectin polymorphisms rs1501299 G/G and rs17300539 G/G genotypes in recipients were associated with early posttransplant graft steatosis. From the 1Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia; the 2Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; the 3Digestive Diseases Institute, the 4Department of Pathology, and the 5Quantitative Health Sciences Department, Cleveland Clinic, Cleveland, Ohio; the 6Department of Surgery, University of Chicago Medical Center, Chicago, Illinois; and the 7Transplant Immunology Department, Baylor University Medical Center, Dallas, Texas, USA Acknowledgements: This work was completed with support of the Cleveland Clinic RPC Award and the Bradford L. Roller and Laura Pederson Philanthropic Fund to Dr. John. The authors have no conflict of interest regarding publication of this paper to declare. *Binu V. John and Taylor Aiken contributed equally to this study. Corresponding author: Binu V. John, Assistant Professor of Medicine, Virginia Commonwealth University, Medical Director of Liver Transplantation, McGuire VA Medical Center, 1201 Broad Rock Blvd., Richmond VA 23249, USA Phone: +1 8046755021 E-mail:
[email protected]
Experimental and Clinical Transplantation (2018) Copyright © Başkent University 2018 Printed in Turkey. All Rights Reserved.
We found no associations between graft steatosis and donor adiponectin polymorphisms. Conclusions: Genetic polymorphisms in the adiponectin gene of recipients (but not donors) are associated with early de novo posttransplant hepatic steatosis, independent of components of metabolic syndrome. Key words: Graft steatosis, Hepatitis C, Liver transplantation Introduction Posttransplant nonalcoholic fatty liver disease (NAFLD) is a common complication after liver transplant.1 Nearly 1 of 3 patients transplanted for a non-NAFLD indication will develop fatty liver disease after transplant, which may predispose patients to fibrosis progression even when their original liver disease is under good control.2 Posttransplant metabolic syndrome and steatosis are precursors to steatohepatitis in the allograft.1 Graft steatosis is partly driven by posttransplant metabolic syndrome, which in turn is influenced by weight gain, drug-induced hyperlipidemia, and diabetes, often related to immunosuppression.1 However, the incidence of NAFLD is different among patients with similar body mass index and metabolic risk factors, raising the possibility of genetic factors driving posttransplant NAFLD mediated both by metabolic syndrome and independent of it. Liver biopsy remains the criterion standard for assessing disease recurrence and severity after liver transplant; in the absence of reliable noninvasive biomarkers of disease severity, many transplant programs have adopted protocol liver biopsy to riskstratify patients before the availability of effective direct-acting antiviral therapies.3 These biopsies, performed routinely in all patients with hepatitis C DOI: 10.6002/ect.2018.0070
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virus (HCV) regardless of liver enzymes, allow identification of de novo hepatic steatosis in the posttransplant setting. Plasma adiponectin levels have been associated with different genetic loci, but the adiponectin gene (ADIPOQ), located at position 3q27, remains the main genetic determinant of plasma levels.4,5 Several single nucleotide polymorphisms located in the ADIPOQ gene have been associated with adiponectin serum levels and obesity, making this gene a candidate for obesity and metabolic syndrome.6 Genetic polymorphisms in the adiponectin gene have been hypothesized to be a risk factor for NAFLD. Our aim was to assess the relationship between donor and recipient genetic polymorphisms in the adiponectin gene and posttransplant hepatic steatosis. We hypothesized that posttransplant hepatic steatosis is driven by metabolic syndrome in the recipient rather than donor factors and therefore likely associated with recipient adiponectin genetic polymorphisms. Materials and Methods Study design We reviewed 302 adult patients (> 18 years old) transplanted for cirrhosis secondary to chronic hepatitis C between 2006 and 2011 at a single tertiary care academic medical center (Cleveland Clinic, Cleveland, OH, USA). This was a retrospective analysis of a prospectively assembled cohort. All patients with chronic HCV who underwent protocol liver biopsies at 6 months and were at 1-year posttransplant were identified. Patients who had a self-reported posttransplant alcohol intake of > 30 g/week were excluded. Patients who lacked donor and recipient DNA results or posttransplant protocol liver biopsies were also excluded. liver biopsy A single pathologist with expertise in posttransplant liver biopsies who was blinded to the adiponectin polymorphism and clinical data interpreted all biopsies. Hepatic steatosis was graded on an ordinal scale from 0 to 3 (grade 0 = less than 5% steatosis; grade 1 = 5%-33% steatosis; grade 2 = 34%-66%; and grade 3 = greater than or equal to 67% steatosis).7 Hepatic fibrosis was quantified from stages 0 to 4, with advanced fibrosis defined as fibrosis stage ≥ 3 and graft cirrhosis defined as stage 4.
Exp Clin Transplant
Posttransplant immunosuppression mainly included tacrolimus, with mycophenolate added for 12 months. Prednisone was weaned within 2 months after transplant. Patients who received transplants for hepatocellular carcinoma and those with chronic kidney disease were considered high risk for recurrence and were switched to sirolimus after 12 weeks based on the discretion of the treating hepatologist. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and 2008 Declaration of Istanbul and was approved by the Institutional Review Board at the Cleveland Clinic. DNA collection and genotyping Donor and recipient DNA results were extracted from whole blood and stored at the time of transplant according to the center’s standard protocol. Adiponectin gene polymorphisms rs1501299 (+276G>T), rs266729 (-11377C>G), rs2241766 (+45T>G), and rs17300539 (-11391 G>A) were analyzed by TaqMan single nucleotide polymorphism genotyping assay (Life Technologies, Carlsbad, CA, USA). Statistical analyses Data are presented as mean and standard deviation, median (with 25th to 75th percentiles), or number and percent (%). The prevalence of each genotype among donors and recipients was estimated by calculating the percentage of patients with each genotype. Pearson chi-square tests were used for categorical variables, and analysis of variance or the nonparametric Kruskal-Wallis tests were used for continuous or ordinal factors. In addition, multivariable logistic regression was performed to assess associations between genotypes and steatosis after adjusting for race and HCV genotype. P < .05 was considered statistically significant. All analyses were performed using SAS (version 9.4, The SAS Institute, Cary, NC, USA). Results recipient characteristics For this study, we evaluated 302 consecutive patients who received transplants for cirrhosis of the liver between 2006 and 2011. Of these, 111 donor/recipient pairs who met the inclusion criteria were included in the analysis. Mean age of recipients at time of transplant was 56 ± 6 years and 73% were male. There
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were 39 patients noted to have grade 1 or greater steatosis in protocol posttransplant liver biopsies, whereas the other 72 patients did not have posttransplant steatosis. Patients with posttransplant steatosis were more likely to be white and less likely to have genotype 1 infection (Table 1). There were no other significant differences between the groups, inclu-
ding coexisting pretransplant liver disease (alcohol/nonalcoholic steatohepatitis [NASH]) or the presence of risk factors for metabolic syndrome (Table 1). Donor characteristics Patients with and without steatosis were compared with respect to donor characteristics (Table 2).
table 1. Recipient Demographics and Pretransplant Characteristics Factor
Overall (N = 111) No. Summary
No Steatosis (n = 72) No. Summary
Steatosis (n = 39) No. Summary
Recipient age at transplant, y Recipient sex, No. (%) Male Female Recipient race, No. (%) White African American Other Recipient white ethnicity, No. (%) Recipient CMV-positive, No. (%) Diagnosis, No. (%) HCV HCV + alcohol HCV + NASH HCV + HCC HCV + alcohol + HCC HCV + HBV ± HCC HCV genotype, No. (%) 1 2 3 4 Hypertension, No. (%) Diabetes, No. (%)
111 111
72 72
39 39
55.8 ± 6.4 81 (73.0) 30 (27.0)
106
106 111 111
51 (70.8) 21 (29.2) 69
79 (74.5) 22 (20.8) 5 (4.7) 79 (74.5) 80 (72.1)
69 72 72
30 (27.0) 18 (16.2) 2 (1.8) 51 (45.9) 7 (6.3) 3 (2.7) 104
111 111
55.9 ± 6.9
46 (66.7) 19 (27.5) 4 (5.8) 46 (66.7) 52 (72.2)
37 39 39
21 (29.2) 8 (11.1) 2 (2.8) 35 (48.6) 3 (4.2) 3 (4.2)
72 72
.039c 33 (89.2) 3 (8.1) 1 (2.7) 33 (89.2) 28 (71.8)
.011c .96c .18d
9 (23.1) 10 (25.6) 0 (0.0) 16 (41.0) 4 (10.3) 0 (0.0) 35
55 (79.7) 1 (1.4) 10 (14.5) 3 (4.3) 35 (48.6) 20 (27.8)
.81a .49c
30 (76.9) 9 (23.1) 37
69 77 (74.0) 8 (7.7) 15 (14.4) 4 (3.8) 55 (49.5) 29 (26.1)
55.6 ± 5.5
P Value
39 39
.010c 22 (62.9) 7 (20.0) 5 (14.3) 1 (2.9) 20 (51.3) 9 (23.1)
.79c .59c
Abbreviations: CMV, cytomegalovirus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis P values were calculated with aANOVA, cPearson chi-square test, and dFisher exact test.
table 2. Donor Characteristics Factor
Overall (N = 111) No. Summary
No Steatosis (n = 72) No. Summary
Steatosis (n = 39) No. Summary
Donor age at death, y Donor sex, No. (%) Male Female Donor race, No. (%) White African American Other Donor white ethnicity, No. (%) Donor CMV-positive, No. (%) Donor HCV-positive, No. (%) Height, cm Partial/split graft, No. (%) Split Whole Donor source, No. (%) Regional share National share Local Cold ischemia time, h Donor COD Anoxia CVA Other Trauma Donor risk index
111 111
72 72
39 39
40.8 ± 14.0 73 (65.8) 38 (34.2)
111
111 111 111 111 111
51 (70.8) 21 (29.2) 72
84 (75.7) 25 (22.5) 2 (1.8) 84 (75.7) 64 (57.7) 16 (14.4) 173.3 ± 10.1
72 72 72 72 72
2 (1.8) 109 (98.2) 111
107 110
106
40.1 ± 14.3
31 (28.2) 41 (37.3) 1 (0.91) 37 (33.6) 2.1 ± 0.49
39 39 39 39 39
2 (2.8) 70 (97.2)
68 71
67
.21c 33 (84.6) 6 (15.4) 0 (0.0) 33 (84.6) 18 (46.2) 3 (7.7) 171.6 ± 10.1
18 (25.4) 26 (36.6) 1 (1.4) 26 (36.6) 2.1 ± 0.47
.11c .071c .14c .19a .54d
0 (0.0) 39 (100.0) 39
39 (54.2) 3 (4.2) 30 (41.7) 7.3 ± 1.6
.45a .13c
22 (56.4) 17 (43.6) 39
51 (70.8) 19 (26.4) 2 (2.8) 51 (70.8) 46 (63.9) 13 (18.1) 174.2 ± 10.0
72 61 (55.0) 6 (5.4) 44 (39.6) 7.4 ± 1.7
42.2 ± 13.6
P Value
39 39
39
Abbreviations: CMV, cytomegalovirus; COD, cause of death; CVA, cerebrovascular accident; HCV, hepatitis C virus P values were calculated with aANOVA, cPearson chi-square test, and dFisher exact test.
.66c 22 (56.4) 3 (7.7) 14 (35.9) 7.5 ± 2.0 13 (33.3) 15 (38.5) 0 (0.0) 11 (28.2) 2.2 ± 0.52
.47a .64c
.54a
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Binu V. John et al/Experimental and Clinical Transplantation (2018)
Median donor age was 40.8 ± 14.0 years, and 75% of all donors were white. There were no significant differences between the 2 groups. The median donor risk index was 2.1, which was comparable between the 2 groups.
Exp Clin Transplant
recipient adiponectin polymorphisms The adiponectin polymorphisms hypothesized to be associated with increased risk of steatosis based on data in the nontransplant population included the rs1501299 G/G, rs266729 non-C/C, rs17300539 G/G, and rs2241766 T/T polymorphisms. On univariate analysis, the risk allele for 3 polymorphisms (rs1501299, rs266729, rs17300539) in recipients was found to be associated with early posttransplant steatosis (Table 4). The recipient rs1501299 G/G polymorphism was more common among patients with posttransplant steatosis (64.1%) than in those without (42.3%) (P = .028; Table 4). Similarly, the recipient adiponectin rs266729 non-C/C genotype was significantly more common among patients with
Posttransplant immunosuppression and metabolic syndrome There were no differences between the 2 groups in terms of immunosuppression used. Both groups were comparable in terms of components of posttransplant metabolic syndrome, including body mass index, diabetes, hypertension, triglycerides, and high-density and low-density lipoprotein levels assessed at 1 year posttransplant (Table 3). table 3. Other Posttransplant Characteristics at 12 Months Factor
BMI, kg/m2 HDL, mg/dL LDL, mg/dL HbA1c Hypertension, No. (%) Diabetes, No. (%) Hyperlipidemia, No. (%) Metabolic syndrome, No. (%) Months from LT to biopsy Tacrolimus, No. (%) Mycophenolate, No. (%) Sirolimus, No. (%) Cyclosporine, No. (%)
Overall (N = 111) No. Summary
110 111 110 55 111 111 111 111 104 106 106 106 106
28.5 ± 6.1 64.8 ± 44.2 128.5 ± 52.8 7.8 ± 3.1 22 (19.8) 40 (36.0) 15 (13.5) 32 (28.8) 11.0 ± 2.3 96 (90.6) 54 (50.9) 19 (17.9) 6 (5.7)
No Steatosis (n = 72) No. Summary
Steatosis (n = 39) No. Summary
72 72 71 35 72 72 72 72 67 68 68 68 68
38 39 39 20 39 39 39 39 37 38 38 38 38
28.3 ± 6.0 67.1 ± 52.2 132.4 ± 60.6 7.9 ± 3.0 12 (16.7) 27 (37.5) 10 (13.9) 19 (26.4) 11.0 ± 2.1 62 (91.2) 31 (45.6) 12 (17.6) 4 (5.9)
28.8 ± 6.3 60.5 ± 22.9 121.3 ± 33.8 7.4 ± 3.2 10 (25.6) 13 (33.3) 5 (12.8) 13 (33.3) 10.9 ± 2.6 34 (89.5) 23 (60.5) 7 (18.4) 2 (5.3)
P Value
.73a .46a .30a .57a .26c .66c .88c .44c .82a .77c .14c .92c .99d
Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LT, liver transplant P values were calculated with aANOVA, cPearson chi-square test, and dFisher exact test.
table 4. Recipient and Donor Genotypes Factor
Recipient rs1501299 GG non-GG Donor rs1501299 GG non-GG Recipient rs2241766 TT non-TT Donor rs2241766 TT non-TT Recipient rs266729 CC non-CC Donor rs266729 CC non-CC Recipient rs17300539 GG non-GG Donor rs17300539 GG non-GG
Overall (N = 111) No. Summary
110
No Steatosis (n = 72) No. Summary
Steatosis (n = 39) No. Summary
71
39
55 (50.0) 55 (50.0) 111
30 (42.3) 41 (57.7) 72
59 (53.2) 52 (46.8) 111
39
69
109
37
71
111
38
72
108
39
72
109
.22c 22 (56.4) 17 (43.6)
36 59 (81.9) 13 (18.1)
71 92 (84.4) 17 (15.6)
.008c 20 (52.6) 18 (47.4)
49 (68.1) 23 (31.9)
94 (87.0) 14 (13.0)
.61c 29 (78.4) 8 (21.6)
55 (77.5) 16 (22.5)
71 (64.0) 40 (36.0)
.83c 31 (79.5) 8 (20.5)
51 (73.9) 18 (26.1)
75 (68.8) 34 (31.2)
.19c 24 (61.5) 15 (38.5)
56 (77.8) 16 (22.2)
80 (75.5) 26 (24.5)
P values were calculated with cPearson chi-square test.
39
72
106
.028c 25 (64.1) 14 (35.9)
35 (48.6) 37 (51.4)
87 (78.4) 24 (21.6)
.026c 35 (97.2) 1 (2.8)
38 61 (85.9) 10 (14.1)
P Value
.55c 31 (81.6) 7 (18.4)
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Binu V. John et al/Experimental and Clinical Transplantation (2018)
The increased incidence among family members and high concordance rates among monozygotic twins with NAFLD indicate a genetic predisposition.8 The ADIPOQ gene is located on human 3q27 and leads to overexpression of adipocytespecific secretory proteins.9 Multiple studies have demonstrated that lower adiponectin levels are associated with type 2 diabetes mellitus, dyslipidemia, and hypertension.10-12 Conversely, weight loss leads to an increase in plasma adiponectin levels.13 Treatment with peroxisome proliferator-activated receptor gamma 2 agonists for hyperglycemia in patients with type 2 diabetes mellitus and blockade of the renin-angiotensin system can increase plasma adiponectin levels.14,15 In the liver, adiponectin has been postulated to play hepatoprotective and antifibrotic roles, possibly through modulation of tumor necrosis factor α, nuclear factor κB, interleukin 6, and hepatic stellate cells.16-19 Previous cardiovascular studies in the literature have suggested an association between adiponectin genetic polymorphisms and metabolic syndrome.20 Although our study did not explore the mechanisms of this association, there are several potential reasons. Genetic polymorphisms in the adiponectin gene have been associated with lower adiponectin levels, which in turn are associated with metabolic syndrome.21 Prior studies have suggested that the rs17300539 G allele is associated with lower adiponectin levels in the nontransplant population; in our study, the G/G phenotype was more common in the steatosis group.21 Similarly, the rs266729 non-C/C phenotype and the rs1501299 G/G phenotype have also been shown to correlate with lower adiponectin levels, with the latter shown to be associated with steatosis in our study.22 The associations of these different recipient genetic polymorphisms are likely due to linkage disequilibrium. Because no association was
steatosis (47% vs 22.5%; P = .008; Table 4). Finally, the recipient rs17300539 G/G polymorphism was more common among patients with steatosis (97.2%) than in patients without steatosis (97.2% vs 81.9%; P = .026; Table 4). The recipient rs2241766 polymorphism did not differ between the 2 groups. On multivariate analysis, 2 recipient polymorphisms (rs1501299 and rs17300539) were found to be significantly associated with posttransplant steatosis (Table 5). After we adjusted for race and HCV genotype, we found that patients who developed posttransplant steatosis were 2.5 times more likely to have the rs1501299 G/G genotype than the non-G/G genotype (odds ratio = 2.5, 95% confidence interval, 1.02-6.2). Recipients with the rs17300539 polymorphism were 20.8 times more likely to have had the G/G genotype than the nonG/G genotype (odds ratio = 20.8, 95% confidence interval, 1.02-425.8). We found no association between any of the donor adiponectin polymorphisms and posttransplant steatosis. Discussion One-third of all patients transplanted for non-NASH indications develop de novo fatty liver disease after transplant. This is driven by metabolic syndrome but can also occur independent of it, with genetic factors likely contributing. Although genetic factors including adiponectin polymorphisms have been studied in nontransplant NAFLD, there are limited data in the posttransplant setting and particularly in the setting of patients transplanted for a non-NASH indication. Moreover, potential genetic contributions from the donor may also play a role in the posttransplant setting. Our data highlight the role of recipient adiponectin polymorphisms in the development of posttransplant hepatic steatosis, independent of individual components of metabolic syndrome. table 5. Adjusted Comparison of Genotypes Factor
Recipient rs1501299: GG vs non-GG Donor rs1501299: GG vs non-GG Recipient rs2241766: TT vs non-TT Donor rs2241766: TT vs non-TT Recipient rs266729: CC vs non-CC Donor rs266729: CC vs non-CC Recipient rs17300539: GG vs non-GG Donor rrs17300539: GG vs non-GG
Unadjusted
Adjusted*
OR (95% CI)
P Value
2.4 (1.09-5.5) 1.7 (0.76-3.7) 1.1 (0.43-2.9) 1.3 (0.50-3.3) 0.32 (0.14-0.75) 0.61 (0.27-1.4) 5.4 (0.89-32.3) 0.72 (0.25-2.1)
.03 .19 .83 .61 .009 .22 .067 .54
Abbreviations: CI, confidence interval; OR, odds ratio *Adjusted for race and HCV genotype (1 vs other).
OR (95% CI)
2.5 (1.02-6.2) 1.9 (0.76-4.6) 0.85 (0.30-2.4) 1.2 (0.43-3.2) 0.47 (0.18-1.2) 0.50 (0.20-1.2) 20.8 (1.02-425.8) 0.70 (0.22-2.2)
P Value
.045 .17 .75 .76 .13 .13 .049 .55
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Binu V. John et al/Experimental and Clinical Transplantation (2018)
noted with donor adiponectin polymorphisms, the de novo steatosis in the graft may be driven by recipient genetic factors. These differences were noted even though there were no statistically significant differences between those with pretransplant versus posttransplant metabolic syndrome in our 2 groups. The fact that all included patients underwent protocol liver biopsy is a strength of this study as it decreased the potential for selection bias. Liver biopsy remains the criterion standard for diagnosing and staging liver disease after liver transplant and is sensitive for the detection of early posttransplant steatosis. Although a controlled attenuation parameter assessed on vibration-controlled transient elastography has been used to assess hepatic steatosis in the nontransplant population, it is less accurate in differentiating grades of steatosis and insensitive to discovering mild steatosis.23 The controlled attenuation parameter has also not been validated in the posttransplant setting. Although our study presented novel observations, we do acknowledge the following limitations. This study was at a single center and retrospective with limited sample size. Only patients with chronic HCV infection transplanted before the universal availability of direct-acting antiviral agents were included because of the need for protocol biopsies that were used for convenience sampling; however, studying this in a primarily non-NASH cohort helps in the understanding of de novo posttransplant steatosis, which is increasingly recognized in this population. Chronic HCV genotype 3 in and of itself can cause hepatic steatosis. However, this was a minority within our cohort and was equally distributed in groups with and without steatosis. We acknowledge that posttransplant NASH or severe steatosis would be the more important clinical outcome of interest; however, none of our patents developed NASH within the study period and the number of cases of grade 2 and 3 steatosis was small. Because few patients underwent protocol liver biopsies in the several years after transplant, we were unable to extend the study to patients with longer follow-up. Despite these limitations, we believe that the findings indicate a meaningful association. The association was only for recipient but not donor genetic polymorphisms, and the findings are consistent with genetic factors associated with recipient visceral adiposity as a driver of posttransplant steatosis in the posttransplant setting.
Exp Clin Transplant
Hepatic steatosis is a precursor to NASH, and genetic factors may play a role in the development of both. In summary, our findings suggest that genetic polymorphisms in the adiponectin gene of recipients (but not donors) are associated with posttransplant hepatic steatosis. These findings merit future studies, including larger cohorts of patients with HCV infection and NAFLD with longer follow-up to validate these observations and to better understand the potential mechanisms. References 1. Dumortier J, Giostra E, Belbouab S, et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil”. Am J Gastroenterol. 2010;105(3):613-620. 2. Martin P, DiMartini A, Feng S, Brown R, Jr., Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59(3): 1144-1165. 3. Firpi RJ, Abdelmalek MF, Soldevila-Pico C, et al. One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection. Liver Transpl. 2004;10(10):1240-1247. 4. Vasseur F, Helbecque N, Dina C, et al. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet. 2002;11(21):2607-2614. 5. Siitonen N, Pulkkinen L, Lindstrom J, et al. Association of ADIPOQ gene variants with body weight, type 2 diabetes and serum adiponectin concentrations: the Finnish Diabetes Prevention Study. BMC Med Genet. 2011;12:5. 6. Menzaghi C, Ercolino T, Di Paola R, et al. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes. 2002;51(7):23062312. 7. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9): 2467-2474. 8. Loomba R, Schork N, Chen CH, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784-1793. 9. Turer AT, Scherer PE. Adiponectin: mechanistic insights and clinical implications. Diabetologia. 2012;55(9):2319-2326. 10. Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab. 2002;87(6):2764-2769. 11. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens. 2003; 16(1):72-75. 12. Snehalatha C, Mukesh B, Simon M, Viswanathan V, Haffner SM, Ramachandran A. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians. Diabetes Care. 2003;26(12):3226-3229. 13. Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab. 2001;86(8):3815-3819. 14. Furuhashi M, Ura N, Higashiura K, et al. Blockade of the reninangiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003;42(1):7681.
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15. Yu JG, Javorschi S, Hevener AL, et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes. 2002;51(10):2968-2974. 16. Kamada Y, Tamura S, Kiso S, et al. Enhanced carbon tetrachlorideinduced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003;125(6):1796-1807. 17. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91-100. 18. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6(10): 772-783. 19. Masaki T, Chiba S, Tatsukawa H, et al. Adiponectin protects LPSinduced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40(1):177-184.
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20. Ohashi K, Ouchi N, Kihara S, et al. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol. 2004;43(7):1195-1200. 21. Hivert MF, Manning AK, McAteer JB, et al. Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study. Diabetes. 2008;57(12):33533359. 22. Hsieh CJ, Wang PW, Hu TH. Association of adiponectin gene polymorphism with nonalcoholic fatty liver disease in Taiwanese patients with type 2 diabetes. PLoS One. 2015;10(6):e0127521. 23. de Ledinghen V, Wong GL, Vergniol J, et al. Controlled attenuation parameter for the diagnosis of steatosis in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016;31(4):848-855.
