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Carmen Ester1,3, Razvan Cerban1,3,, Razvan Iacob1,3, Speranta Iacob1,3, Andrei Sorop4, Lorand Savu6, Mihaela Lita1, Georgiana Constantin2, Liliana Paslaru2,3 , Camelia Grancea5,
Simona Ruta3,5, Irinel Popescu4, Liana Gheorghe1,3
1. Department of Hepatology and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
2. Department of Biochemistry – Liver Transplant Unit, Fundeni Clinical Institute, Bucharest, Romania
3. Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
4. Department of General Sugery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
5. Stefan Nicolau Virology National Institute, Bucharest, Romania
6. Genetic Lab, Bucharest, Romania
PoPoster 11
Metabolic syndrome in liver transplant recipients – The role of genetic testing and blood based biomarkers
Introduction
No significant statistical difference was found for the TM6SF2 SNP (OR=0.4, p=0.42).
For the PNPLA3 SNP rs we can observe a progressive decrease in the mean serum total cholesterol values when the mutation is present (from 176 mg/dl in CC SNP, to 170 mg/dl in CG SNP to 165 mg/dl in GG SNP) and a slight increase in the median triglycerides serum levels from 106 mg/dl with the CC SNP towards 126 mg/dl with the GG SNP.
Table 2. PNPLA3 rs polymorphisms in serum lipids and BMI
Table 3: TM6SF2 rs polymorphisms in serum lipids and BMI
The multivariate logistic regression results identified PNPLA3 variants and CXCL10 > 350 ng/ml as independent risk factors for fibrosis, although for CG variant of PNPLA3 the evidence is inconclusive (p = 0.062).
Table 4: Multivariate logistic regression :
Liver transplant recipients are more likely to develop de-novo or recurrent non-alcoholic fatty liver disease (NAFLD), most of them fulfilling the criteria for metabolic syndrome. Our aim was to assess the impact of single nucleotide polymorphyisms of PNPLA3 rs ( C>G) and TM6SF2 ( C>T) and novel blood biomarkers (CXCL-10 and CXCL-12) on the presence of steatosis, fibrosis progression and metabolic syndrome. .
Materials and methods
Variable CC CG GG
BMI – Mean ± S.D.
27.85 ± 4.95
27.30 ± 4.37
25.94 ± 3.72
Total Chol – Mean ± S.D.
± 31.61
± 51.14
± 45.90
TGL – Median (IQR)
(35.00)
(188.50)
(89.00)
Variable CC CT
BMI – Mean ± S.D.
26.75 ± 4.28
28.93 ± 5.11
Total Chol – Mean ± S.D.
169.1 ± 42.65
± 56.99
TGL – Median (IQR)
(78.00)
98.00 (31.00)
We assessed 61 liver transplant recipients for clinical and biological features and genetic polymorphism in the PNPLA3 and TM6SF2 genes using the automated TaqMan pre-designed SNP genotyping assay. All patients performed abdominal ultrasound, Fibroscan® with CAP module and non-invasive scores for liver fibrosis (APRI, FIB-4, NAFLD).
Results
Parameter
Coeficient
p value
Odds Ratio [CI95%]
PNPLA3   - CC
                   CG
                   GG
reference
1.69
2.65 -
0.062
0.021
5.42 [1.07 to 43.85]
14.15 [1.67 to ]
CXCL10 >= 350 No
                           Yes
1.87
0.020
6.54 [1.43 to 37.20]
HCV cirrhosis was the main indication for liver transplantation (69% of patients), 62.3% were males and the mean age at evaluation was 56 years. The incidence of metabolic syndrome was 53.33% in the studied population. The heterozygous SNP polymorphisms of PNPLA3 (CG) was the most frequent in the studied population (52,83%), and the homozygous mutation was found in 13,21% (7 patients).
Figure 1: PNPLA3 SNP
Regarding the TM6SF2 polymorphism the heterozygous type was found in 11,32% of patients and no patients presented the homozygous form.
Figure 2: TM6SF2 SNP
The univariate logistic regression for the predictors of liver fibrosis identified PNPLA3 SNP that a genotype other than CC for PNPLA3 is associated with a lower risk for metabolic syndrome  : for CG variant OR = 5.15 (p = 0.053), and for GG variant OR = with p =0.031.
Table 1: Univariate logistic regression for liver fibrosis :
Conclusions
PNPLA3 polymorphism impacts on the key elements of metabolic syndrome like the increase in serum tryglicerides and fibrosis progression. The observed result of lower serum cholesterol in patients with heterozygous and even more in patients with homozygous polymorphism of PNPLA3 gene could be closely correlated with the increase in intrahepatic cholesterol deposits, but this should be confirmed by larger histology-based studies. PNPLA3 polymorphism and CXCL-10 have been identified as the main predictors for advanced fibrosis in liver transplant recipients.
Bibliography
1. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet, 2008, 40(12): 1461–146
2. Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis[J]. Am J Gastroenterol, 2014, 109(3): 325–334
3. Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet, 2014, 46(4): 352–356.
4. Meena BB, Scott LF. Hepatic Fibrogenesis. In: James S Dooley, Anna SF Lok, Andrew K Burroughs, E Jenny Heathcote., editors. Sherlock's Diseases of the Liver and Biliary System. 11th Edition. Wiley Blackwell; Oxford, United Kingdom: pp. 94–101.
5. Valenti L, Al‐Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al. Homozygosity for the PNPLA3 / adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. HEPATOLOGY 2010; 51: 1209‐1217.
Contact information
Parameter
Coefficent
p value
Odds Ratio [CI95%]
Age
0.05
0.166
1.05 [0.97 to 1.15]
Sex  F
       M
reference
-0.25 -
0.650
0.77 [0.26 to 2.33]
PNPLA3   - CC
                   CG
                   GG
1.64
2.30
0.053
0.031
5.15 [1.14 to 37.01]
10.00 [1.35 to ]
TM6SF2  - CC
                     CT
-0.91
0.421
0.40 [0.01 to 2.78]
CXCL10 >= 350 No
                           Yes
1.85
0.007
6.37 [1.74 to 27.29]
CXCL12 >= 1800  No
                              Yes
0.62
0.414
1.87 [0.40 to 8.78]
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