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Genetic Variants in Nicotinamide-N-Methyltransferase (NNMT) Gene are Related to the Stage of Non-Alcoholic Fatty Liver Disease Diagnosed by Controlled Attenuation Parameter (CAP)-FibroScan

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Eman M. Hasan1, Rasha A. Abd Al Aziz1, Dina Sabry2, Samar K. Darweesh1, Hedy A. Badary1, Aisha Elsharkawy1, Mahmood M. Abouelkhair 1, Ayman Yosry1

1) Hepato-Gastroenterology and Endemic Medicine Department,
2) Medical Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt

DOI: http://dx.doi.org/10.15403/jgld.2014.1121.273.wsh

Background & Aims: Various genetic polymorphisms play a key-role in the pathogenesis of NAFLD and progression to NASH with fibrosis to cirrhosis. We aimed to study the association between single-nucleotide polymorphisms (SNPs) in NNMT gene, namely rs694539 and the development of different stages of NAFLD diagnosed by controlled attenuation parameter (CAP) of FibroScan Echosens®.

Methods: Transient elastography (FibroScan®) with controlled attenuation parameter (CAP) measurement was performed in 81 NAFLD patients (35 of them with liver biopsy) and 80 non-NAFLD controls. The accuracy of CAP and FibroScan for the detection and quantification of hepatic steatosis/fibrosis, respectively, was assessed based on liver biopsy aspect. Genetic variants of NNMT gene rs694539 were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results: According to BMI (kg/m2), among the patients, 17 (21%) were overweight, 56 (69.1%) obese, and 8 (9.9%) morbidly obese. CAP and FibroScan diagnosed steatosis/fibrosis correlated significantly with liver biopsy. There was a significant association between polymorphisms of rs694539-NNMT gene and NAFLD presence and stages. The mutant type (AA-genotype) was found in 33% NAFLD patients versus 1.2% controls (P<0.001), whereas the wild type (GG-genotype) was present in 21% versus 63.8% controls (P<0.001). Moreover, the AA-genotype significantly correlated with the steatosis degree by CAP but not the fibrosis degree by FibroScan. Multivariate regression analysis of all the independent risk factors showed non-significant correlations with the degree of steatosis on CAP. However, by using a stepwise approach, waist circumference showed significance as an independent predictor of NAFLD.

Conclusions: Polymorphisms in rs694539-NNMT gene (mutant AA-genotype) could be a genetic risk factor for developing NAFLD and NASH (indicating susceptibility for progression and complications). Individuals with wild type (GG-genotype) are at less risk of NAFLD development. CAP and FibroScan efficiently diagnosed steatosis and fibrosis.

Key words: Non-alcoholic Fatty Liver Disease (NAFLD) − Non-alcoholic Steatohepatitis (NASH) − Nicotinamide-N-methyltransferase (NNMT) gene − Single Nucleotide Polymorphisms (SNPs) − Controlled attenuation parameter (CAP) − FibroScan.

Abbreviations: CAP: controlled attenuation parameter; FBG: fasting blood glucose; LSM: Liver stiffness measurement; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic Steatohepatitis; NNMT: Nicotinamide-N-methyltransferase; PCR-RFLP: Polymerase chain reaction-Restriction fragment length polymorphism; SNPs: Single Nucleotide Polymorphisms; TE: transient elastography; TG: triglycerides; T2DM: type 2 dabetes mellitus.