Abstract
Alcoholic liver disease (ALD) is a highly prevalent spectrum of pathologies caused by alcohol overconsumption. Morbidity and mortality related to ALD are increasing worldwide, thereby demanding strategies for early diagnosis and detection of ALD predisposition. A potential candidate as a marker for ALD susceptibility is the transcription factor nuclear factor erythroid-related factor 2 (Nrf2), codified by the nuclear factor erythroid 2-related factor 2 gene (NFE2L2). Nrf2 regulates expression of proteins that protect against oxidative stress and inflammation caused by alcohol overconsumption. Here, we assessed genetic variants of NFE2L2 for association with ALD. Specimens from patients diagnosed with cirrhosis caused by ALD were genotyped for three NFE2L2 single nucleotide polymorphisms (SNP) (SNPs: rs35652124, rs4893819, and rs6721961). Hematoxylin & eosin and immunohistochemistry were performed to determine the inflammatory score and Nrf2 expression, respectively. SNPs rs4893819 and rs6721961 were not specifically associated with ALD, but analysis of SNP rs35652124 suggested that this polymorphism predisposes to ALD. Furthermore, SNP rs35652124 was associated with a lower level of Nrf2 expression. Moreover, liver samples from ALD patients with this polymorphism displayed more severe inflammatory activity. Together, these findings provide evidence that the SNP rs35652124 variation in the Nrf2-encoding gene NFE2L2 is a potential genetic marker for susceptibility to ALD.
Highlights
Alcoholic liver disease (ALD), a spectrum of pathologies that include fatty liver disease, alcoholic hepatitis, and cirrhosis caused by alcohol overconsumption [1,2], is a global public health issue
It is estimated that 2 million people die of liver disease each year, and up to 50% of these cases are due in part to alcoholic cirrhosis [1]
A/G: n = 16 patients—88.9%; allele G/G: n = 2 patients—11.1%) (Table 4). These results suggest that the presence of the nucleotide A in the position -178 of the promoter region of nuclear factor erythroid 2-related factor 2 gene (NFE2L2) is associated with cirrhotic liver disease, since both ALD and hepatitis C virus (HCV) samples preferentially showed this polymorphism
Summary
Alcoholic liver disease (ALD), a spectrum of pathologies that include fatty liver disease, alcoholic hepatitis, and cirrhosis caused by alcohol overconsumption [1,2], is a global public health issue. 2.4 billion people consume alcohol worldwide, and 75 million people are at risk of alcohol-associated liver disease [3]. It is estimated that 2 million people die of liver disease each year, and up to 50% of these cases are due in part to alcoholic cirrhosis [1]. ALD, as with other chronic liver diseases, may not be clinically apparent early in the disease process. This highlights the importance of early diagnosis for management and treatment to prevent cirrhosis-related morbidity and mortality, as well as to detect ALD susceptibility.
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