GENETIC BACKGROUND ASSOCIATED WITH THE PROGRESSION OF NON- ALCOHOLIC FATTY LIVER DISEASE TO LIVER FIBROSISHTML Full Text
GENETIC BACKGROUND ASSOCIATED WITH THE PROGRESSION OF NON- ALCOHOLIC FATTY LIVER DISEASE TO LIVER FIBROSIS
Madiha Nooreen * 1, Shafia Fatima 2, Mahenaaz Sultana 1, Zeba Fatima 2 and Zeenath Unnissa 2
Department of Pharmacy Practice 1, Mesco College of Pharmacy, Hyderabad - 500006, Telangana, India.
Department of Pharmacy Practice 2, Deccan School of Pharmacy, Hyderabad - 500001, Telangana, India.
ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease around the world. Individuals with obesity, diabetes, hyperlipidemia, metabolic syndrome, and insulin resistance are more likely to develop steatosis; however, it seldom progresses to steatohepatitis, fibrosis, and cirrhosis. In addition to the environmental factors, genetic variations further modify NAFLD progression. Several epidemiological, familial, and twin studies have elucidated the role of heritability. More recent genome-wide association studies and candidate gene studies have reported certain genes that play a key role in the susceptibility and advancement of NAFLD. The genetic basis of the disease further enhances the understanding of the pathogenic mechanism, which helps in developing novel biomarkers and therapeutic strategies. This review provides a summary of the genes involved in the susceptibility of NAFLD.
Obesity, Insulin Resistance, Steatohepatitis, Oxidative Stress
INTRODUCTION: In the development of non-alcoholic fatty liver disease NAFLD, a range of factors influence its progression. Some of the factors involved are: environmental factors (diet and sedentary lifestyle), genetic susceptibility, heredity - its involvement has been suggested by various epidemiological, familial, twin studies and case series, race, and ethnicity 1. NAFLD is more prevalent in the East Asian Indian population, followed by Hispanics, Asians, Caucasians, and African Americans 2, 3. In addition to the metabolic risk factors, genetic susceptibility in the pathogenesis of metabolic syndrome also impacts NAFLD progression.
In the past decade, interesting data has been put forth, indicating a strong involvement of genetics in NAFLD. For easier understanding, genetic studies can be divided into two branches: candidate gene studies and genome-wide association studies (GWAS). A candidate gene study analyses the results of previous genomic/proteomic and animal studies. A gene is then selected to investigate its presumed role in the pathogenesis of the disease. Genome-wide association study tests the association between the common traits found in the human genome with that of its polymorphic traits such as disease progression, drug response, etc. Statistical bias can be a roadblock in GWAS 4.
Genome-Wide Association Studies on NAFLD Development And Progression: The first GWAS for non-alcoholic steatohepatitis (NASH) was conducted by Romeo et al., comprised of 9229 single nucleotide polymorphisms (SNPs) from a mixed population that included Hispanic, African American, and European ancestry derived from the Dallas Heart Study 5, 6. Hepatic steatosis was evaluated by the non-invasive proton magnetic resonance spectroscopy (1H-MRS) technique 7. The result was path-breaking as it inferred PNPLA3 variants as strong modifiers of NASH, especially rs738409[G]; I148M- that was entailed with higher hepatic triglyceride content and hepatic inflammation in all ethnic groups but most frequently in Hispanics. The hepatic triglyceride content was found to be twice in PNPLA3 homozygous individuals than in its non-carriers. The homozygous carriers had twice serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. On the other hand, variation in rs6006460[T] was correlated with lower hepatic fat 5, 8.
The association of PNPLA3 in NAFLD has been observed in different Asian ethnicities such as as- Japanese 9, Indian 10, and Chinese 11. There were elevated levels of serum ALT in both histologically established NAFLD and NASH 9, 10. A meta-analysis which aimed to estimate the strength of the effect of I148M (rs738409 C/G) PNPLA3 on NAFLD and its severity among the different population has reported a strong influence of rs738409 on both liver fat accumulation and severity of the disease 12. A more recent meta-analysis that included 23 case-control studies (6071 NAFLD and 10366 controls) has revealed a significant association of the variant rs738409 with NAFLD and NASH, irrespective of the subject's ethnicities and age 13.
In the past decade, various studies involving PNPLA3 rs738409 variant have revealed its prominent role in hepatic fat content. More recent studies have indicated its role in the portal and lobular inflammation, Mallory-Denk bodies and NASH progression, and advanced fibrosis 14.
Chalasni et al. conducted the second GWAS study in 236 non-Hispanic Caucasian women with NAFLD. This study included clinical, laboratory, and histological data and analyzed 324,623SNPs from the 22 autosomal chromosomes. The inferences were drawn after age, body mass index (BMI), diabetes, waist:hipratios, and levels of glycated hemoglobin (HbA1c) were adjusted in multivariate logistic models. Though this study has reported any relationship between PNLPA3 and NASH progression, but the potential markers identified needs to be validated in larger cohort studies. The NAFLD activity score was found to be associated with SNP rs2645424 on chromosome 8 in the gene encoding farnesyl diphosphate farnesyl transferase 1 (FDFT1) (p=6.8×10−7), an enzyme that plays a role in cholesterol biosynthesis. In addition to SNP rs2645424, SNP rs1227756 on chromosome 10 in COL13A1 (P=2.0×10−7), rs6591182 on chromosome 11 (P=8.6×10−7), and rs887304 on chromosome 12 in EFCAB4B (P=7.7×10−7) were associated with hepatic lobular inflammation. rs2499604 on chromosome 1 (P=2.2×10−6), rs6487679 on chromosome 12 in PZP (P=1.3×10−6), rs1421201 on chromosome 18 (P=1.0×10−5), and rs2710833 on chromosome 4 (P=6.3×10−7) were associated with increased serum alanine aminotransferase levels. No significant association was established between genetic markers and phenotypic features such as steatosis, ballooning degeneration, portal inflammation, or other features of NAFLD.15 It is noteworthy to mention that a cohort study carried out in Britain with a sample size of 340 NAFLD patients showed no significant role of FDFT1 rs2645424 SNP in determining the severity of steatosis and fibrosis 16.
Spelioetes et al. carried out a meta-analysis of combined GWAS studies datasets. Computed Tomography (CT) was used to analyze the population-based samples for hepatic steatosis. Primarily, the study confirmed the SNP rs738409 of PNPLA3 presence with the NAFLD susceptibility 17. Furthermore, the study has identified four additional SNPs that were localized in or near the following genes-
Neurocan (NCAN - rs2228603): In a replication study, NCAN was found to be related to histologically established hepatic steatosis. NCAN plays a role in cell adhesion mechanisms and lipoprotein metabolism. Its locus is closely associated with the TM6SF2 minor allele 18.
Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 3B (PPP1R3B - Rs4240624): The encoded protein is involved in regulating glycogen synthesis in liver and skeletal muscle tissue. Alteration in variants near it affects glycemic levels.
Glucokinase Regulator (GCKR - rs780094): This SNP encodes glucose metabolism regulator in the liver. Its alteration affects glucokinase activity, eventually leading to elevated hepatic glycolytic flux, de novo lipogenesis, and triglyceride levels. Many studies have confirmed a connection between NAFLD susceptibility, progression to NASH, and GCKR - rs780094 19. A study which included both Asian and non-Asian population has also reported similar results 20.
Lysophospholipase-like 1 (LYPLAL1 - rs12137 855): This SNP provides a complementary function to the PNPLA3 in triglyceride metabolism.
The presence of PPP1R3B - Rs4240624 along with PNPLA3 results in increased CT assessed hepatic steatosis but not histologically assessed NAFLD. On the contrary, the rest of the three SNPs, i.e., NCAN, GCKR, and LYPLAL1 together with PNPLA3 resulted not only in increased CT assessed hepatic steatosis but also histologically assessed NAFLD 21.
Following Table 1 summarizes the effects of genes that were found to be involved in the disease progression in GWAS studies.
TABLE 1: GENES AND SNPS CONFIRMED BY GWAS
|GWAS||Author||Gene||SNPs||Effect on liver|
|First||Romeo et al.||PNPLA3 (Patatin-like phospholipase domain-containing 3)||Rs738409[G]
|Increases triglyceride levels|
|Second||Chalasni et al.||FDFT1 (Farnesyl diphosphate farnesyl transferase 1)||Rs2645424||Hepatic lobular inflammation|
|COL13A1 (Collagen, type XIII, alpha 1)||Rs1227756
|Hepatic lobular inflammation|
|EFCAB4B (EF-hand calcium binding domain 4B)||Rs887304||Hepatic lobular inflammation|
|PZP (Pregnancy zone protein)||Rs249604
|Third||Speliotes et al.
|PNPLA3 (Patatin-like phospholipase domain-containing 3)||Rs738409||Increases ALT/AST|
|NCAN (Neurocan)||Rs2228603||Alters lipoprotein metabolism|
|PPP1R3B (Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 3B)||Rs4240624||Alters glycemic levels|
|GCKR (Glucokinase regulator)||Rs780094||Increases hepatic glycotic flux|
|LYPLAL1 (Lysophospholipase-like 1)||Rs12137855||Increases triglyceride levels|
Potential Candidate Genes Influencing NAFLD/ NASH:
Genetic Modifiers Influencing Risk for Metabolic Syndromes: Certain gene modifies the etiological conditions known to be involved in the disease progression such as obesity and insulin resistance. Apart from the environmental factors, these are affected by the genetic makeup of an individual as well.
Obesity: A cohort of obese patients included in a GWAS has identified the FTO gene, a novel gene candidate. To date, its role in fatty liver disease has not been confirmed, but some studies have used targeted and random mutagenesis techniques which have indicated insights in the pathogenic mechanism 22. Some studies have also explored the epigenetic imprinting role in obese patients with NAFLD 23.
Insulin Resistance: Various GWAS analysis has identified and confirmed multiple loci for type 2 diabetes mellitus (T2DM) and insulin resistance but very few were identified for NAFLD. Alterations in ectoenzyme nucleotide pyrophosphate phospho-diesterase 1(ENPP1/PC-1), and insulin receptor substrate-1 (IRS-1) influences NAFLD. A study involving 702 NAFLD cases and 310 healthy controls examined the effect of functional ENPP1, PC-1 and IRS-1polymorphisms influencing insulin receptor activity on liver function in NAFLD and the hepatic manifestation of the metabolic syndrome, reported that the ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidemia and diabetes risk, respectively with the fibrosis score of >1 24. A smaller study has failed to replicate the results 25.
Genetic Variants Influencing Steatohepatitis / Triglycerides Accumulation in the Liver:
Patatin-like Phospholipase Domain-Containing 3 (PNPLA3): PNPLA3 gene has been identified, validated, and concluded to be associated with NAFLD in varied groups of populations and is considered as a major risk factor in NAFLD susceptibility 5. Adiponutrin encodes for trans-membrane polypeptide chain that is expressed on endoplasmic reticulum and the lipid membrane of hepatocytes and adipose tissue. The polypeptide chain exhibits triglyceride hydrolase activity 26. Certain animal and human studies have demonstrated that PNPLA3 gene activity is regulated by glucose and insulin by a mechanism involved in sterol regulatory element-binding protein-1c 27. PNPPLA3 variant sensitizes the liver and makes it prone to environmental factors. An SNP named I148M variant was found with a risk allele in European and Indian-Asian descentpopulation- it deteriorates the phospholipase activity leading to decreased lipid catabolism and increased phosphatidic acid. Furthermore, a link was found between loss of lipase activity in hepatic stellate cells and a PNPLA3 variant 28. These studies indicate a relationship between the PNPLA3 gene and its involvement in liver damage. Its involvement has been observed independently in cohorts of both adults and children and is known to phenotypically increase the serum AST/ALT levels 29. Not only in NAFLD, but I148M have also been associated with an elevated risk of advanced fibrosis and cirrhosis in chronic alcoholics 27.
Microsomal Triglyceride Transfer Protein (MTTP): In liver and intestines, microsomal triglyceride transfer protein (MTTP) is involved in the synthesis and secretion of very-low-density lipoprotein (VLDL). A frame-shift mutation in MTTP leading to loss of its function causes Bassen-Kornzweig syndrome, a rare autosomal recessive disorder wherein the triglycerides are accumulated in hepatocytes 30. In the promoter region, a transversion from guanine to thiamine has been linked to decreased transcription, lower levels of MTTP, and hepatic failure in triglycerides excretion. A cohort study of 63 patients has suggested that NAFLD patients with low activity homozygous Gallelehave increased the risk of steatohepatitis and higher NASH grade histologically. This data needs to be validated by larger studies. Another study from Brazil which involved biopsy-proven NASH, has failed to replicate the results 31.
Phosphatidylethanolamine Methyltransferase (PEMT): Phosphatidylcholine is involved in VLDL synthesis, and PEMT catalyzes phosphatidylcholine synthesis. A transversion in the non-synonymous region of exon 8 from guanine to adenine has been linked to NAFLD. A study from Japan that included 107 biopsy-proven NASH patients has indicated the V175M amino acid loss of function to be more frequent than that of controls. But these V175M positive cases had lower BMI suggesting an underlying genetic predisposition 32. Furthermore, another biopsy-based study has concluded similar results, i.e., the positive association of V175M variant with NASH 33.
Apolipoprotein C3 (ApoC3) and Apolipoprotein E: ApoC3 protein expressed in the liver inhibits the lipoprotein lipase (LPL) activity that hydrolyzes the triglycerides into VLDL and chylomicrons inside the plasma. Hypertriglyceridemia can occur due to its overexpression, and hypo-triglyceridaemia occurs due to its absence. Two SNPs, rs2854116 (T-455C) and rs2854117 (C-482T), present in the promoter region of apolipoprotein C3 have been linked to the severity of steatosis in cohorts of Asian Indians and non-Asian descent. Both above-mentioned SNPs in ApoC3 were identified as mediators in postprandial triglyceridaemia by hindering the lipoprotein lipase activity in human and animal studies. The hepatic receptor scavengers engulf the increased chylomicron load, thereby leading to steatosis 34. It is noteworthy to mention that a study including about 1228 African Americans, 843 European Americans, and 426 Hispanics reported that there is no significant causal relationship between these two SNPs and hepatic triglyceride content or insulin resistance 35. Another study that included biopsy-proven NAFLD patients have confirmed the dissociation between these two SNPs and the degree of severity of steatosis or fibrosis or NASH 36. Other studies conducted on Italian 36, British 36, American 35, and Chinese Han 37 subjects have not confirmed the positive association of the ApoC3 SNPs in NAFLD. A meta-analysis has concluded the absence of a significant association of the ApoC3 SNPs in the pathogenesis of NAFLD 38. The disparity of the data available questions the methodology and the quality of some of these studies.
Apolipoprotein E plays a crucial role in the metabolism of triglycerides. It helps in the removal of circulating chylomicrons and VLDL by enhancing its preferential uptake in LDL receptors 39. Two SNPs have been identified, each with a different allele (e2, e3, e4) and a total of six ApoE genotypes 40. The studies conducted on ApoE SNPs have presented conflicting results. A study conducted on the Turkish population reported the association of ApoE 3/3 genotype with an elevated risk of NAFLD and ApoE3/4 genotype showed a protective effect 41. Interestingly, while Lee et al. reported the distribution of ApoE genotype to have no significant difference in NAFLD patients and healthy controls in the Korean population 42. Yang et al. have shown the protective effect of the e4 allele in fatty liver disease 43. Further-more, e4 carriers have been shown to reduce the risk of NAFLD twice compared to the e3 homozygous carriers 44.
TABLE 2: GENES ALTERED IN DIFFERENT DISEASE CONDITIONS THAT EFFECT THE NAFLD PROGRESSION
|Disease condition||Candidate genes identified||Effect on NAFLD progression|
|Obesity||FTO||Increases the risk of disease progression|
|Insulin Resistance||· ENPP1 (ectoenzyme nucleotide pyrophosphate phosphodiesterase 1),
· IRS-1 (insulin receptor substrate-1)
|Increases the risk of disease progression|
|Steatohepatitis||· PNPLA3 (Patatin-like phospholipase domain-containing 3),
· MTTP (Microsomal triglyceride transfer protein),
· PEMT (Phosphatidylethanolamine methyltransferase),
· Apo C3 (Apolipoprorein C3)
|Increases the risk of disease progression|
|· Apo E (Apolipoprotein E)||Protective effect|
|Oxidative Stress||· TNF-α (Tumor Necrosis Factor-α),
· IL-1β (Interlukine-1β),
· IL-1α (Interlukine-1α),
· IL-28B (Interlukine-28B),
· MnSOD (Manganese Superoxide Dismutase),
· MTHFR (MethylenetetrahydrofolateReductase)
|Increases the risk of disease progression|
|· TLR4 (Toll-Like Receptor 4),
· KLF-6 (Kruppel-Like Factor 6),
· UCP (Uncoupling protein 2/3)
Genetic Variants Influencing Oxidative Stress in NAFLD/NASH:
Tumor Necrosis Factor-α: Tumor necrosis factor-α (TNF-α) is a crucial pro-inflammatory cytokine having a wide range of functions, including metabolic regulation, auto-immunity, and in the presence of oxidative stress causes cell apoptosis. TNF-α levels are increased in the NASH patients and also has been linked to the development of NAFLD. Higher TNF-α levels correspond to the insulin resistance and activate the inflammatory mediators leading to elevated risk for NASH 45. TNF2 allele (at position -308) and TNFA allele (at position -238) present in the promoter region is related to an increased susceptibility of NAFLD.A study that was conducted on the Italian population has found a higher prevalence of polymorphism at 238 in the promoter region of TNF-α than that of -308 in NAFLD patients. Polymorphism at TNF-α 238 has also been indicated not only in impaired insulin sensitivity but also a lower level of LDL-cholesterol and lower BMI suggesting the alterations in the pathways of glucose and lipid metabolism 46.
Polymorphism at TNF-α 1031 and -863 in the promoter region was found more commonly in NASH patients than in simple steatosis in the Japanese population. Interestingly, Japanese patients failed to show polymorphism at -238 and -308 positions due to the lower recurrence of these variants in this ethnicity. A meta-analysis has identified TNF-α 238 as the susceptibility factor in NAFLD but not the TNF-α 308 47.
Interleukin (IL)-6 and IL- 1β: Interleukin-6 (IL-6) is another cytokine that is involved in both inflammation and insulin resistance. It is produced by hepatic cells, adipocytes, and immune cells. Its serum levels are elevated in people with type 2 diabetes and obesity 48. Two variants of IL-6 have been identified: IL-6 −174C and IL-6-174G 34. The IL-6 174C variant has been linked to insulin resistance, T2D, and MS 48, 49 in an Italian cohort with NAFLD 25. In contrast, certain studies have reported the presence of the IL-6 174G variant to be related to metabolic syndromes 50.
Studies have suggested that IL-1α and IL-1β are involved in the progression of steatosis to steatohepatitis and ultimately liver fibrosis 51. Polymorphism of IL-1β-511 T/C genotypes that affects the in-vitro protein interactions was reported by a Japanese study where NASH cases were compared to 100 healthy controls. This study has suggested that the serum levels of IL-1β were significantly elevated in NASH cases 52. Furthermore, the number of IL-1β-511 T SNP and T/T genotypes was greater in NASH patients.
Toll-Like Receptor 4: Toll-like receptor 4 (TLR 4) is a transmembrane receptor that plays a vital role in cellular apoptosis and is involved in the activation of Kupffer cells in NAFLD. Recently, bacterial growth and endotoxemia have been reported to be involved in NASH pathogenesis 53. Disruption in its hepatic signaling can cause hepatic inflammation and injury in NAFLD 54.
TLR4-D299G and T3991 variants have been indicated to decrease the response towards endotoxins, thus suggesting to have an effect on insulin resistance, T2D, and MS 54. A study by Guo et al., has reported that D299G and T3991 have a protective function in the progression of fibrosis.55 Animal studies have suggested the relationship between TLR4 and Kupffer cells in NASH pathogenesis 53. A case-control study has shown a decreased number of mutations at -299 in NAFLD cases than that in controls 56. Though animal and human studies have suggested a protective role of TLR4 in NAFLD/NASH, more studies are required to provide strong evidence.
IL- 28B: Various studies have reported genetic variants in IL-28B in removing hepatic C infection. IL-28B- rs12979860 CC and rs8099917 TT variants are associated with the consistent viral response after anti-viral therapy 57. Some studies have suggested that IL-28B polymorphism can be attributed to the degree of severity of inflammation and progression to fibrosis 58. A study with 160 NAFLD cases has identified IL-28 rs 12979860 CC in the severity of the hepatic diseases 59.
As the IL-28 rs12979860 CC variant was frequently observed in patients with the PNPLA3 G allele, a hypothesis was assumed regarding their inter-dependence. Eslam et al., have tested and confirmed this hypothesis on a larger cohort with 3129 CHC, 555 hepatitis B, and 488 NAFLD patients. They have reported that the presence of rs`12979860 SNP can be used as a genetic marker in inflammation and fibrosis in chronic hepatic diseases 60. A North American study conducted on the Caucasian population with NAFLD did not reveal any association between the SNP and inflammation 61.
Superoxide Dismutase 2 and Cytochrome P450 2E1: MnSOD plays a vital role in protecting the hepatic cells from the mitochondrial superoxide radicals. MnSOD is encoded by superoxide dismutase 2 (SOD 2) gene.62 C47T rs4880 SNP in SOD 2 gene has been linked to the disruption in the signal sequence that leads to the substitution of Ala16Val 63. The Ala allele causes relatively increased protein import leading to elevated enzymatic activity. A Japanese study that included 63 subjects has demonstrated the decreased enzyme activity in homozygous T genotype patients 64. An Egyptian study has revealed similar results in obese children with hepatic steatosis and NASH 65. Al Serri et al., have reported the association of C4TT and fibrosis, suggesting that oxidative stress is a crucial factor in the pathogenesis of NAFLD 66.
Uncoupling Protein 3 and Uncoupling Protein 2: Uncoupling protein 3 (UCP 3) is a mitochondrial transporter that increases the proton leak from the inner mitochondrial membrane and catalyzes the oxidative phosphorylation. It regulates the body’s energy modulation and lipid homeostasis. It is usually expressed in skeletal muscle 67. The polymorphism in the promoter region of UCP 3 i.e., rs1800849-55 C/T variants, has been associated with greater susceptibility to T2D and obesity in atherosclerotic patients 68. A Spanish study has linked the CT genotype to IR, the higher adiponectin levels, the presence of steatosis and NASH 69.
Some studies have reported the protective role of the increased hepatic expression of uncoupling protein 2 (UCP-2) in NASH. An SNP in the promoter region of-2, -866 G>A variant affects the extra-hepatic expression of UCP-2 and insulin release and sensitivity 70. A more recent study has suggested the role of -866 A/A genotype in decreasing the progression of NASH after the confounding factors were adjusted 71. Further studies are needed to establish the protective or the susceptibility role of UCP in NAFLD/NASH.
Methylenetetrahydrofolate Reductase: Hyper-homocysteinaemia is considered a risk factor in liver diseases. Any disruption in the metabolic pathway of cysteine due to genetic polymorphism affects liver damage. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the methylation of homocysteine 72. Sazci et al., have reported MTHFR 1298C in NASH, C677C/C1298C variants in women, and C677C/A12988C in men increases the susceptibility to NASH progression 73. Interestingly, other studies have failed to replicate similar results. Thus, its definite role in NAFLD/NASH cannot be stated 74.
Kruppel-Like Factor 6: Liver injury leads to the cytokine release that increases the Kruppel-like factor 6 (KLF-6) gene expression that plays a vital role in the activation of other genes involved in the progression of liver fibrosis 75. A study has reported the relationship between the polymorphism in KLF-6 gene IVS1-27G>A SNP (rs3750861) and the severity of NAFLD. The levels of total and wild-type KLF-6 expression are increased in NAFLD and steatosis. On the other hand, KLF-6 IVS1-27G>A SNP has been linked to the protective action against the progression of NASH 76.
CONCLUSION: NAFLD is a complex disease, and its development and progression are influenced by various genetic and environmental factors. Recent findings from GWAS and candidate gene studies have confirmed various genetic variants that are involved in the progression of NASH. This has further enhanced the understanding of the rapid advancement of NAFLD to NASH. Genetic assessment of the patients for the risk factors can be used as a tool that will help provide tailored and targeted therapy to halt the progression to NASH. The greater challenge is to translate the newer genetic findings into therapeutic benefits.
CONFLICTS OF INTEREST: None
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How to cite this article:
Nooreen M, Fatima S, Sultana M, Fatima Z and Unnissa Z: Genetic background associated with the progression of non- alcoholic fatty liver disease to liver fibrosis. Int J Pharm Sci & Res 2021; 12(1): 85-94. doi: 10.13040/IJPSR.0975-8232.12(1).85-94.
All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
M. Nooreen *, S. Fatima, M. Sultana, Z. Fatima and Z. Unnissa
Department of Pharmacy Practice, Mesco College of Pharmacy, Hyderabad, Telangana, India.
12 January 2020
24 April 2020
27 April 2020
01 January 2021