Genetic Susceptibility to Chronic Liver Disease in Individuals from Pakistan

Raja, Asad Mehmood; Ciociola, Ester; Ahmad, Imran; Dar, Faisal Saud; Naqvi, Syed Muhammad Saqlan; Moaeen‐ud‐Din, Muhammad; Raja, Ghazala Kaukab; Romeo, Stefano; Mancina, Rosellina Margherita

doi:10.3390/ijms21103558

Cited by 12 publications

(12 citation statements)

References 63 publications

(80 reference statements)

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“…Genotyping was performed using TaqMan probes 31 . The genotypes of PNPLA3 (rs738409), TM6SF2 (rs58542926), MBOAT7 (rs641738) and GCKR (rs1260326) were analysed using commercially available TaqMan probes and a 7500 Fast Real‐Time PCR System, both from Thermo Fisher, according to the manufacturer's instruction 30 …”

Section: Methodsmentioning

confidence: 99%

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Effect of common genetic variants on the risk of cirrhosis in non‐alcoholic fatty liver disease during 20 years of follow‐up

Holmer

Ekstedt

Nasr

et al. 2022

Liver International

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Background and Aims Several genotypes associate with a worse histopathological profile in patients with non‐alcoholic fatty liver disease (NAFLD). Whether genotypes impact long‐term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. Method DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non‐alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population‐based registers. Events of severe liver disease and all‐cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. Results In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66–8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79–4.14). After up to 40 years of follow‐up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15–4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85–11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14–59.47). Overall mortality was not affected by any genetic variant. Conclusion The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies.

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Section: Methodsmentioning

confidence: 99%

“…Three 10‐μm sections of FFPE blocks were processed according to the manufacturer's protocol (User bulletin, Version: MAN0010642 Rev. D.0) and as previously described 30 . Briefly, the FFPE slides were deparaffinized and digested with protease.…”

Section: Methodsmentioning

confidence: 99%

Effect of common genetic variants on the risk of cirrhosis in non‐alcoholic fatty liver disease during 20 years of follow‐up

Holmer

Ekstedt

Nasr

et al. 2022

Liver International

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“…Only a single study on the present subject is available from Pakistan that reported a significant prevalence of PNPLA3 risk variant, but not TM6SF2 polymorphism, in end stage hepatic ailment patients with mixed etiology (viral as well as non-viral origin) who received living donor liver transplantation, when compared to normal controls [18].…”

Section: Univariate Regression Analysismentioning

confidence: 87%

“…To this point, despite the fact that PNPLA3 and TM6SF2 polymorphisms represent most commonly investigated lipid metabolism based host genetic variants in NAFLD, their potential influence in CHC mediated CLP is less defined. Additionally, PNPLA3 and TM6SF2 variants based genetic predisposition to liver scarring data in CHC patients is mainly available for different Caucasian ethnic groups with scarce representation of other populations, together with Indo-Pak region and mixed populations [18].…”

Section: Introductionmentioning

confidence: 99%

PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study

et al. 2022

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Background The present study investigates if common missense functional variants p.I148M and p.E167K in PNPLA3 and TM6SF2 genes, respectively, associate with development of hepatic fibrosis and cirrhosis in a geographically novel cohort of Pakistani chronic hepatitis C (CHC) patients. Methods In total, 502 Pakistani CHC patients [242 males, median age 40 years, 220 with significant hepatic fibrosis, including 114 with cirrhosis] were genotyped for PNPLA3 and TM6SF2 variants using TaqMan genotyping assays. Associations between genotypes, biochemical and clinical parameters were evaluated. Results Genotypic distributions for PNPLA3 and TM6SF2 polymorphisms conformed to Hardy–Weinberg equilibrium and did not associate with fibrosis grades ≥ F2 or cirrhosis in any of the genetic models tested (all p = > 0.05). PNPLA3 and TM6SF2 variants did not modulate baseline characteristics and serum markers of liver injury in CHC patients. Similarly, increasing number of risk alleles of PNPLA3 and TM6SF2 polymorphisms had no trend effect on serum liver enzyme activities or proportion of CHC patients with significant or advanced fibrosis or cirrhosis (p = > 0.05). The same trend of no association with hepatic fibrosis or cirrhosis persisted in the multivariate logistic regression models adjusting for age, gender, body mass index and HCV viral load (p = > 0.05). Conclusions PNPLA3 and TM6SF2 variants do not appear to modulate development of hepatic fibrosis or cirrhosis in present CHC patients of Pakistani origin, and may be of more relevance in liver pathology involving abnormalities in hepatic fat accumulation. These results also reflect the divergent associations observed for different genetic modifiers of hepatic fibrosis and cirrhosis in distinct ethnicities.

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“…Regarding Asian countries, Seko Y et al described that the HSD17B13 genetic variant attenuated the risk of the PNPLA3 minor allele for NAFLD [ 40 ]. Regardless of FLD, the protective effects of this variant on ALD or any chronic liver diseases were confirmed among the Chinese or Pakistani population [ 41 , 42 ].…”

Section: Role Of Hsd17b13 Genetic Variants In Liver Diseasementioning

confidence: 99%

Is HSD17B13 Genetic Variant a Protector for Liver Dysfunction? Future Perspective as a Potential Therapeutic Target

Mizutani

Amirneni

Diaz-Aragon

et al. 2021

JPM

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As diet and lifestyle have changed, fatty liver disease (FLD) has become more and more prevalent. Many genetic risk factors, such as variants of PNPLA3, TM6SF2, GCKR, and MBOAT7, have previously been uncovered via genome wide association studies (GWAS) to be associated with FLD. In 2018, a genetic variant (rs72613567, T > TA) of hydroxysteroid 17-β dehydrogenase family 13 (HSD17B13) was first associated with a lower risk of developing alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) in minor allele carriers. Other HSD17B13 variants were also later linked with either lower inflammation scores among NAFLD patients or protection against NAFLD (rs6834314, A > G and rs9992651, G > A) respectively. HSD17B13 is a lipid droplet-associated protein, but its function is still ambiguous. Compared to the other genetic variants that increase risk for FLD, HSD17B13 variants serve a protective role, making this gene a potential therapeutic target. However, the mechanism by which these variants reduce the risk of developing FLD is still unclear. Because studies in cell lines and mouse models have produced conflicting results, human liver tissue modeling using induced pluripotent stem cells may be the best way to move forward and solve this mystery.

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Genetic Susceptibility to Chronic Liver Disease in Individuals from Pakistan

Cited by 12 publications

References 63 publications

Effect of common genetic variants on the risk of cirrhosis in non‐alcoholic fatty liver disease during 20 years of follow‐up

Effect of common genetic variants on the risk of cirrhosis in non‐alcoholic fatty liver disease during 20 years of follow‐up

PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study

Is HSD17B13 Genetic Variant a Protector for Liver Dysfunction? Future Perspective as a Potential Therapeutic Target

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