Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non‐alcoholic fatty liver disease

Seko, Yuya; Yamaguchi, Kanji; Tochiki, Nozomi; Yano, Kota; Takahashi, Aya; Okishio, Shinya; Kataoka, Seita; Okuda, Keiichiroh; Umemura, Atsushi; Moriguchi, Michihisa; Tanaka, Saiyu; Mori, Kumiko; Okanoue, Takeshi; Itoh, Yoshito

doi:10.1111/liv.14495

Cited by 31 publications

(38 citation statements)

References 38 publications

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“…Both rs72613567T>TA in HSD17B13 12 and rs2642438G>A in MARC1 13 were originally identified as GWAS-significant risk-reducing loci for liver disease in adults, most recently as risk-reducing variants for all-cause cirrhosis (as well as NAFLD cirrhosis). HSD17B13 has subsequently been validated in multiple cohorts of adults 6,14,15,29,57-59 though the histological features associated with this variant in MARC1 has not been described in children until now 18 . We therefore selected these two variants to study in children, in addition to the well-established risk-increasing locus rs738409C>G in PNPLA3 and rs58542926C>T in TM6SF2 .…”

Section: Resultsmentioning

confidence: 99%

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Hudert

Alisi

Anstee

et al. 2020

Preprint

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Background & aims: Genome-wide association studies in adults have identified variants in HSD17B13 and MARC1 as protective against NAFLD. It is not known if they are similarly protective in children and, more generally, whether the peri-portal inflammation of pediatric NAFLD and lobular inflammation seen in adults share common genetic influences. Therefore, we aimed to: establish if these variants are associated with NAFLD in children, and to investigate the function of these variants in hepatic metabolism using metabolomics. Methods: 960 children (590 with NAFLD, 394 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MARC1. Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of samples. In silico tools were used to model the effect of rs2642438G>A (p.Ala165Thr) on MARC1. Results: rs72613567T>TA in HSD17B13 was associated with lower odds of NAFLD diagnosis (OR 0.7 (95%CI 0.6-0.9) and lower grade of portal inflammation (P<0.001) whilst rs2642438G>A in MARC1 was associated with lower grade of hepatic steatosis (P=0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective allele, whereas MARC1 levels were not affected by genotype. Both variants showed downregulation of hepatic fibrotic pathways, upregulation of retinol metabolism and perturbation of phospholipid species. Modelling suggests that p.Ala165Thr would disrupt the stability and metal-binding of MARC1. Conclusions: There are shared genetic mechanisms between pediatric and adult NAFLD, despite their differences in histology. MARC1 and HSD17B13 are involved in phospholipid metabolism and suppress fibrosis in NAFLD.

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Section: Resultsmentioning

confidence: 99%

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Hudert

Alisi

Anstee

et al. 2020

Preprint

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“…Indeed, when the patients achieved BW reduction of more than 5% or 7%, recommended in guidelines, the reduction of LSM was significantly greater in patients with the AG/GG genotype than the AA genotype. We previously reported that carriage of the HSD17B13 G allele attenuated the effect of the PNPLA3 GG genotype in advanced liver fibrosis [ 16 ]. To our knowledge, no report has investigated the effect of the HSD17B13 polymorphisms in response to BW reduction in Asian patients with NAFLD.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the carriage of this variant attenuated the risk of developing liver injury conferred by PNPLA3 polymorphisms. We recently reported that carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease

Seko

Yamaguchi

Tochiki

et al. 2021

Genes

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Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. Results: the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). Conclusions: in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.

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“…The HSD17B13 gene is a recently discovered candidate gene associated with ALD and may serve as a therapeutic target to combat ALD. More and more studies recently confirmed that the polymorphisms of HSD17B13 are associated with ALD or NAFLD 25‐28,31,35‐37 . However, more attention should be paid in further studies to the role of HSD17B13 protein in ALD.…”

Section: Discussionmentioning

confidence: 98%

Genetic variant rs72613567 of HSD17B13 gene reduces alcohol‐related liver disease risk in Chinese Han population

Chen

Zhang

Guo

et al. 2020

Liver International

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Background & Aims Recently, the variant rs72613567:TA in the 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been associated with reduced levels of ALT and AST and a reduced risk of alcohol‐related liver disease (ALD) in the European population. Therefore, the aim of this study was to investigate the association between the polymorphisms of HSD17B13 and ALD, liver serum markers and patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) p.I148M in the Chinese Han population. Methods A case‐control study was performed from five centres and included 769 ALD patients and 767 healthy controls. Two SNPs (rs72613567 and rs6834314) in HSD17B13 were genotyped using the Sequenom MassArray system and allele association analysis was performed using PLINK 1.90 software. Results HSD17B13 rs72613567:TA allele was associated with a reduced risk of ALD by 19% (95% confidence interval [CI]: 0.05‐0.31, P = .01), uniformly, the G allele in the rs6834314 reduced the risk of ALD by 19% (95% CI: 0.05‐0.31, P = 8.28 × 10−3). And the genotypes of two SNPs were associated with reducing the risk of ALD in three genetic model analysis. In addition, we found that TA allele was associated with lower levels of serum ALT, AST and GGT (P = .005, .007 and .02, respectively), higher level of serum ALB (P = .02), but not associated with ALP. In this cohort, the interaction between HSD17B13 rs72613567 and the steatogenic allele PNPLA3 rs738409 was not validated. Conclusion The present study revealed that HSD17B13 rs72613567 was significantly associated with a reduced risk of ALD in Chinese Han population.

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Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non‐alcoholic fatty liver disease

Cited by 31 publications

References 38 publications

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

Variants in MARC1 and HSD17B13 reduce severity of NAFLD in children, perturb phospholipid metabolism, and suppress fibrotic pathways

The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease

Genetic variant rs72613567 of HSD17B13 gene reduces alcohol‐related liver disease risk in Chinese Han population

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