Dataset Information

The Protection Conferred by HSD17B13 rs72613567 Polymorphism on Risk of Steatohepatitis and Fibrosis May Be Limited to Selected Subgroups of Patients With NAFLD.

ABSTRACT:

Introduction

Our study aimed to explore how PNPLA3 rs738409 or phenotypic risk factors may moderate the relationship between HSD17B13 rs72613567 and risk of steatohepatitis and fibrosis.

Methods

This analysis consisted of 1,153 non-Hispanic whites with biopsy-proven nonalcoholic fatty liver disease enrolled in the nonalcoholic steatohepatitis Clinical Research Network studies. Nonalcoholic fatty liver disease severity was determined by liver histology scored centrally according to the nonalcoholic steatohepatitis Clinical Research Network criteria. Moderation and logistic regression analyses were performed to identify the influence of moderators (PNPLA3 rs738409, age, sex, body mass index, and diabetes) on the relationship between HSD17B13 rs72613567 and risk of steatohepatitis and fibrosis.

Results

HSD17B13 rs72613567 genotype frequency was as follows: (-/-), 64%; (-/A), 30%; (A/A), 6%. Moderation analysis showed that the protective effect of HSD17B13 rs72613567 A-allele on risk of steatohepatitis remained only significant among patients with PNPLA3 rs738409 genotype CC (β coeff: -0.19, P = 0.019), women (β coeff: -0.18, P < 0.001), patients of age ≥ 45 years (β coeff: -0.18, P < 0.001), patients with body mass index ≥ 35 kg/m2 (β coeff: -0.17, P < 0.001), and patients with diabetes (β coeff: -0.18, P = 0.020). Among women, the protective effect of HSD17B131 rs72613567 A-allele on risk of steatohepatitis was stronger in those aged ≥ 51 years. Logistic regression-based sensitivity analysis including various important subgroups confirmed our observations.

Discussion

The protection conferred by HSD17B13 rs72613567 A-allele on risk of steatohepatitis and fibrosis may be limited to selected subgroups of individuals who are aged ≥ 45 years, women and have class ≥ 2 obesity or diabetes, and those with PNPLA3 rs738409 CC genotype.

SUBMITTER: Vilar-Gomez E

PROVIDER: S-EPMC8437218 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND & AIMS:The loss-of-function rs72613567 T > TA-variant in the 17?-hydroxysteroid dehydrogenase 13 (HSD17B13) gene might protect from alcoholic and non-alcoholic fatty liver disease (ALD/NAFLD) and associated fibrosis/cirrhosis. We investigated the impact of the T > TA-variant on hepatic decompensation and mortality and investigated its implications on retinol and sex steroid metabolism in patients who had already developed advanced chronic liver disease (ACLD). METHODS:Retrospective analysis in prospectively characterized patients with viral hepatitis- and ALD/NAFLD-induced portal hypertension (hepatic venous pressure gradient (HVPG) ? 6 mmHg) diagnosed at the Medical University of Vienna. RESULTS:Among 487 patients who were followed longitudinally, 166 (34%) were heterozygous and 24 (5%) were homozygous for the 'protective' TA-allele. Patients harbouring at least one TA-allele had a lower MELD (9 (8-12) vs 10 (8-13) points; P = .003) and showed a trend towards lower HVPG (16 ± 6 vs 17 ± 7 mmHg; P = .067). Interestingly, in competing risk analyses adjusted for age, HVPG and MELD, harbouring the TA-allele was associated with numerically increased risks for mortality (adjusted subdistribution hazard ratio (aSHR): 1.3 (95% confidence interval (95% CI): 0.888-1.91); P = .18), liver-related death (aSHR: 1.34 (95% CI: 0.9-1.98); P = .15) and hepatic decompensation (aSHR: 1.29 (95% CI: 0.945-1.77); P = .11). This might be explained by trends towards worse outcomes (eg liver-related death: aSHR: 1.64 (95% CI: 0.95-2.84); P = .076) in patients with viral hepatitis-induced ACLD. In a cross-sectional analysis of 211 additional patients, serum retinol levels were comparable between HSD17B13 genotypes, but in males, serum testosterone levels numerically decreased with an increasing number of TA-alleles. CONCLUSION:In patients with viral hepatitis- and ALD-induced portal hypertension, the T > TA-variant was not protective of hepatic decompensation and mortality. Further studies should investigate the pathophysiological mechanisms underlying the effects of HSD17B13 genotype at different stages of liver disease.

Project description:BACKGROUND:Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS:We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS:A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS:A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Project description:Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health. Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered "protective," and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population.