Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese

Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle.To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4 × 10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6 × 10(-6)) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8 × 10(-6), OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7 × 10(-16), OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6 × 10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6 × 10(-4)).With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population

Long‐term impact of angiotensin receptor‐neprilysin inhibitor based on short‐term treatment response in heart failure

Abstract Aims The long‐term effect of angiotensin receptor–neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment. Methods and results The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow‐up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all‐cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow‐up (median follow‐up, 44 [interquartile range, 34–51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. Conclusions Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF

Predictors of stroke or systemic embolism in patients with non‐valvular atrial fibrillation with CHA2DS2‐VASc score of 0

Abstract Background Anticoagulant therapy has been important for stroke prevention in patients with atrial fibrillation (AF). However, it was not recommended due to its relatively higher risk of bleeding than its lower risk of stroke in patients with a CHA2DS2‐VASc score of 0. Hypothesis This study aimed to evaluate the predictors of stroke in AF patients with very low risk of stroke. Methods Between 1990 and 2020, 542 patients with non‐valvular AF (NVAF) with a CHA2DS2‐VASc score of 0 followed up for at least 6 months were enrolled. Patients with only being woman as a risk factor were included as a CHA2DS2‐VASc score of 0 in this study. The primary outcome was stroke or systemic embolism. Results The primary outcome rate was 0.78%/year. In Cox hazard model, age of ≥50 years at diagnosis (hazard ratio [HR] 6.710, 95% confidence interval [CI] 1.811–24.860, p = .004), LVEDD of ≥46 mm (HR 4.513, 95% CI 1.038–19.626, p = .045), and non‐paroxysmal AF (HR 5.575, 95% CI 1.621–19.175, p = .006) were identified as independent predictors of stroke or systemic embolism. Patients with all three independent predictors had a higher risk of stroke or systemic embolism (4.21%/year), whereas those without did not have a stroke or systemic embolism. Conclusion The annual stroke or systemic embolism rate in NVAF patients with CHA2DS2‐VASc score of 0 was 0.78%/year, and age at AF diagnosis, LVEDD, and non‐paroxysmal AF were independent predictors of stroke or systemic embolism in patients considered to have a very low risk of stroke

Histogram of odds ratios for genotype distribution of rs738409 between Matteoni types.

<p>Each box denotes the odds ratio (OR) comparing the corresponding Matteoni types on the horizontal axes. N represents the number of samples. Odds ratios and <i>p</i>-values are calculated for the higher Matteoni type per risk allele (G) on additive model by multivariable logistic regression adjusted for age, sex and BMI, and are shown with 95% CI above each box.</p

A schematic organization of the human <i>PNPLA3</i> locus at 22q13.31 with the genome scan results.

<p><i>P</i>-values calculated by the exact trend test were plotted in –log₁₀ scale. Red and blue dots indicate the <i>p</i>-values of genotyped and imputed SNPs, respectively. Local recombination rate obtained from HAPMAP release 22 is indicated by a red line plotted in cm/Mb scale. The structure and orientation of four genes in the region are shown below the plots with their transcriptional orientations according to NCBI Reference Sequence Build 36.3. LD blocks were generated according to pairwise LD estimates of the SNPs located within the region using the genome scan results. The LD block showing the strongest association is highlighted with the triangle, and the corresponding chromosomal region is represented by the dotted lines.</p

Manhattan plot of the GWA study.

<p>Association <i>p</i>-values are calculated by exact trend test and plotted along the chromosome in −log₁₀ scale. The horizontal line indicates Bonferroni-adjusted significance threshold (<i>p</i> = 1.03×10⁻⁷).</p

Clinical characteristics according to the histological classification.

<p>Measurements are shown as mean ± standard deviation. Categorical values are shown by the count number. <i>P</i>-values are calculated by Jonckheere-Terpstra test unless otherwise stated;</p>‡<p>Chochran-Armitage trend test,</p>*<p>Kruskal-Wallis test. Abbreviations used for each trait are summarized in materials and methods.</p