The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization.
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ABSTRACT:
SUBMITTER: Innes H
PROVIDER: S-EPMC7912355 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
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The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization.
Innes Hamish H Buch Stephan S Barnes Eleanor E Hampe Jochen J Marjot Thomas T Stickel Felix F
Gastroenterology 20210227 7
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Project description:BackgroundData regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce.ObjectiveThis study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations.MethodsPatients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC was composed of the presence and absence of complications, such as variceal bleeding, hepatic ascites, and hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort and (ii) the presence and absence of complications in the patients with LC.ResultsThere was a significant difference among the patients without LC and those with alcohol, NAFLD-related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD-related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol-related cirrhosis unless there was a presence of G alleles.ConclusionThe PNPLA3 polymorphism was associated with the risk of NAFLD-related LC and its complications.
| S-EPMC9501715 | biostudies-literature
Project description:In this study we profiled 288 new serum proteomics samples measured at admission from patients hospitalized within the Mount Sinai Health System with positive SARS-CoV-2 infection. We first computed Th1 and Th2 pathway enrichment scores by gene set variation analysis and then compared the differences in Th2 and Th1 pathway scores between patients that died compared to those that survived.
2022-06-16 | GSE178399 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals.The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population (n?=?63) examined by a hyperinsulinemic euglycemic clamp (n(total)?=?255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome (n?=?5,847) and traits related to metabolic disease (n?=?5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR).The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(?)?=?-9.9% [-14.4%;-4.0% (95% CI)], p?=?5.1×10(-5)) and fasting total cholesterol (??=?-0.2 mmol/l [-0.3;-0.01 mmol/l(95% CI)], p?=?1.5×10(-4)). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele.Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.
| S-EPMC3390392 | biostudies-literature
Project description:Background/aimAdult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. Fluvoxamine strongly binds to the sigma-1 receptor (S1R) that regulates inflammation by inhibiting the production of cytokines, believed to be responsible for severe COVID-19. We evaluated the S1R locus on chr 9p13.3 in subjects tested positive for SARS-CoV-2. We focused on SNP rs17775810 that has been previously identified by examining loss-of-function mutations in the S1R gene associated with distal hereditary motor neuropathy.Patients and methodsWe utilized UK Biobank (UKB) data. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai.ResultsThe effect of rs17775810 genotype on survival was significant (p=0.036, 2 tailed Fisher exact test). The minor allele homozygotes (TT) had the lowest death rate (0%), whereas the non-TT genotypes (i.e. CT and CC) had the highest death rate (16.2%).ConclusionThe rs17775810 analysis corroborates the favorable effect of fluvoxamine on COVID-19 survival.
| S-EPMC8045077 | biostudies-literature
Project description:ObjectiveThe role of uncontrolled blood pressure (BP) in COVID-19 severity among patients with hypertension is unclear. We evaluated the association between uncontrolled BP and the risk of hospitalization and/or mortality in patients with hypertension from a large US integrated healthcare system.MethodsWe identified patients with hypertension and a positive RT-PCR test result or a diagnosis of COVID-19 between March 1 - September 1, 2020 from Kaiser Permanente Southern California. BP categories was defined using the most recent outpatient BP measurement during 12 months prior to COVID-19 infection. The primary outcome of interest was all-cause hospitalization or mortality within 30 days from COVID-19 infection.ResultsAmong 12,548 patients with hypertension and COVID-19 (mean age = 60 years, 47% male), 63% had uncontrolled BP (≥130/80 mm Hg) prior to COVID-19. Twenty-one percent were hospitalized or died within 30 days of COVID-19 infection. Uncontrolled BP was not associated with higher hospitalization or mortality (adjusted rate ratios for BP ≥ 160/100 mm Hg vs < 130/80 mm Hg = 1.00 [95% CI: 0.87, 1.14]; BP 140-159/90-99 mm Hg vs < 130/80 mm Hg = 1.02 [95% CI: 0.93, 1.11]). These findings were consistent across different age groups, treatment for antihypertensive medications, as well as atherosclerotic cardiovascular disease risk.ConclusionAmong patients with hypertension, uncontrolled BP prior to COVID-19 infection did not appear to be an important risk factor for 30-day mortality or hospitalization.
| S-EPMC8576055 | biostudies-literature
Project description:BackgroundRecent reports suggested a different predictive value for TyG index compared to HOMA-IR in coronary artery calcification (CAC) and other atherosclerotic outcomes, despite that both indices are proposed as surrogate markers of insulin resistance. We hypothesized a key role for liver pathology as an explanation and therefore assessed the relationship among the two indices and the intrahepatic lipid content stratified by PNPLA3 rs738409 genotypes as a known non-alcoholic fatty liver disease (NAFLD) genetic risk.MethodsThirty-nine women from a prior GDM-genetic study were recalled with PNPLA3 rs738409 CC and GG genotypes for metabolic phenotyping and to assess hepatic triglyceride content (HTGC). 75 g OGTT was performed, fasting lipid, glucose, insulin levels and calculated insulin resistance indices (TyG and HOMA2-IR) were used. HTGC was measured by MR based methods. Mann-Whitney-U, χ2 and for the correlation analysis Spearman rank order tests were applied.ResultsThe PNPLA3 rs738409 genotype had a significant effect on the direct correlation between the HOMA2-IR and TyG index: the correlation (R = 0.52, p = 0.0054) found in the CC group was completely abolished in those with the GG (NAFLD) risk genotype. In addition, the HOMA2-IR correlated with HTGC in the entire study population (R = 0.69, p < 0.0001) and also separately in both genotypes (CC R = 0.62, p = 0.0006, GG: R = 0.74, p = 0.0058). In contrast, the correlation between TyG index and HTGC was only significant in rs738409 CC genotype group (R = 0.42, p = 0.0284) but not in GG group. A similar pattern was observed in the correlation between TG and HTGC (CC: R = 0.41, p = 0.0335), when the components of the TyG index were separately assessed.ConclusionsPNPLA3 rs738409 risk genotype completely decoupled the direct correlation between two surrogate markers of insulin resistance: TyG and HOMA2-IR confirming our hypothesis. The liver lipid content increased in parallel with the HOMA2-IR independent of genotype, in contrast to the TyG index where the risk genotype abolished the correlation. This phenomenon seems to be related to the nature of hepatic fat accumulation and to the different concepts establishing the two insulin resistance markers.
| S-EPMC10031960 | biostudies-literature
Project description:Background and aimsIt is unclear whether rs738409 (p.I148M) missense variant in patatin-like phospholipase domain-containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy-proven NAFLD.Approach and resultsCausal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non-Hispanic White patients. Total effect of rs738409 on fibrosis was β = 0.19 (95% CI: 0.09-0.29). The direct effect of rs738409 on fibrosis after removing mediators' effects was β = 0.09 (95% CI: 0.01-0.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were β = 0.010 (95% CI: 0.04-0.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (β = 0.09, 95% CI: 0.05-0.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (β = 0.023, 95% CI: 0.011-0.037). Mediation analysis in a separate group of 404 individuals with biopsy-proven NAFLD from other races and ethnicity showed similar results.ConclusionsIn NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.
| S-EPMC9519813 | biostudies-literature
Project description:The COVID-19 epidemic of 2019-20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system. Whole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline clinical characteristics of patients and their outcome data including their hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death. Full length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 infections was observed (p = 0.06, Fisher's exact). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction. In summary, SARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.
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Project description: Not available
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| S-EPMC8662082 | biostudies-literature