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Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia.

ABSTRACT: Lipid metabolism disorders, especially hypertriglyceridemia (HTG), are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the association between genetic factors related to HTG and the risk of NAFLD has been scarcely studied. A total of 185 subjects with moderate HTG were prospectively included. We investigated the association between genetic factors' (five allelic variants with polygenic hypertriglyceridemia) clinical and biochemical biomarkers with NAFLD severity. The five allelic variants' related clinical and biochemical data of HTG were studied in all the subjects. NAFLD was assessed by abdominal ultrasound and patients were divided into two groups, one with no or mild NAFLD and another with moderate/severe NAFLD. Patients with moderate/severe NAFLD had higher weight and waist values and a higher prevalence of insulin resistance than patients with no or mild NAFLD. Moderate/severe NAFLD was independently associated with APOA5 rs3134406 and ZPR1 rs964184 variants, and also showed a significant inverse relationship with lipoprotein(a) [Lp(a)] concentrations. APOA5 rs3135506 and ZPR1 rs964184 variants and lipoprotein(a) are associated with moderate/severe NAFLD. This association was independent of body weight, insulin resistance, and other factors related to NAFLD.

SUBMITTER: Esteve-Luque V

PROVIDER: S-EPMC7914661 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia.

Esteve-Luque Virginia V Padró-Miquel Ariadna A Fanlo-Maresma Marta M Corbella Emili E Corbella Xavier X Pintó Xavier X Candás-Estébanez Beatriz B

Nutrients 20210208 2

<h4>Background</h4>Lipid metabolism disorders, especially hypertriglyceridemia (HTG), are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the association between genetic factors related to HTG and the risk of NAFLD has been scarcely studied.<h4>Methods</h4>A total of 185 subjects with moderate HTG were prospectively included. We investigated the association between genetic factors' (five allelic variants with polygenic hypertriglyceridemia) clinical and biochemical biomarker ...[more]

PMID: 33567543

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Project description:ImportanceHypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors.ObjectivesTo analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile.Design, setting, and participantsThis case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed.Main outcomes and measuresPrimary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied.ResultsAmong 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02).Conclusions and relevanceThese results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

Project description:Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG > or = 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-epsilon4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG.Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the epsilon4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.

Project description:Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver damage in people living with HIV (PLWHIV). Several studies have investigated candidate genes for susceptibility to NAFLD and to steatohepatitis. PNPLA3, TM6SF2, and MBOAT7-TMC4 have been reported to be associated with elevated ALT levels and the histologic parameters of nonalcoholic steatohepatitis and severity of fibrosis. Our objective was to analyze the relationship between PNPLA3, TM6SF2, and MBOAT7-TMC4 and steatosis, steatohepatitis, and liver fibrosis in PLWHIV with NAFLD. Method: A cohort of PLWHIV with persistently elevated aminotransferase levels and suspected NAFLD who underwent liver biopsy and determination of genetic variants was assessed at two large centers in Spain. All participants included in the current study were genotyped for rs738409 (PNPLA3), rs58542926 (TM6SF2), and rs641738 (MBOAT7-TMC4). Results: The study population comprised PLWHIV who were on stable antiretroviral therapy [7.7% women; median age, 49.3 years (44-53.4)]. The median CD4 count was 829 (650-980), 60% had metabolic syndrome, and 18.5% were diabetic. The median BMI was 28.9 (25.5-30.8). Patients with liver steatosis (any grade) vs. nonsteatosis tended to harbor the PNPLA3 G allele variant [57.6% vs. 16.7% (p = 0.09)], but not TM6SF2 or MBOAT7-TMC4 variants. However, those with steatohepatitis vs. nonsteatohepatitis significantly more frequently had the PNPLA3 G allele variant [69.4% vs. 39.1% (p < 0.05)] and the MBOAT7-TMC4 A allele variant [75% vs. 42% (p < 0.05)]. In our cohort, the TM6SF2 gene variant was not associated with steatosis or steatohepatitis. The PNPLA3 G allele variant was associated with steatohepatitis [OR 4.9 (1.3-18); p 0.02] and liver fibrosis [OR 4.3 (1.1-17.4); p 0.04], and the MBOAT7-TMC4 A allele variant was associated with steatohepatitis [OR 6.6 (1.6-27.6); p 0.01]. Conclusion: The PNPLA3 G allele variant and MBOAT7-TMC4 A allele variant were associated with steatohepatitis and liver fibrosis in PLWHIV with persistently elevated aminotransferases and NAFLD. We recommend routine genotyping for PNPLA3 and MBOAT7-TMC4 in PLWHIV with NAFLD to identify those at higher risk of progression.

Dataset Information

Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia.

Publications

Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia.

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