Increased Risk Of Nonalcoholic Fatty Liver Disease Research Articles

Decreased plasma n6:n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type2 diabetes patients.

Aims/IntroductionTo explore relationships between polyunsaturated fatty acids (PUFA) and non‐alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression.Materials and MethodsWe extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography–tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut‐off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD.ResultsOf 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 μmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20–2.71), and the effect size was amplified by high C‐peptide (odds ratio 8.89, 95% confidence interval 4.48–17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant.ConclusionDecreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co‐presence of high C‐peptide.

Mitochondrial haplogroup G is associated with nonalcoholic fatty liver disease, while haplogroup A mitigates the effects of PNPLA3.

ObjectivesMitochondrial dysfunction plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We hypothesized that mitochondrial DNA (mtDNA) haplogroups affect the risk of NAFLD in Han Chinese patients and interact with PNPLA3 genotypes.DesignNAFLD and control patients were recruited from a tertiary care centre. The mitochondrial genome was amplified in overlapping segments and sequenced. Mitochondrial haplogroups were determined using Mitomaster. PNPLA3 rs738409 genotyping was performed using restriction fragment length polymorphism analysis.PatientsWe enrolled 655 NAFLD patients and 504 controls.ResultsMore NAFLD patients encoded haplogroup G; odds ratio (OR) 1.85 (95% confidence interval [CI] 1.16, 2.80). Subhaplogroup G3 was present more frequently in NAFLD patients (25.8% vs 6.5%). The PNPLA3 CG genotype resulted in an OR of 1.66 (95% CI 1.25, 2.21), and the GG genotype resulted in an OR of 2.33 (95% CI 1.72, 3.17) for NAFLD. Patients with mitochondrial haplogroup A had a significantly higher frequency of genotype GG. Among patients with haplogroup A, no PNPLA3 genotype was associated with increased NAFLD risk (CG: OR 1.17, 95% CI 0.55, 2.34; GG: OR 1.04 95% CI 0.66, 2.65). Excluding haplogroup A, the OR for CG was 1.58 (95% CI 1.18, 2.12), and the OR for GG was 1.81 (95% CI 1.30, 2.51).ConclusionHaplogroup G was associated with an increased risk of NAFLD PNPLA3 GG genotype was overrepresented among patients encoding haplogroup A and was not associated with NAFLD risk among haplogroup A patients. Mitochondrial genetics influence NAFLD risk and interact with PNPLA3 genotypes.

Association between fasting plasma glucose and nonalcoholic fatty liver disease in a nonobese Chinese population with normal blood lipid levels: a prospective cohort study

BackgroundFasting plasma glucose (FPG) is an easily quantifiable and inexpensive metabolic marker, which is often used to assess cardiovascular disease and diabetes. However, there have been limited studies on the association between FPG and nonalcoholic fatty liver disease (NAFLD) risk in nonobese people, especially in Chinese individuals. The purpose of this study was to investigate the association between FPG and NAFLD in nonobese Chinese people with normal blood lipid levels.MethodsIn this prospective cohort study, 9767 nonobese participants with normal blood lipid levels without NAFLD were recruited and prospectively followed for 5 years. The Cox proportional hazard model was used to evaluate the risk factors of NAFLD. Moreover, a Cox model with cubic spline functions and smooth curve fitting (the cubic spline smoothing) were used to identify the nonlinear association between FPG and NAFLD.ResultsDuring the 5-year follow-up, 841 (8.61%) participants were diagnosed with NAFLD. The good functional results (without NAFLD) estimated by the Kaplan-Meier method for 1 year, 2 years, 3 years, 4 years, and 5 years were 98.84, 95.35, 91.67%, 87.57 and 74.86%, respectively. Additionally, through the Cox proportional hazard model, after adjusting for other covariates, there was an independent positive correlation between FPG and increased NAFLD risk (HR:1.21, 95% CI:1.15–1.28, P < 0.0001), and the NAFLD risk was incrementally higher with the rising FPG quartile. The nonlinear association between FPG and NAFLD was visualized by cubic spline smoothing technique. It was calculated that the inflection point of FPG was 5.54. When FPG ≤ 5.54, there was a positive correlation between FPG and the risk of NAFLD (HR:2.20, 95% CI:1.78–2.73, P < 0.0001). When FPG > 5.54, the risk of NAFLD increased by 50% (HR:1.10, 95% CI:1.02–1.18, P = 0.0159) compared with the left side of the inflection point and gradually leveled off.ConclusionsIn a nonobese Chinese population with normal lipid levels, there is an independent nonlinear association between FPG and NAFLD, and the increase in FPG may indicate an increased risk of NAFLD. Additionally, this independent association is more obvious in the short stature population.

Genome-Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus.

Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two‐stage analysis to identify NAFLD‐associated loci in Japanese patients. In stage I, 275 metabolically healthy normal‐weight patients with NAFLD were compared with 1,411 non‐NAFLD controls adjusted for age, sex, and alcohol consumption by a genome‐wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E‐08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E‐07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E‐07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E‐07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non‐NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11‐1.28; P = 2.10E‐06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04‐1.27; P = 6.19E‐03) with increased NAFLD risk. Imputation‐based typing of HLA showed a significant difference in the distribution of HLA‐B, HLA‐DR‐beta chain 1 (DRB1), and HLA‐DQ‐beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next‐generation sequence‐based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA‐B allele distribution and the significant increase of the HLA‐B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta‐diversity analysis of rs2076529 and HLA‐B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA‐B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping

Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases. Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms. Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice. Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping. Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.

A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank

The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n= 1,703) and confirming controls (n= 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses. The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95% CI 1.15-1.53; p <0.0001) among whom a NAFLD diagnosis was 15% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95% CI 1.349-1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95% CI 1.28-1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95× 10-6) where the risk variant also associated with earlier age of diagnosis. Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies. Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.

Visceral-to-Subcutaneous Abdominal Fat Ratio Is Associated with Nonalcoholic Fatty Liver Disease and Liver Fibrosis.

BackgroundWe evaluated the association of visceral-to-subcutaneous fat ratio (VSR) with nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis degree based on noninvasive serum fibrosis markers in the general population with NAFLD.MethodsThis is a cross-sectional study, in 7,465 Korean adults who underwent health screening examinations. NAFLD was defined as fatty liver detected on ultrasonography, and visceral and subcutaneous abdominal fat was measured using computed tomography. We predicted fibrosis based on the fibrosis-4 (FIB-4) score and aspartate aminotransferase-to-platelet ratio index (APRI) and categorized the risk for advanced fibrosis as low, indeterminate, or high.ResultsThe multivariable-adjusted prevalence ratios for indeterminate to high risk of advanced fibrosis based on FIB-4, determined by comparing the second, third, and fourth quartiles with the first quartile of VSR, were 3.38 (95% confidence interval [CI], 0.64 to 17.97), 9.41 (95% CI, 1.97 to 45.01), and 19.34 (95% CI, 4.06 to 92.18), respectively. The multivariable-adjusted prevalence ratios for intermediate to high degree of fibrosis according to APRI also increased across VSR quartiles (5.04 [95% CI, 2.65 to 9.59], 7.51 [95% CI, 3.91 to 14.42], and 19.55 [95% CI, 9.97 to 38.34], respectively). High VSR was more strongly associated with the prevalence of NAFLD in nonobese subjects than in obese subjects, and the associations between VSR and intermediate to high probability of advanced fibrosis in NAFLD were stronger in obese subjects than in nonobese subjects.ConclusionHigh VSR values predicted increased NAFLD risk and advanced fibrosis risk with NAFLD, and the predictive value of VSR for indeterminate to high risk of advanced fibrosis was higher in obese subjects than in nonobese subjects.

Association between nonalcoholic fatty liver disease and serum magnesium level in patients with type 2 diabetes mellitus

Objective To investigate the association between nonalcoholic fatty liver disease (NAFLD) and serum magnesium level in patients with type 2 diabetic mellitus (T2DM). Methods Clinical data of 1 273 consecutive patients with T2DM admitted in hospital from June 2013 to June 2017 were retrospectively analyzed. According to the quartile of serum magnesium levels, patients were divided into 4 groups: Q1 group (≤ 0.79 mmol/L, n=376), Q2 group (0.80-0.84 mmol/L, n=296), Q3 group (0.85-0.89 mmol/L, n=287) , and Q4 group (≥0.90 mmol/L, n=314). Logistic regression was used to analyze the association between NAFLD and serum magnesium level. Results The average age of the study population was (56.4±13.8) years, males accounted for 52.7%(671/1 273), NAFLD patients accounted for 58.4%(743/1 273). The prevalence of NAFLD in Q4, Q3, Q2 and Q1 groups was 53.8%(169/314), 52.6%(151/287), 57.4%(170/296) and 67.3%(253/376), respectively (χ2=19.00, P=0.000). Logistic regression showed that compared with the Q4 group, OR(95%CI) for NAFLD in the Q1 group was 1.49 (1.03-2.16), Ptrend=0.011 after adjusting for age, sex, duration of diabetes, BMI, systolic blood pressure, alcohol consumption, TG, glycosylated hemoglobin and serum uric acid. After further adjusting for estimated glomerular filtration rate (eGFR), OR(95%CI) for NAFLD was 1.33 (0.92-1.94) and Ptrend=0.065 in the Q1 group compared with the Q4 group. Conclusion Reduction in serum magnesium is associated with an increased risk of NAFLD in T2DM patients, and eGFR may be a confounding factor. Key words: Diabetes mellitus, type 2; Fatty liver; Magnesium, serum; Cross-sectional studies

IRGM Gene Variants Modify the Relationship Between Visceral Adipose Tissue and NAFLD in Patients With Crohn's Disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized comorbidity in Crohn's disease (CD), but the mechanisms are poorly understood. Autophagy is a highly conserved process regulating innate immunity that contributes to CD susceptibility. Emerging data suggest that variants in the autophagy-governing IRGM gene may contribute to the accumulation of visceral adipose tissue (VAT) and hepatic fat. Our objective was to characterize the relationship between VAT, IRGM gene variants, and NAFLD risk in patients with CD. We included all CD patients in the Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM) without history of alcohol abuse or liver disease. Hepatic fat was quantified by liver attenuation (LA) on computed tomography, with NAFLD defined by the validated liver:spleen (L:S) ratio. NAFLD severity was estimated by the FIB-4 Index and alanine aminotransferase (ALT). Using logistic regression modeling, we examined the relationship between VAT, autophagy gene variants, and NAFLD risk. Among 462 patients, 52% had NAFLD. Increasing VAT quartile was associated with reduced LA (mean change, -7.43; 95% confidence interval [CI], -10.05 to -4.81; Ptrend < 0.0001). In the fully adjusted model, patients in the highest VAT quartile had a 2.2-fold increased NAFLD risk (95% CI, 1.21 to 4.14; Ptrend = 0.032) and a 4.2-fold increased risk of ALT>upper limit of normal (ULN) (95% CI, 1.19 to 14.76; Ptrend = 0.017). The relationship between VAT and NAFLD was modified by IRGM variants rs4958847 and rs13361189 (Pinteraction = 0.005 and Pinteraction < 0.001, respectively). In a large CD cohort, VAT was directly associated with prevalent NAFLD, and this relationship was augmented by functionally annotated IRGM variants associated with impaired autophagy.

Increased Plasma Proneurotensin Levels Identify NAFLD in Adults With and Without Type 2 Diabetes.

Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated. To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels. For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery. Plasma pro-NT levels in relation to NAFLD/NASH. Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P < 0.001). Greater pro-NT correlated with NAFLD presence (P < 0.001) and severity (P < 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P < 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders. Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance.

Association between gallstone and non-alcoholic fatty liver disease in middle-aged and elderly Chinese in Shanghai local communities

Objective To investigate the association between gallstone and non-alcoholic fatty liver disease (NAFLD)in middle-aged and elderly Chinese. Methods A cross-sectional study was conducted in 8934 Chinese adults from Jiading District, Shanghai. Questionnaire interview, anthropometric measurements, biochemical evaluation, and abdominal ultrasonography were performed in all the participants. Results Compared with participants without gallstone, individuals with gallstone had significantly higher prevalence of NAFLD (28.8% and 42.9%, respectively; P<0.01). Using participants without gallstone as the reference, participants with gallstone were associated with an increased risk of NAFLD after adjustment for multiple covariates [odds ratios(OR)and 95% confidence interval(CI)was 1.39(1.45-1.69)]. In addition, compared with participants without cholecystectomy, participants with cholecystectomy were associated with an increased risk of NAFLD(OR=1.44, 95%CI 1.04-1.99). Conclusion The presence of gallstone and cholecystectomy were positively associated with NAFLD in middle-aged and elderly Chinese. (Chin J Endocrinol Metab, 2017, 33: 937-942) Key words: Gallstone; Cholecystectomy; Non-alcoholic fatty liver diseases

Relationship between the waist-to-height ratio and the non-alcoholic fatty liver disease

Objective To analysis the relationship between of waist-to-height ratio(WHtR) and the non-alcoholic fatty liver disease(NAFLD). Methods A total of 7 896 were selected as observed subjects from the Kailuan Group in 2011-2012 health physical examination.A questionnaire survey, blood biochemical and abdominal ultrasound examination were finished by trained medical staff.According to previous study recommended cut points the observed subjects was divided into two groups: abdominnal obesity group(WHtR≥0.5, n=3 185) and non-abdominnal obesity group(WHtR<0.5, n=479). According to the WHtR and its quartile, the observed subjects was divided into four groups(first(WHtR<0.47), second(0.47≤WHtR<0.51), third(0.51≤WHtR<0.55) and forth(WHtR≥0.55) quartile groups). NAFLD detection rate of the four groups were Compared.Multiple Logistic regression analysis was used to analyze the influencing factors of the NAFLD. Results (1)The detection rate of NAFLD in abdominnal obesity group was higher than that in non-obesity group(62.7% vs.21.5%, P<0.01). Along with increasing WHtR level in the 4 quartile groups, the incidence of NAFLD was progressively increased, being 12.6 %, 38.1%, 57.5% and 72.5% respectively in the total population.After stratified by gender, 15.1%, 40.6%, 59.6% and 75.0% in male, 7.8%, 31.5%, 48.3% and 63.8% in female.In the same WHtR group, the NAFLD detection rate of male was higher than female, the differences were statistically significant(P<0.01). (2)Multiple logistic regression analysis showed that compared with the first quartile group, the second, third and forth quartile groups had increased risk of NAFLD after adjusting age, gender and other risk factors, the OR value being 3.19, 5.93 and 9.81 in the total population.After adjusting above factors, the OR value being 3.12, 6.02 and 10.45 in male, 3.32, 5.37 and 7.57 in female, respectively. Conclusion The incidence of NAFLD is increased along with the increasing the WHtR. Key words: Waist-to-height ratio; Non-alcoholic fatty liver disease; Abdominnal obesity; Relationship; Risk

Association of patatin-like phospholipase domain-containing protein 3 gene polymorphisms with susceptibility of nonalcoholic fatty liver disease in a Han Chinese population.

Gene polymorphisms had been found to be associated with increased risk of nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to assess the association between rs2896019 and rs3810622 in PNPLA3 with the susceptibility to NAFLD in Han Chinese population.A total of 384 NAFLD patients and 384 controls were enrolled in the study. Blood samples collected from each subject were used for biochemical index analysis and DNA extraction. Genotyping analyses of PNPLA3 rs2896019 and rs3810622 were performed by real-time PCR methods.Results showed that patients with genotype GG of rs2896019 had a higher incidence of NAFLD than patients with genotypes GT and TT (62.4% vs 52.0% and 43.3%, respectively, P = 0.002), and a higher risk of moderate to severe NAFLD than patients with genotypes GT and TT (60.3% vs 46.2% and 40.2%, respectively, P = 0.03). Furthermore, patients with genotype GG of rs2896019 had higher levels of low-density lipoprotein (LDL, P < 0.001), ALT (P = 0.003), and AST (P = 0.002). Patients with genotype TT of rs3810622 had a higher incidence of NAFLD than patients with genotypes CT and CC (56.7% vs 48.4% and 41.5%, respectively, P = 0.013). Likewise, patients with genotype TT of rs3810622 had higher levels of ALT (P = 0.021) and blood glucose (GLU) (P = 0.034). Haplotype association analysis showed that GT haplotype conferred a statistically significant increased risk for NAFLD (OR = 1.49; 95% CI = 1.20-1.84, P < 0.01).These results suggest that PNPLA3 rs2896019 and rs3810622 polymorphisms significantly contribute to increased NAFLD risk in Han Chinese population.

The relationship between the waist circumference level and the non-alcoholic fatty liver disease of the Kailuan Group population

Objective To explore the relationship between the waist circumference (WC) level and the non-alcoholic fatty liver disease (NAFLD) in the Kailuan Group population. Methods A total of 7 896 individuals were selected as observed subjects from the Kailuan Group in 2011-2012 health physical examination. A questionnaire survey, blood biochemical, and abdominal ultrasound examination were finished by trained medical staff. According to the WC measurement and its quartile in the health examination, the observed subjects were divided into four groups (first, second, third, and forth quartile groups). Multivariate logistic regression analysis was used to analyze the relationship between the WC level and the NAFLD. Results (1)The detection rate of NAFLD in central obesity group was higher than that in non-obesity group (67.1% vs 27.9%, P<0.01). Along with increasing WC level in the 4 quartile groups, the incidences of NAFLD were progressively increased, being 7.1%, 23.4%, 33.4%, and 36.1%, respectively. In the total population, the detection rates were 18.8%, 42.5%, 62.0%, and 76.1% in males; 5.4%, 24.1%, 44.7% and 62.9% in females. (2)Multivariate logistic regression analysis showed that WC is an independent risk factor after adjusting age, gender, and other risk factors, the OR value being 1.08. It was also noticed that compared with the first quartile group, the second, third, and forth quartile groups had increased risk of NAFLD after adjusting above factors in different genders, with the OR values being 2.74, 6.59, and 11.15 in males, while 2.61, 5.03, and 3.67 in females, respectively. Conclusion WC was an independent risk factor for NAFLD; the incidence of NAFLD increased with increasing WC level in the Kailuan Group population. (Chin J Endocrinol Metab, 2016, 32: 483-487) Key words: Waist circumference; Non-alcoholic fatty liver disease; Relationship

Thyroid Function and the Risk of Nonalcoholic Fatty Liver Disease: The Rotterdam Study.

Although thyroid function is associated with several risk factors of nonalcoholic fatty liver disease (NAFLD), its role in NAFLD development remains unclear. We aimed to prospectively investigate the association between variations in thyroid function and NAFLD. The Rotterdam Study, a large population-based, prospective cohort study. Participants with thyroid function measurements at baseline and NAFLD data (ie, at baseline fatty liver index/at follow-up ultrasound) were eligible. Transient elastography was performed to assess the presence of fibrosis in patients with NAFLD, using the liver stiffness measurements more than or equal to 8 kPa as cutoff for clinically relevant fibrosis. The association between thyroid parameters and incident NAFLD was explored by using logistic regression models. A total of 9419 participants (mean age, 64.75 y) were included. The median follow-up time was 10.04 years (interquartile range, 5.70-10.88 y). After adjusting for age, sex, cohort, follow-up time, use of hypolipidemic drugs, and cardiovascular risk factors, higher free T4 levels were associated with a decreased risk of NAFLD (odds ratio, 0.42; 95% confidence interval [CI], 0.28-0.63). In line, higher TSH levels were associated with an increased risk of having clinically relevant fibrosis in NAFLD (odds ratio, 1.49; CI, 1.04-2.15). Compared with euthyroidism, hypothyroidism was associated with a 1.24-fold higher NAFLD risk (CI, 1.01-1.53). Moreover, NAFLD risk decreased gradually from hypothyroidism to hyperthyroidism (P for trend = .003). Lower thyroid function is associated with an increased NAFLD risk. These findings may lead to new avenues regarding NAFLD prevention and treatment.

Association of adiponectin gene polymorphisms and additional gene-gene interaction with nonalcoholic fatty liver disease in the Chinese Han population.

To investigate the association between the single nucleotide polymorphisms (SNPs) of the adiponectin gene and nonalcoholic fatty liver disease (NAFLD) as well as the impact of the interaction of multiple SNPs on NAFLD risk, based on a Chinese population study. A total of 612 subjects (411 male, 201 female) were selected, including 302 NAFLD patients and 310 controls. Three SNPs were selected for genotyping in the case-control study: rs266729, rs822393, and rs1501299. A logistic regression model was used to examine the interaction between the SNPs and NAFLD. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the interaction among SNPs. Logistic analysis showed a significant association between genotypes of variants in rs266729 and rs822393 and increased NAFLD risk. The carriers of the homozygous mutant of two SNP polymorphisms revealed increased NAFLD risk compared to those with wild-type homozygotes; ORs (95% CI) were 1.31 (1.14-1.81) (p=0.001) and 1.18 (1.05-1.71) (p=0.005), respectively. There was a significant two-locus model (p=0.0010) involving rs266729 and rs822393, indicating a potential gene-gene interaction between rs266729 and rs822393. Overall, the two-locus models had a cross-validation consistency of 10 and testing accuracy of 62.17%. Subjects with the CG or GG and CT or TT genotype have the highest NAFLD risk compared to subjects with the CC-CC genotype; the OR (95% CI) was 2.52 (1.31-3.82), p<0.001, after covariate adjustment. Our results support an important association of the rs266729 (-11377 G/C) and rs822393 (-4522 C/T) polymorphism with increased risk of NAFLD. The interaction analysis showed a combined effect of rs266729 and rs822393 on NAFLD.

Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups

BackgroundThe Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity.MethodsSamples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis.Resultsrs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (±3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (±11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (±3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289–2.196, p value 0.00013).ConclusionThis study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.

Serum Uric Acid Levels and Risk of Metabolic Syndrome: A Dose-Response Meta-Analysis of Prospective Studies.

An excess circulating uric acid level, even within the normal range, is always comorbid with metabolic syndrome (MS), several of its components, and nonalcoholic fatty liver disease (NAFLD), which was regarded as hepatic manifestation of MS; however, these associations remain controversial. This study aimed to quantitatively assess the relationship between the serum uric acid (SUA) levels and the MS/NAFLD risk. We searched for related prospective cohort studies including SUA as an exposure and MS/NAFLD as a result in MEDLINE (PubMed) and EMBASE databases up to January 31, 2015 and July 28, 2015, respectively. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were extracted. A random-effects model was used to evaluate dose-response relationships. On the basis of 11 studies (54 970 participants and 8719 MS cases), a combined RR of 1.72 (95% CI, 1.45-2.03; P < .0001) was observed for the highest SUA level category compared with the lowest SUA level category. Furthermore, based on nine studies (51 249 participants and 8265 MS cases), dose-response analysis suggested that each 1 mg/dL SUA increment was roughly linearly associated with the MS risk (RR, 1.30; 95% CI, 1.22-1.38; P < .0001). Beyond that, SUA level increased NAFLD risk (RR, 1.46; 95% CI, 1.31-1.63). Each 1 mg/dL SUA level increment led to 21% increase in the NAFLD risk. This meta-analysis suggests that higher SUA levels led to an increased risk of MS regardless of the study characteristics, and were consistent with a linear dose-response relationship. In addition, SUA was also a causal factor for the NAFLD risk.

Variant adiponutrin confers genetic protection against cholestatic itch.

Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91–17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47–0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin.

Patent Foramen Ovale is Associated with an Increased NAFLD Risk for Health of Young Men

Between March 2012 and July 2013, 1000 asymptomatic young military male underwent hepatic ultrasonography and echocardiography at Medical Check-up Center for general young health screening. Blood biochemistry, arterial blood pressure and anthropometric measurements were studied. All analyses were performed using the statistical package SPSS 15.0, where the statistical significance was assessed at the two-tailed 0.05 threshold. It was found that among 1000 persons, 60 had patent foramen ovale (PFO) and 110 subjects had symptoms of nonalcoholic fatty liver disease (NAFLD). The PFO-group consisted of 20 male with 33.3% of NAFLD symptoms, while the group without PFO consisted of 90 male with 9.6% of NAFLD symptoms only. There were significant differences between two groups: p<0.001. Moreover, such factors as the mean age, BMI, triglycerides, hemoglobin, and aspartate aminotransferase level, the mean HDL cholesterol, alanine aminotransferase, platelet count did not differ between the two groups. The main cause of the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has not been sufficiently elucidated. Serotonin of plasma is removed from circulation in capillary beds, predominantly in the lung. Nevertheless, metabolism of serotonin can be by-passed by patent foramen ovale (PFO) that can lead to NAFLD. Therefore, the aim of this study was to test the hypothesis that echocardiographic diagnosed PFO predicts the subsequent NAFLD, which can be diagnosed by ultrasonography. The statistical analysis of the 1000 young male supports the hypothesis that PFO can be associated with increased NAFLD risk for the health of young men.