| 1. |
- Burza, Maria Antonella, 1980, et al.
(författare)
-
DEPDC5 variants increase fibrosis progression in Europeans with chronic HCV infection.
- 2016
-
Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 63:2, s. 418-427
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in Europeans with chronic HCV infection. In a Northern Italian discovery cohort (n=477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n=150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n=300; p=0.049). The association of rs1012068 with moderate-severe fibrosis was confirmed in an independent cross-sectional German cohort (n=415; p=0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n=247; p=0.027). Next, we examined the distribution of non-synonymous DEPDC5 variants in the overall cross-sectional cohort (n=912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (p=0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of β-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression.
|
|
| 2. |
- Pirazzi, Carlo, et al.
(författare)
-
PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:15, s. 4077-4085
-
Tidskriftsartikel (refereegranskat)abstract
- Retinoids are micronutrients that are stored as retinyl esters in the retina and hepatic stellate cells (HSCs). HSCs are key players in fibrogenesis in chronic liver diseases. The enzyme responsible for hydrolysis and release of retinyl esters from HSCs is unknown and the relationship between retinoid metabolism and liver disease remains unclear. We hypothesize that the patatin-like phospholipase domain-containing 3 (PNPLA3) protein is involved in retinol metabolism in HSCs. We tested our hypothesis both in primary human HSCs and in a human cohort of subjects with non-alcoholic fatty liver disease (N = 146). Here we show that PNPLA3 is highly expressed in human HSCs. Its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression results in reduced lipid droplet content. PNPLA3 promotes extracellular release of retinol from HSCs in response to insulin. We also show that purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid. Conversely, this enzymatic activity is markedly reduced with purified PNPLA3 148M, a common mutation robustly associated with liver fibrosis and hepatocellular carcinoma development. We also find the PNPLA3 I148M genotype to be an independent (P = 0.009 in a multivariate analysis) determinant of circulating retinol-binding protein 4, a reliable proxy for retinol levels in humans. This study identifies PNPLA3 as a lipase responsible for retinyl-palmitate hydrolysis in HSCs in humans. Importantly, this indicates a potential novel link between HSCs, retinoid metabolism and PNPLA3 in determining the susceptibility to chronic liver disease.
|
|
| 3. |
- Burza, Maria Antonella, 1980, et al.
(författare)
-
Effect of Excess Body Weight on the Genetic Susceptibility to Cancer
- 2014
-
Ingår i: Journal of Clinical Gastroenterology. - 0192-0790. ; 48, s. S78-S79
-
Tidskriftsartikel (refereegranskat)abstract
- Excess body weight and genetics play important roles in cancer susceptibility. Although several studies have reported on obesity and genetic variants as separate risk factors for cancer, very few studies have investigated the interaction between excess body weight and genetic variants in cancer susceptibility. In this review, we focus on the interplay between these 2 risk factors, which are a major determinant of the individual risk of cancer onset.
|
|
| 4. |
- Burza, Maria Antonella, 1980, et al.
(författare)
-
Long-Term Effect of Bariatric Surgery on Liver Enzymes in the Swedish Obese Subjects (SOS) Study
- 2013
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Aim: Obesity is associated with elevated serum transaminase levels and non- Methods: The Swedish Obese Subjects (SOS) study is a prospective controlled intervention study Results: Compared to usual care, bariatric surgery was associated with lower serum ALT and AST levels Conclusions: Bariatric surgery results in a sustained reduction in transaminase levels and a long-term
|
|
| 5. |
- Burza, Maria Antonella, 1980, et al.
(författare)
-
PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis
- 2014
-
Ingår i: Liver International. - : Wiley. - 1478-3223 .- 1478-3231. ; 34:4, s. 514-520
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence. A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested. A higher incidence of alcoholic cirrhosis was observed in individuals with an older (>= 24years) compared with a younger (<24) age at onset of at-risk alcohol consumption (P-value<0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value<0.001). Both age at onset of at-risk alcohol consumption and PNPLA3148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value<0.001; 1.53(1.07-2.19), P-value=0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38). Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.
|
|
| 6. |
- Burza, Maria Antonella, 1980, et al.
(författare)
-
PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals
- 2012
-
Ingår i: Digestive and Liver Disease. - : Elsevier BV. - 1590-8658. ; 44:12, s. 1037-1041
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n=4047). Methods: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. Results: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value=0.001), but not in the surgery group (log-rank P-value=0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value=0.013) of developing hepatocellular carcinoma was observed only in the control group. Conclusion: The current study is the first prospective report showing the association of the PNPLA3I148M genetic variant and hepatocellular carcinoma in severely obese individuals.
|
|
| 7. |
- Burza, Maria Antonella, 1980
(författare)
-
Susceptibility to chronic liver disease
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The onset and the progression of chronic liver disease involve environmental and genetic factors. Hepatic stellate cells (HSCs) are important players in these processes and are the main storage site for retinol. We studied the role obesity, alcohol and patatin-like phospholipase domain-containing 3 (PNPLA3) I148M variant on the susceptibility to chronic liver disease. Moreover, we tried to understand the molecular mechanism underlying the association between PNPLA3 and chronic liver disease. In paper I we analysed the long-term effect of weight loss due to bariatric surgery on liver damage in a large prospective controlled cohort, the Swedish Obese Subjects study. We analysed changes in serum transaminases between follow-up and baseline values in the bariatric surgery and control groups. Serum transaminases at 2- and 10-year follow-up were lower in the bariatric surgery than in the control group. The transaminase reduction was proportional to the degree of weight loss. In addition, the prevalence of severe liver disease was lower in the surgery than in the control group during the follow-up. In paper II we examined the effect of age at onset of at-risk alcohol intake and PNPLA3 I148M variant on the incidence of alcoholic cirrhosis. Both variables were independent risk factors for the onset of alcoholic cirrhosis. However, the risk conferred by the 148M variant was higher in subjects who started at-risk drinking earlier than in those who started later. In paper III, we tested the hypothesis that PNPLA3 is involved in the retinol release from HSCs. We found that PNPLA3 is regulated by the availability of retinol in HSCs and that it has an esterase activity on retinyl palmitate, which is impaired in the 148M mutant protein. In conclusion, our data show that modifying environmental factors may affect the natural history of chronic liver disease and that the interplay between environmental and genetic factors defines the individual risk to the disease. Specifically, obesity-related chronic liver damage is reduced by sustained weight loss after bariatric surgery and this may prevent the onset of severe liver disease. Age of exposure to alcohol affects the degree of the risk conferred by PNPLA3 I148M variant. In addition, we suggest that the retinol release from HSCs mediated by PNPLA3 may be one important step in the onset of chronic liver disease.
|
|
| 8. |
- Carlsson, Lena M S, 1957, et al.
(författare)
-
The incidence of albuminuria after bariatric surgery and usual care in swedish obese subjects (SOS): a prospective controlled intervention trial.
- 2015
-
Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 39:1, s. 169-175
-
Tidskriftsartikel (refereegranskat)abstract
- Background:Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.Subjects:The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI⩾34 in men and BMI⩾38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years.Results:During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P<0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Conclusions:Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.International Journal of Obesity advance online publication, 10 June 2014; doi:10.1038/ijo.2014.72.
|
|
| 9. |
|
|
| 10. |
- Maglio, Cristina, 1983, et al.
(författare)
-
The IRS1 rs2943641 Variant and Risk of Future Cancer Among Morbidly Obese Individuals.
- 2013
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 98:4, s. E785-E789
-
Tidskriftsartikel (refereegranskat)abstract
- Context:Obesity and insulin resistance are risk factors for cancer development. The IRS1 rs2943641 genetic variant has been widely associated with insulin resistance.Objective:The aim of the study was to examine whether the IRS1 rs2943641 associates with cancer incidence in obese individuals.Design, Setting and Patients:The IRS1 rs2943641 was genotyped in participants from the Swedish Obese Subjects (SOS) study, an intervention trial on the effect of bariatric surgery on mortality and morbidity compared with usual care and in the population-based Malmö Diet and Cancer (MDC) cohort. In both studies, the median follow-up for cancer incidence was about 15 years.Intervention and Main Outcome Measure:Cancer incidence was assessed in both the SOS and the MDC cohorts through national and local registers.Results:The IRS1 T allele was associated with lower insulin resistance in both the SOS and the MDC studies. A lower cancer incidence was found in T allele carriers from the SOS control group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62-0.96; P = .021) and was restricted to morbidly obese individuals (HR 0.67, 95% CI 0.50-0.91; P = .011). No evidence of such association was detected in the surgery group (interaction P = .005). In the MDC cohort, a nonsignificant tendency for lower cancer incidence in T allele carriers was observed only in morbidly obese individuals. A meta-analysis of morbidly obese individuals (body mass index > 40 kg/m(2)) from the two cohorts strengthened the evidence for the association (HR 0.66, 95% CI 0.50-0.87; P = .004).Conclusions:Our results suggest that the T allele of rs2943641 near IRS1 may associate with lower cancer incidence in morbidly obese individuals.
|
|
