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The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.
Pillai, S, Duvvuru, S, Bhatnagar, P, Foster, W, Farmen, M, Shankar, S, Harris, C, Bastyr, E, Hoogwerf, B, Haupt, A
The pharmacogenomics journal. 2018;(3):487-493
Abstract
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.
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Added value of pharmacogenetic testing in predicting statin response: results from the REGRESS trial.
van der Baan, FH, Knol, MJ, Maitland-van der Zee, AH, Regieli, JJ, van Iperen, EP, Egberts, AC, Klungel, OH, Grobbee, DE, Jukema, JW
The pharmacogenomics journal. 2013;(4):318-24
Abstract
It was investigated whether pharmacogenetic factors, both as single polymorphism and as gene-gene interactions, have an added value over non-genetic factors in predicting statin response. Five common polymorphisms were selected in apolipoprotein E, angiotensin-converting enzyme, hepatic lipase and toll-like receptor 4. Linear regression models were built and compared on R(2) to estimate the added value of single polymorphisms and gene-gene interactions. The selected polymorphisms and the gene-gene interactions had a small added value in predicting change in low-density lipoprotein cholesterol levels (LDL-c) as response to statins over the non-genetic predictors (P=0.104), and also in predicting LDL-c in non-treated patients (P=0.016). Moreover, four gene-gene interactions with statin therapy were identified. The added value of genetic factors over non-genetic variables is for the greater part produced by gene-gene interactions. This underlines the importance to examine gene-gene interactions in future (pharmaco)genetic research.
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3.
A high-carbohydrate diet effects on the A allele of hepatic lipase polymorphism on the apoB100/apoAI ratio in young Chinese males.
Hu, M, Li, Z, Fang, DZ
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2012;(6):751-7
Abstract
BACKGROUND Diet induces changes in plasma lipid profiles, and the plasma lipid profiles vary among different genetic backgrounds. OBJECTIVES The aim of this study was to investigate how a high-carbohydrate (high-CHO) diet interacts with hepatic lipase G-250A promoter polymorphism to affect the ratios of plasma lipids and apolipoproteins (apo) in a young Chinese population. MATERIAL AND METHODS Experiments were conducted on 56 university students. A stabilization diet was given for 7 days and a high-CHO diet was followed for 6 days. The diets used in this study were described by Song et al. and the following parameters were evaluated: total plasma triglyceride (TG), total plasma cholesterol (TC), plasma high-density lipoprotein cholesterol (HDL-C), plasma low-density lipoprotein cholesterol (LDL-C), apoB100 and apoAI. The plasma lipids and apoB100/apoAI ratios were also calculated and hepatic lipase G-250A polymorphism was analyzed. RESULTS At baseline, no significant difference was detected for subjects with different genotypes and genders. All the parameters showed significant differences before and after the high-CHO diet, and these differences are gender-specific: after the high-CHO diet, the TG/HDL-C ratios significantly increased in females (GG genotype: P = 0.004; A carriers: P = 0.005). The TC/HDL-C ratios significantly decreased in GG genotype males (P = 0.007), A carrier males (P < 0.0001) and A carrier females (P = 0.016) and the LDL-C/HDL-C ratios significantly decreased in the GG genotype males (P = 0.011), A carrier males (P < 0.0001) and A carrier females (P = 0.001). However, comparing the apoB100/apoAI ratio before and after the high-CHO diet, a significant difference only existed in male A carriers (P = 0.009). CONCLUSIONS The results of this study show that the high-CHO diet induces the positive effects on the lipid ratios in general, only except the TG/HDL-C ratio in females. Noticeably, the decreased apoB100/apoAI ratio is associated with the A allele of hepatic lipase G-250A polymorphism only in young Chinese males.
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[Serum pancreatic enzyme elevation under treatment with sorafenib].
Hyodo, I, Adachi, M, Tsukamoto, T, Murai, M, Naito, S, Akaza, H
Gan to kagaku ryoho. Cancer & chemotherapy. 2012;(11):1651-6
Abstract
OBJECTIVE Sorafenib is an oral multi-kinase inhibitor of Raf-1, VEGF and PDGF receptors and others, resulting in tumor regression and anti-angiogenesis. We studied serum pancreatic enzyme increase associated with sorafenib treatment. PATIENTS AND METHODS In a phase II study of Japanese patients with metastatic renal cell carcinoma, a total of 131 patients received sorafenib 400 mg twice per day. Serum levels of lipase and amylase were measured on day 7 and every 3-4 weeks thereafter during treatment period. When grade 3 or 4 enzyme abnormalities were observed, ultrasound or computed tomography scan was performed to detect pancreatitis. RESULTS The incidence of all-grades lipase and amylase increases were 55. 7% and 38. 2%, respectively, while those of grade 3 or 4 were 30. 5% and 5. 3%, respectively. The majority of these events were observed in the first 3 weeks of sorafenib treatment. Grade 3 or 4 lipase increase was detected in 32 patients (24. 4%)on day 7 measurement. These abnormal elevations spontaneously resolved in all patients. Regarding grade 3 lipase increase, the median time to recovery to grade 2 and 1 were 7 and 14 days, respectively. Three patients required interruption of the treatment. No patient showed any clinical manifestation or abnormal imaging finding suggesting pancreatitis. CONCLUSION Pancreatic enzyme increases observed frequently under sorafenib treatment were transient and asymptomatic. They were not related to symptomatic pancreatitis.
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Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans.
Sevastianova, K, Kotronen, A, Gastaldelli, A, Perttilä, J, Hakkarainen, A, Lundbom, J, Suojanen, L, Orho-Melander, M, Lundbom, N, Ferrannini, E, et al
The American journal of clinical nutrition. 2011;(1):104-11
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Abstract
BACKGROUND The rs738409 C→G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. OBJECTIVE We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. DESIGN We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([(2)H(5)]glycerol infusion) were measured before and after the diet. RESULTS At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 ± 0.5 kg; PNPLA3-148II: -3.1 ± 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). CONCLUSION Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775.
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Pragmatic study of orlistat 60 mg on abdominal obesity.
Thomas, EL, Makwana, A, Newbould, R, Rao, AW, Gambarota, G, Frost, G, Delafont, B, Mishra, RG, Matthews, PM, Berk, ES, et al
European journal of clinical nutrition. 2011;(11):1256-62
Abstract
BACKGROUND/OBJECTIVES It is well established that combining a reduced calorie, low-fat diet with the lipase inhibitor orlistat results in significantly greater weight loss than placebo plus diet. This weight loss is accompanied by changes in adipose tissue (AT) distribution. As 60 mg orlistat is now available as an over-the-counter medication, the primary objective of this study was to determine whether 60 mg orlistat is effective as a weight loss option in a free-living community population with minimal professional input. METHODS AT and ectopic lipid content were measured using magnetic resonance imaging and (1)H MR spectroscopy, respectively, in 27 subjects following 3 months treatment with orlistat 60 mg and a reduced calorie, low-fat diet. RESULTS Significant reductions in intra-abdominal AT (-10.6%, P=0.023), subcutaneous (-11.7% P<0.0001) and pericardial fat (-9.8%, P=0.034) volumes and intrahepatocellular lipids (-43.3%, P=0.0003) were observed. These changes in body fat content and distribution were accompanied by improvements in plasma lipids and decreases in blood pressure and heart rate. CONCLUSION These findings suggest that over-the-counter 60 mg orlistat, in combination with the type of advice a subject could expect to be given when obtaining 60 mg orlistat in a community setting, does indeed result in potentially clinically beneficial changes in body composition and risk factors for metabolic diseases.
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Effect of Orlistat in obese patients with heart failure: a pilot study.
Beck-da-Silva, L, Higginson, L, Fraser, M, Williams, K, Haddad, H
Congestive heart failure (Greenwich, Conn.). 2005;(3):118-23
Abstract
Heart failure is the leading cause of hospitalization. Obesity is increasingly common and is a major public health problem. The aim of this study is to assess whether obese patients with heart failure can benefit from losing weight via an orlistat-assisted diet. This randomized clinical trial included obese patients with ejection fractions < or =40%. Orlistat and diet counseling were compared with diet counseling alone. Twenty-one consecutive obese patients with heart failure were recruited. Significant improvement in 6-minute walk test (45.8 m; 95% confidence interval, 5.2-86.4 m; p=0.031), functional class (-0.6+/-0.5, p=0.014), weight loss (-8.55 kg; 95% confidence interval, -13.0 to -4.1 kg; p<0.001) and also significant decreases in total cholesterol (p=0.017), low-density lipoprotein cholesterol (p=0.03), and triglycerides (p=0.036) were observed in the orlistat group. Orlistat can promote significant weight loss and symptoms of relief in obese patients with heart failure, as measured by 6-minute walk test and functional capacity. The lipid profile improved. Orlistat was safe and well tolerated.
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Combining unprotected pancreatic enzymes with pH-sensitive enteric-coated microspheres does not improve nutrient digestion in patients with cystic fibrosis.
Kalnins, D, Corey, M, Ellis, L, Durie, PR, Pencharz, PB
The Journal of pediatrics. 2005;(4):489-93
Abstract
OBJECTIVES To assess the efficacy of combining unprotected powder enzymes and oral enteric-coated microsphere (ECM) and to ECM alone in treating nutrient maldigestion in patients with cystic fibrosis. STUDY DESIGN Patients were randomly assigned into 2 consecutive, 2-week phases; ECM alone, and ECM plus unprotected powder enzymes. Fecal fat, energy, and nitrogen output were compared with intake at the end of each phase. Two-tailed, paired t tests were performed to compare outcomes. RESULTS The mean age of the 14 patients (3 girls) was 5.7 +/- 3.2 years (range, 1.9 to 13.4 years). There was no significant difference in percent malabsorption of fat (15.6% vs 18.2%), energy (13.3% vs 13.4%), or nitrogen (11.8% vs 11.3%) between phases. CONCLUSIONS The addition of powder enzymes to ECM did not improve nutrient maldigestion compared with ECM alone.
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Hepatic lipase C-480T genotype-dependent benefit from long-term hormone replacement therapy for atherosclerosis progression in postmenopausal women.
Fan, YM, Dastidar, P, Jokela, H, Punnonen, R, Lehtimäki, T
The Journal of clinical endocrinology and metabolism. 2005;(6):3786-92
Abstract
Hepatic lipase (HL) is a lipolytic enzyme that hydrolyzes triglycerides and phospholipids in almost all major classes of lipoproteins. The HL gene has a functional promoter polymorphism at position -480, which affects transcription and leads to CC, CT, and TT genotypes. We investigated the effect of long-term hormone replacement therapy (HRT) on the progression of atherosclerosis in a 5-yr follow-up observational study of 88 postmenopausal women with different HL genotypes (CC, n = 49; CT, n = 34; TT, n = 5). These women, aged 45-71 yr, were divided into three groups based on the use of HRT. The HRT-EVP group (n = 26) used sequential estradiol valerate (EV) plus progestin (levonorgestrel), the HRT-EV group used EV alone (n = 32), and the control group (n = 30) used no HRT. The HRT-EV and HRT-EVP groups started estrogen at menopause for estrogen-deficiency symptoms, whereas the control group took no estrogen due to either the absence of such symptoms or a dislike of estrogen therapy. In addition to serum lipid concentration and HL genotype, the atherosclerosis severity score (ASC) for the abdominal aorta and carotid arteries was determined by ultrasonography. There was a significant interaction between HRT therapy and HL genotypes on the increase in ASC (P = 0.046) after adjustment for age, body mass index, changes in high-density lipoprotein cholesterol and baseline ASC. In subjects with the T allele, the progression of ASC was significantly faster in the control group than the HRT group (P = 0.0006), whereas in the CC genotype, there were no significant differences in ASC progression between the control and HRT groups. Our results suggest that the beneficial effect of HRT on atherosclerosis progression was restricted to women with the T allele, in whom the progression of ASC was slower by half. These results may help us understand in greater detail the benefits and possible risks associated with HRT in atherosclerotic diseases.
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The -514C/T polymorphism of the hepatic lipase gene significantly modulates the HDL-cholesterol response to statin treatment.
Lahoz, C, Peña, R, Mostaza, JM, Laguna, F, García-Iglesias, MF, Taboada, M, Pintó, X, ,
Atherosclerosis. 2005;(1):129-34
Abstract
A number of studies have evaluated the effect of the -514C/T polymorphism of the hepatic lipase (HL) gene on concentration and composition of the plasma lipoproteins. However, the effect of this polymorphism on the response to hypolipaemic treatment has not been addressed. We evaluated the effect of this polymorphism on baseline lipids and lipoproteins and their response to treatment comprising 20mg/day pravastatin for 3 months. The study was multi-centred, prospective and interventional in 236 hypercholesterolaemic subjects (mean age 57.3 years; 45% males) from 21 Primary Health-care Centres. The lipid and genotype measurements were conducted centrally. The genotype distribution was 60.2% homozygous for the C allele and 36.0% heterozygous. No significant differences in baseline lipid concentrations between the genotypes were observed, except that carriers of the T allele had higher concentrations of triglycerides (p=0.021). Post-pravastatin, concentrations of HDL-C increased by 6.9% (95% CI: 2.9-10.8%) in those carrying the T allele with almost no change (0.8%) in the CC genotypes (95% CI: -2.3-4.0%) (p=0.019). The significance remained (p=0.014) following adjustment for other confounding factors (age, basal HDL-cholesterol, LDL-cholesterol and triglycerides). We conclude that the -514C/T polymorphism modulates significantly the HDL-C response to pravastatin, irrespective of the baseline lipoprotein concentrations.