The PNPLA3 rs738409 variant can increase the risk of liver toxicity in multiple sclerosis patients treated with beta-interferon.

BACKGROUND: Liver toxicity can limit the use of interferon-beta (IFNß), a well-established treatment for multiple sclerosis (MS). Unfortunately, known risk-factors for IFNß-associated liver toxicity are few and of limited clinical utility. Susceptibility to drug-induced toxicity is influenced by genetic factors affecting hepatic lipid metabolism and drug-metabolizing activity. METHODS: We designed a retrospective, multicentre study to evaluate whether specific polymorphisms in genes involved in hepatic lipid metabolism are associated with a higher risk of developing IFNß-induced hepatotoxicity. The following single nucleotide polymorphisms were examined: rs738409 C > G in PNPLA3; rs4880 C > T in SOD2; rs3750861 C > T in KLF6; rs13412852 C > T in LPIN1; rs58542926 C > T in TM6SF2. Liver toxicity was defined as a new increase of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) plasma levels above the laboratory upper normal limit after the start of IFNß treatment. RESULTS: One-hundred-thirteen MS patients were enrolled and twenty-nine experienced liver toxicity. Logistic regression analysis revealed that the PNPLA3 variant was significantly associated with the occurrence of liver toxicity. No associations were found between other polymorphisms and liver toxicity. CONCLUSIONS: The results of our exploratory study suggest that the PNPLA3 variant can help to identify those patients at higher risk of IFNß toxicity. The stratification of the risk of liver toxicity could increase the safety of IFNß therapy.

Endothelial Dysfunction, Fibrinolytic Activity, and Coagulation Activity in Patients With Atrial Fibrillation According to Type II Diabetes Mellitus Status.

Recent findings in atrial fibrillation (AF) patients receiving oral anticoagulation showed that diabetes without insulin therapy has a thromboembolic risk comparable to nondiabetic patients, whereas only diabetic patients on insulin have a heightened thromboembolic risk. We explored possible pathophysiological correlates of such finding on 90 AF patients on oral anticoagulation, divided according to diabetes status (n = 30 without diabetes; n = 29 with diabetes on oral antidiabetic drugs; n = 31 with insulin-requiring diabetes). We assessed von Willebrand Factor (VWF) concentration (VWF:Ag) and activity (VWF R:Co) as measures of endothelial dysfunction; and thrombin-activatable fibrinolysis inhibitor (TAFI) and prothrombin fragment 1 + 2 (F1+2) levels as markers of fibrinolytic activity and thrombin generation. Values of VWF:Ag, VWF:RCo, and TAFI were similar in the 3 groups. Patients with diabetes requiring insulin had significantly higher levels of F1+2 (median 23.1 pg/ml [interquartile range 17.6; 33.5]) than those without diabetes (16.3 pg/ml [11.5; 22.5], p = 0.036) and diabetic patients on oral antidiabetic drugs (20.6 pg/ml [13.3; 29], p = 0.046). Thus, in AF patients receiving oral anticoagulation, those with diabetes, regardless of the diabetes type (with or without insulin therapy), and those without diabetes have comparable indices of the explored parameters of endothelial dysfunction and fibrinolytic activity. Despite anticoagulant therapy, thrombin generation is selectively higher in diabetic patients' on insulin than in those without diabetes or with diabetes on oral antidiabetic drugs, with no differences between these latter 2 conditions. Thrombin generation might thus be a predominant contributor to the excess of thromboembolic risk in AF patients on insulin-requiring diabetes.

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis.

In patients with acute myocardial infarction (AMI), a persistently occluded infarct-related artery (IRA) is associated with unfavorable prognosis and genetic factors may be contributing factors to thrombolysis failure. One-hundred and one consecutive patients treated with intravenous thrombolysis during AMI were blind-tested for methylenetetrahydrofolate reductase (MTHFR) and circulating homocysteine levels and underwent protocol angiography 14 +/- 6 days after the event. IRA was patent in 61 patients and occluded in 40. Overall MTHFR 677TT frequency was 22%. Patients with MTHFR 677TT homozygosis had higher prevalence of occluded IRA (73%) versus those with MTHFR 677CT/CC genotype (30%, P < 0.001); MTHFR 677TT genotype predicted independently the risk of IRA occlusion with a specificity of 90% (odds ratio 3.8, 95% confidence interval 1.1-9.1; P = 0.03). Moreover, patients with occluded IRA and MTHFR 677TT genotype had the highest homocysteine levels (21 +/- 7.6 micromol/l vs. < or =14.9 +/- 3.8 micromol/l; P = 0.011). In patients with AMI, MTHFR 677TT homozygosis is independently associated with a persistently occluded IRA after thrombolysis. This finding may have pathophysiological and therapeutic implications for recanalization strategies in patients with AMI.