Congenital long QT syndrome (LQTS) is a genetic disease that predisposes affected individuals to arrhythmias, syncope, and sudden death. Mutations in several ion channel genes have been discovered in different families with LQTS: KCNQ1 (KVLQT1, LQT1), KCNH2 (HERG, LQT2), SCN5A (LQT3), KCNE1 (minK, LQT5), and KCNE2 (MiRP1, LQT6). Previously, the P448R-KVLQT1 missense mutation has been reported as an LQT1-causing mutation. In this report, we demonstrate the presence of the P448R polymorphism in two, unrelated Chinese LQTS families. Although absent from 500 reference alleles derived from 150 white and 100 African-American subjects, P448R was present in 14% of healthy Chinese volunteers. Given the inconsistencies between the genotype (LQT1) and clinical phenotype (LQT2) in our two LQTS families, together with the finding that the P448R appears to be a common, ethnic-specific polymorphism, mutational analysis was extended to the other LQTS-causing genes resulting in the identification of distinct HERG missense mutations in each of these two families. Heterologous expression of P448R-KVLQT1 yielded normal, wild-type (WT) currents. In contrast, the two unique HERG mutations resulted in dominant-negative suppression of the WT HERG channel. Our study has profound implications for those engaged in genetic research. Importantly, one child of the original proband was initially diagnosed with LQT1 based upon the presence of P448R-KVLQT1 and was treated with beta-blockers. However, he did not possess the subsequently determined LQT2-causing mutation. On the other hand, his untreated P448R-negative brother harbored the true, disease-causing HERG mutation. These findings underscore the importance of distinguishing channel polymorphisms from mutations pathogenic for LQTS and emphasize the importance of using appropriate ethnically matched controls in the genotypic analysis of LQTS.
Background: Inflammation has important effects on lipid metabolism, but the relationship between hyperlipidemia, inflammation, and disease remains unknown in rabbits. While rabbits are sensitive to dietary hypercholesterolemia, the etiology of hyperlipidemia when fed non-atherogenic diets is uncertain. Objectives:This study aimed to determine the association between hypercholesterolemia and patient characteristics, diseases, and select CBC and biochemistry analytes in rabbits, and to measure plasma lipoprotein lipid fractions in rabbits with inflammatory and other diseases. Methods:Complete blood count and plasma biochemistry data, including total cholesterol concentrations, were evaluated in 531 companion rabbits. Lipoprotein cholesterol fractions (non-high-density lipoprotein cholesterol [non-HDLc] and highdensity lipoprotein [HDLc]) and triglycerides were measured using a colorimetric enzymatic assay in archived plasma from a subset of 267 rabbits. Rabbits were categorized by age, sex, spay/neuter status, breed, diet status (fed atherogenic dietary components or not), the organ system affected by disease, and the pathologic process.Results: Cholesterol was associated with fibrinogen (P = 0.01), globulins (P < 0.01), and heterophil (P < 0.01) concentrations. Adjusting for diet, rabbits with severe infection or sepsis (odds ratio [OR] = 13.25, 95% CI = 5.83-30.12), renal failure (OR = 14.42, 95% CI = 5.69-36.54), and hepatopathy (OR = 8.55, 95% CI = 3.55-20.62) had increased risks of hypercholesterolemia. Increased non-HDLc and triglyceride concentrations were also associated with these three disease states (P < 0.05). Conclusions:Hyperlipidemia is associated with biochemical and CBC markers of inflammation, and with severe infection or sepsis, renal failure, and hepatopathy. Independent of diet, increased cholesterol, non-HDLc, and triglycerides are indicators of disease in companion rabbits. K E Y W O R D Shepatopathy, hyperlipidemia, lipoprotein, renal failure, sepsis
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