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We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

It has long been recognized that many children with asthma outgrow the disease after the onset of puberty, but little is known about genetic factors influencing this outcome

Background:A variety of definitions of asthma and atopy traits have been used in genetic studies. The variables used may be correlated, increasing the likelihood of type I error. Objective:We sought to clarify and quantify phenotypes that may be characterized by related traits. Principal components and factor analysis were applied to the correlation matrix of asthma and atopy traits before linkage analysis. Methods:Factor analysis was performed on 468 Hispanic and non-Hispanic white children enrolled in the Tucson Children's Respiratory Study, with complete information on 24 items, including skin test response to 7 allergens, total serum IgE levels, presence or absence of asthma attacks, wheezing episodes, hay fever, and cough. Factor score coefficients were then applied to all siblings (n = 877), and quantitative factor scores were derived. Single-point and multipoint nonparametric sib-pair analyses were performed to assess linkage to markers on chromosome 5q31-33. Analyses were also performed for individual items. Results:Two main factors were identified: Factor I had high loadings on atopic items, including skin test responses, IgE, and hay fever, and Factor II had high loadings that included asthma diagnosis, wheezing, cough, and Alternariaspecies skin test response. Factors I and II were correlated at an rvalue of 0.19. For the quantitative factor scores, significant single-point linkage (P< .0001) was demonstrated only for atopic Factor I, and a peak multipoint LOD score of 2.7 was seen for marker D5S479. Multipoint LOD scores for individual items were 1.1 or less. Conclusion:These analyses suggest evidence for a locus or loci mapping to chromosome 5q31-33 associated with this composite atopic phenotype. (J Allergy Clin Immunol 2001;108:772-80.)

Background:Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. Objective:We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. Methods:We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3′ untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. Results:We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P= .000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. Conclusion:These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype. (J Allergy Clin Immunol 2000;105:506-13.)

The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t½s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 mi/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t½ of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t½ of an intermediate length and may have significant therapeutic advantages.

The kinetics of digitoxin and two of its major metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six subjects with renal insufficiency and compared to those in six age- and sex-matched normal control subjects. No significant differences between the two groups were found in elimination t½, total body clearance, or volume of distribution. Average renal clearances of all three drugs were reduced in subjects with renal failure, but the differences were significant only in the case of digitoxin. The bis-digitoxoside of digitoxigenin has kinetic properties that offer clinical advantages.

Digoxin scrum concentration rises in the presence of quinidine. To determine whether quinidine alters digoxin bioavailability, six subjects received 1.0 mg of digoxin intravenously alone and by mouth on alternate weeks during steady-state oral quinidine administration. The area under the digoxin concentration:time curves (AUC) and the amount of digoxin excreted in the urine (Xxu) were determined for the 96 hr after each of the four experiments. Values for digoxin bioavailability relative to the corresponding intravenous study in the absence and presence of quinidine were (±S.D.) 73.5 ± 8.6% and 79.5 ± 22.69c (P > 0.05) for serum and 69.8 ± 6.8% and 70.2 ± 10.5% (P > 0.05) for urine. There was no difference in the steady-state quinidine serum concentration during the 4 days after intravenous and oral digoxin. We conclude that quinidine does not alter digoxin bioavailability and therefore that altered absorption does not explain the rise in digoxin serum concentration in the presence of quinidine.

Six subjects were evaluated for the effect of quinine, the 1-isomer of quinidine, on digoxin pharmacokinetics. A 1.0-mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half-life (t½) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from \[xmacr] = 628.29 μg to \[xmacr] = 772.52 μg (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quantitatively different, from quinidine.Clinical Pharmacology and Therapeutics (1980) 28, 425–430; doi:10.1038/clpt.1980.183

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