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To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants inSALL4- c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency forSALL4due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants inSALL4inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype.SALL4is expressed in the developing lens and regulatesBMP4, leading us to speculate that alteredBMP4expression was responsible for the eye defects, but we could not demonstrate alteredBMP4expressionin vitroafter using small interfering RNAs (siRNAs) to reduceSALL4expression. We conclude thatSALL4hypomorphic variants may influence eye development. [ABSTRACT FROM AUTHOR]

Inhaled short-acting beta-agonist (SABA) medication is commonly used in asthma patients to rapidly reverse airway obstruction and improve acute symptoms. We performed a genome-wide association study of SABA medication response using gene-based association tests. A linear mixed model approach was first used for single-nucleotide polymorphism associations, and the results were later combined using GATES to generate gene-based associations. Our results identified SPATA13-AS1 as being significantly associated with SABA bronchodilator response in 328 healthy African Americans. In replication, this gene was associated with SABA response among the two separate groups of African Americans with asthma (n=1073, P=0.011 and n=1968, P=0.014), 149 healthy African Americans (P=0.003) and 556 European Americans with asthma (P=0.041). SPATA13-AS1 was also associated with longitudinal SABA medication usage in the two separate groups of African Americans with asthma (n=658, P=0.047 and n=1968, P=0.025). Future studies are needed to delineate the precise mechanism by which SPATA13-AS1 may influence SABA response. [ABSTRACT FROM AUTHOR]

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8. [ABSTRACT FROM AUTHOR]

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P = 0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin. [ABSTRACT FROM AUTHOR]

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five-located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1-exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response. [ABSTRACT FROM AUTHOR]

The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). In this study, we sequence the coding portions of the gene to identify contributing causal polymorphisms that may explain some of the observed associations. A collection of 123 individuals from the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection, each with multiple AIDs (mean=2.2 confirmed diagnoses), and 397 unrelated healthy controls were used for initial sequencing. A total of 32 polymorphisms were identified in the sequencing experiments, including 16 novel and 11 coding variants. Association testing in the entire MADGC collection (1,008 Caucasians with one or more AIDs and 770 unaffected family controls) revealed association of a novel intronic insertion-deletion polymorphism with rheumatoid arthritis (RA) (odds ratio (OR)=2.48, P=0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed a significant association with Sjögren's syndrome (OR=3.38, P=0.038), Crohn's disease (OR=2.25, P=0.041), psoriasis (OR=0.037, P=0.036) and RA (OR=1.9, P=0.025). Finally, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5′ and 3′ untranslated region variants (one-sided P-value=0.04), but not specifically for common (>2% minor allele frequency), rare, exonic, intronic, non-synonymous or synonymous variants. [ABSTRACT FROM AUTHOR]

In this study, artificial intelligence, namely multilayer perception neural networks (MLP-NN), was employed to predict the hydrodynamic performance of undulatory median fin propulsion in Xenomystus nigri. Good agreement was found between MLP-NN predictions and actual mean thrust and power values calculated from elongated-body theory. MLP-NN has the ability to be a predictive tool for autonomous underwater vehicle design and hydrodynamic performance. [ABSTRACT FROM AUTHOR]

Station holding in Pterygoplichthys spp. was associated with a lower energy cost relative to similarly sized fishes that swam against the free stream current. Pterygoplichthys spp. was characterized by a low, stable mass-specific metabolic rate ( c. 50 mg O2 kg−1 h−1) relative to subcarangiform swimmers that held position in the free stream, until it slipped backwards and burst swam against the current. Furthermore, the maximum range of the rate of oxygen consumption (aerobic scope) of Pterygoplichthys spp. was small relative to many non-benthic fishes. [ABSTRACT FROM AUTHOR]

The fast-start performance of three-spined sticklebacks Gasterosteus aculeatus infected with Schistocephalus solidus and Bunodera spp. was determined and two distinct fast-start responses (A and B) were observed. ‘A’ starts were of higher flexibility than B and three-way ANOVA showed significant effects of A and B starts ( P < 0·05), time ( P < 0·05) and per cent standard body length, LS ( P < 0·05) on the orientation angle (angle of an individual segment of the fish with respect to the direction of travel). Schistocephalus solidus infection reduced maximum velocity ( P < 0·05) and maximum acceleration ( P < 0·05) of infected fish. Uninfected fish and fish infected with S. solidus up to a parasite index (parasite mass divided by the sum of fish and parasite mass) of 0·1 executed both types. Infected fish exclusively executed B starts for parasite index between 0·1 and 0·2. This was not due to a reduction in body flexibility associated with mechanical obstruction caused by S. solidus as no significant difference in the ratios of body width ( P > 0·05) or depth ( P > 0·05) to LS were found between uninfected and infected fish. At a parasite index >0·2, infected fish were unable to perform escape fast-starts increasing the likelihood of predation by their definitive hosts such as loons or belted kingfishers. Three-spined sticklebacks infected with S. solidus with a parasite index of c. 0·2–0·3, however, were compromised by a suite of behavioural ( e.g. increased foraging activity and amount of food consumed, increased risk associated with feeding and increased response latency to predatory stimuli), physiological ( e.g. increased rate of oxygen consumption, slower growth, delayed sexual maturation and breeding success) and biomechanical ( e.g. decreased fast-start performance) factors. Bunodera spp. did not affect the escape fast-start performance of three-spined sticklebacks and no significant difference for maximum velocity ( P > 0·05) and maximum acceleration ( P > 0·05) was found. [ABSTRACT FROM AUTHOR]

Describes the properties of allelic association between the pairs of loci derived in terms of the association probability as a function of recombination, effective population size, linear systematic pressure and decrease of association. Evidence suggesting less sensitivity to variations in marker allele frequencies; Confirmation of robustness for six alternative samples.

The article presents the author's views about technological advances in genetics. Recent technological advances have increased drastically the number of experiments or assays one can perform with a small team of researchers and a manageable set of instruments. Whether one is performing DNA sequencing, genotyping of genetic markers, determining the global gene expression patterns of a tissue or profiling the protein content of a cell type, quality control must be done consistently throughout the course of a study. Knowing the degree of uncertainty in the data, and taking this into account during data analysis, enhances the power of the analysis and strengthens the conclusions derived from the results.

Background Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle-arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD. Methods The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus. Results The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95% CI 1.29 to 2.76). Conclusion This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans. [ABSTRACT FROM AUTHOR]