A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans

The evidence for the existence of genetic susceptibility variants for the common form of hypertension (“essential hypertension”) remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8×10−7) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1×10−7). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments

Development of admixture mapping panels for African Americans from commercial high-density SNP arrays

<p>Abstract</p> <p>Background</p> <p>Admixture mapping is a powerful approach for identifying genetic variants involved in human disease that exploits the unique genomic structure in recently admixed populations. To use existing published panels of ancestry-informative markers (AIMs) for admixture mapping, markers have to be genotyped <it>de novo </it>for each admixed study sample and samples representing the ancestral parental populations. The increased availability of dense marker data on commercial chips has made it feasible to develop panels wherein the markers need not be predetermined.</p> <p>Results</p> <p>We developed two panels of AIMs (~2,000 markers each) based on the Affymetrix Genome-Wide Human SNP Array 6.0 for admixture mapping with African American samples. These two AIM panels had good map power that was higher than that of a denser panel of ~20,000 random markers as well as other published panels of AIMs. As a test case, we applied the panels in an admixture mapping study of hypertension in African Americans in the Washington, D.C. metropolitan area.</p> <p>Conclusions</p> <p>Developing marker panels for admixture mapping from existing genome-wide genotype data offers two major advantages: (1) no <it>de novo </it>genotyping needs to be done, thereby saving costs, and (2) markers can be filtered for various quality measures and replacement markers (to minimize gaps) can be selected at no additional cost. Panels of carefully selected AIMs have two major advantages over panels of random markers: (1) the map power from sparser panels of AIMs is higher than that of ~10-fold denser panels of random markers, and (2) clusters can be labeled based on information from the parental populations. With current technology, chip-based genome-wide genotyping is less expensive than genotyping ~20,000 random markers. The major advantage of using random markers is the absence of ascertainment effects resulting from the process of selecting markers. The ability to develop marker panels informative for ancestry from SNP chip genotype data provides a fresh opportunity to conduct admixture mapping for disease genes in admixed populations when genome-wide association data exist or are planned.</p

Transcriptional profiles of drought-responsive genes in modulating transcription signal transduction, and biochemical pathways in tomato

To unravel the molecular mechanisms of drought responses in tomato, gene expression profiles of two drought-tolerant lines identified from a population of Solanum pennellii introgression lines, and the recurrent parent S. lycopersicum cv. M82, a drought-sensitive cultivar, were investigated under drought stress using tomato microarrays. Around 400 genes identified were responsive to drought stress only in the drought-tolerant lines. These changes in genes expression are most likely caused by the two inserted chromosome segments of S. pennellii, which possibly contain drought-tolerance quantitative trait loci (QTLs). Among these genes are a number of transcription factors and signalling proteins which could be global regulators involved in the tomato responses to drought stress. Genes involved in organism growth and development processes were also specifically regulated by drought stress, including those controlling cell wall structure, wax biosynthesis, and plant height. Moreover, key enzymes in the pathways of gluconeogenesis (fructose-bisphosphate aldolase), purine and pyrimidine nucleotide biosynthesis (adenylate kinase), tryptophan degradation (aldehyde oxidase), starch degradation (β-amylase), methionine biosynthesis (cystathionine β-lyase), and the removal of superoxide radicals (catalase) were also specifically affected by drought stress. These results indicated that tomato plants could adapt to water-deficit conditions through decreasing energy dissipation, increasing ATP energy provision, and reducing oxidative damage. The drought-responsive genes identified in this study could provide further information for understanding the mechanisms of drought tolerance in tomato

UGT1A1 is a major locus influencing bilirubin levels in African Americans

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10−8. The lowest P-value was 1.7 × 10−22 for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10−11; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r2≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations

Comparison of hydrochloric acid infusion radiofrequency ablation with microwave ablation in an ex vivo liver model

Objectives To compare sizes and shapes of ablation zones resulting from hydrochloric acid infusion radiofrequency ablation (HRFA) and microwave ablation (MWA), using normal saline infusion radiofrequency ablation (NSRFA) as a control, at a variety of matched power settings and ablation durations, in an ex vivo bovine liver model. Methods A total of 90 ablation procedures were performed, using each of three modalities: NSRFA, HRFA, and MWA. For each modality, five ablation procedures were performed for each combination of power (80 W, 100 W, or 120 W) and duration (5, 10, 20, 30, 45, or 60 min). The size of ablation zones were compared using ANOVA, the Kruskal-Wallis test, or generalized linear regression. Results For ablation durations up to 30 min, mean transverse diameter (TD) after HRFA and MWA did not differ significantly (β = 0.13, p = .20). For ablation durations greater than 30 min, mean TD was significantly larger after HRFA than after MWA (β = 1.657, p < .001). The largest TD (9.46 cm) resulted from HRFA performed with 100 W power for 60 min. Conclusions Compared to MWA, monopolar HRFA with power settings of 80 W–120 W and durations of less than 30 min showed no significant difference. When duration of more than 30 min, HRFA created larger ablation zones than MWA

Discrepant responses of methane emissions to additions with different organic compound classes of rice straw in paddy soil

Crop straw incorporation has become a prevailing agricultural practice that guarantees the food production and security. There is a significant body of work on the effects of straw incorporation on the methane (CH4) emissions in paddy fields. However, it is unclear whether there are diverse links between CH4 emission dynamics and incorporations of different organic compound classes of straw to paddy fields. In this study, soil incubations were conducted to assess the respective effect of incorporations of hydrolysable amino acid (HAA), dilute-acid extractable carbohydrate (DAC), lipid and acid-insoluble organic matter (ATOM) fractions of rice straw on the CH4 emission in paddy soil. It is revealed that incorporations of HAA and DAC fractions exert the greatest intensities to stimulate the CH4 emissions, which mainly takes place in the early period of incubation; on contrary, the incorporation of lipid fraction exerts the lowest intensity and mainly takes place in the late period. The pattern of CH4 emission after incorporation of ATOM fraction occurs peaks both in the early and late periods of incubation. Our findings highlight that the time of occurrence and intensity of effects of rice straw incorporation on CH4 emissions vary significantly depending on the different organic compound classes of rice straw, which may be key to proposing a promising management strategy for mitigating CH4 emissions in paddy fields in the context of straw incorporation. (C) 2013 Elsevier B.V. All rights reserved

Identification, Genetic Characterization and Validation of Highly Diverse HIV-1 Viruses for Reference Panel Development

The continued diversification of HIV poses potentially significant challenges to HIV diagnostics and therapeutics. The dynamic evolution of emerging variants is highlighted in countries such as Cameroon in West Central Africa, where all known subtypes and circulating recombinant forms (CRFs) have been shown to be prevalent. We obtained several hundred HIV-positive plasma and viruses from this region for characterization and identification of highly divergent HIV strains. A total of 163 viral strains were cultured to high titers and high volumes using donor peripheral blood mononuclear cells (PBMCs). Initially, 101 viruses representing 59 strains were well characterized and categorized. Results showed that the viral load (VL) range was 0.36–398.9 × 107 copies/mL, p24 values was 0.2–1134 ng/mL. Phylogenetic analysis of thirty-six near full-length HIV-1 genomic sequences demonstrated that most recombinants were highly diverse CRF02 containing unique recombinant forms (URFs). There were seven viral isolates identified as pure subtype/sub-subtypes (F2, A1, G, and D), six as CRFs (CRF06, CRF18, and CRF22), and ten as URFs. These extensively characterized reagents reflect the current dynamic and complex HIV epidemic in Cameroon and provide valuable insights into the potential phylogenetic evolutionary trend of global HIV molecular epidemiology in the future. These materials may be useful for development of HIV validation and reference panels to evaluate the performance of serologic antigen and nucleic acid assays for their ability to detect and quantitate highly divergent HIV strains

Transferability and fine-mapping of genome-wide associated loci for adult height across human populations

Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a wellpowered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3 % of these loci transferred (pvalues#0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r 2 $0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8 % for associations originally reported as genome-wide significant and 38.0 % for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation o