Genetic predisposition influences plasma lipids of participants on habitual diet, but not the response to reductions in dietary intake of saturated fatty acids

Objective: SNPs identified from genome wide association studies associate with lipid risk markers of cardiovascular disease. This study investigated whether these SNPs altered the plasma lipid response to diet in the ‘RISCK’ study cohort. Methods: Participants (n = 490) from a dietary intervention to lower saturated fat by replacement with carbohydrate or monounsaturated fat, were genotyped for 39 lipid-associated SNPs. The association of each individual SNP, and of the SNPs combined (using genetic predisposition scores), with plasma lipid concentrations was assessed at baseline, and on change in response to 24 weeks on diets. Results: The associations between SNPs and lipid concentrations were directionally consistent with previous findings. The genetic predisposition scores were associated with higher baseline concentrations of plasma total(P = 0.02) and LDL (P = 0.002) cholesterol, triglycerides (P = 0.001) and apolipoprotein B (P = 0.004), and with lower baseline concentrations of HDL cholesterol (P < 0.001) and apolipoprotein A-I (P < 0.001). None of the SNPs showed significant association with the reduction of plasma lipids in response to the dietary interventions and there was no evidence of diet-gene interactions. Conclusion: Results from this exploratory study have shown that increased genetic predisposition was associated with an unfavourable plasma lipid profile at baseline, but did not influence the improvement in lipid profiles by the low-saturated-fat diets.

Sequential methods for pharmacogenetic studies

A study or experiment can be described as sequential if its design includes one or more interim analyses at which it is possible to stop the study, having reached a definitive conclusion concerning the primary question of interest. The potential of the sequential study to terminate earlier than the equivalent fixed sample size study means that, typically, there are ethical and economic advantages to be gained from using a sequential design. These advantages have secured a place for the methodology in the conduct of many clinical trials of novel therapies. Recently, there has been increasing interest in pharmacogenetics: the study of how DNA variation in the human genome affects the safety and efficacy of drugs. The potential for using sequential methodology in pharmacogenetic studies is considered and the conduct of candidate gene association studies, family-based designs and genome-wide association studies within the sequential setting is explored. The objective is to provide a unified framework for the conduct of these types of studies as sequential designs and hence allow experimenters to consider using sequential methodology in their future pharmacogenetic studies.

Genetic predisposition to type 2 diabetes is associated with impaired insulin secretion but does not modify insulin resistance or secretion in response to an intervention to lower dietary saturated fat

Genome-wide association studies have identified SNPs reproducibly associated with type 2 diabetes (T2D). We examined the effect of genetic predisposition to T2D on insulin sensitivity and secretion using detailed phenotyping in overweight individuals with no diagnosis of T2D. Furthermore, we investigated whether this genetic predisposition modifies the responses in beta-cell function and insulin sensitivity to a 24-week dietary intervention. We genotyped 25 T2D-associated SNPs in 377 white participants from the RISCK study. Participants underwent an IVGTT prior to and following a dietary intervention that aimed to lower saturated fat intake by replacement with monounsaturated fat or carbohydrate. We composed a genetic predisposition score (T2D-GPS) by summing the T2D risk-increasing alleles of the 25 SNPs and tested for association with insulin secretion and sensitivity at baseline, and with the change in response to the dietary intervention. At baseline, a higher T2D-GPS was associated with lower acute insulin secretion (AIRg 4% lower/risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si). T2D-GPS did not modify changes in insulin secretion, insulin sensitivity or the disposition index in response to the dietary interventions to lower saturated fat. Participants genetically predisposed to T2D have an impaired ability to compensate for peripheral insulin resistance with insulin secretion at baseline, but this does not modify the response to a reduction in dietary saturated fat through iso-energetic replacement with carbohydrate or monounsaturated fat.

Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome

Background Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. Methods In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). Results We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. Conclusions These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

Analysis of the genetic diversity and structure across a wide range of germplasm reveals prominent gene flow in apple at the European level

Abstract Background: The amount and structure of genetic diversity in dessert apple germplasm conserved at a European level is mostly unknown, since all diversity studies conducted in Europe until now have been performed on regional or national collections. Here, we applied a common set of 16 SSR markers to genotype more than 2,400 accessions across 14 collections representing three broad European geographic regions (North+East, West and South) with the aim to analyze the extent, distribution and structure of variation in the apple genetic resources in Europe. Results: A Bayesian model-based clustering approach showed that diversity was organized in three groups, although these were only moderately differentiated (FST=0.031). A nested Bayesian clustering approach allowed identification of subgroups which revealed internal patterns of substructure within the groups, allowing a finer delineation of the variation into eight subgroups (FST=0.044). The first level of stratification revealed an asymmetric division of the germplasm among the three groups, and a clear association was found with the geographical regions of origin of the cultivars. The substructure revealed clear partitioning of genetic groups among countries, but also interesting associations between subgroups and breeding purposes of recent cultivars or particular usage such as cider production. Additional parentage analyses allowed us to identify both putative parents of more than 40 old and/or local cultivars giving interesting insights in the pedigree of some emblematic cultivars. Conclusions: The variation found at group and sub-group levels may reflect a combination of historical processes of migration/selection and adaptive factors to diverse agricultural environments that, together with genetic drift, have resulted in extensive genetic variation but limited population structure. The European dessert apple germplasm represents an important source of genetic diversity with a strong historical and patrimonial value. The present work thus constitutes a decisive step in the field of conservation genetics. Moreover, the obtained data can be used for defining a European apple core collection useful for further identification of genomic regions associated with commercially important horticultural traits in apple through genome-wide association studies.

Copy number variants on the X chromosome in women with primary ovarian insufficiency

Objective: To investigate whether submicroscopic copy number variants (CNVs) on the X chromosome can be identified in women with primary ovarian insufficiency (POI), defined as spontaneous secondary amenorrhea before 40 years of age accompanied by follicle-stimulating hormone levels above 40 IU/L on at least two occasions. Design: Analysis of intensity data of single nucleotide polymorphism (SNP) probes generated by genomewide Illumina 370k CNV BeadChips, followed by the validation of identified loci using a custom designed ultra-high-density comparative genomic hybridization array containing 48,325 probes evenly distributed over the X chromosome. Setting: Multicenter genetic cohort study in the Netherlands. Patient(s): 108 Dutch Caucasian women with POI, 97 of whom passed quality control, who had a normal karyogram and absent fragile X premutation, and 235 healthy Dutch Caucasian women as controls. Intervention(s): None. Main Outcome Measure(s): Amount and locus of X chromosomal microdeletions or duplications. Result(s): Intensity differences between SNP probes identify microdeletions and duplications. The initial analysis identified an overrepresentation of deletions in POI patients. Moreover, CNVs in two genes on the Xq21.3 locus (i.e., PCDH11X and TGIF2LX) were statistically significantly associated with the POI phenotype. Mean size of identified CNVs was 262 kb. However, in the validation study the identified putative Xq21.3 deletions samples did not show deviations in intensities in consecutive probes. Conclusion(s): X chromosomal submicroscopic CNVs do not play a major role in Caucasian POI patients. We provide guidelines on how submicroscopic cytogenetic POI research should be conducted. (Fertil Steril (R) 2011;95:1584-8. (C) 2011 by American Society for Reproductive Medicine.)

Fatores de risco individuais e familiares no desenvolvimento da pré-eclâmpia

Preeclampsia is a spectral disease, with different clinical forms which can evolve with severe multisystemic complications. This present study aimed to determine the risk factors associated with preeclampsia (PE); to validate the existence of aggregation of hypertensive disease in families of women with preeclampsia and verify the existence of association between polymorphisms in the VEGF gene and level of VEGF and its soluble receptor (sFlt1). A case-control study was performed (n = 851). Genotyping of VEGF was performed and serum levels of VEGF and sFlt1 were measured by ELISA. It was observed that 38% of mothers (173, 455) of a case of preeclampsia and 30.8% (78 of 361) of controls had history of hypertension (p <0.0001). Similarly, when examining the history of maternal preeclampsia, we observed that 14.6% (48 of 328) of mothers of women with preeclampsia and 9.6% (12 of 294) of mothers of controls had a history of preeclampsia (p = 0.0001). As for maternal history of preeclampsia, we found that 5.1% (15 of 295) of cases and 3.6% (7 of 314) of controls had a history of preeclampsia (p = 0.0568). Sisters of women with preeclampsia also had a history of hypertensive disease in 9% (41 of 455) versus 6.6% (13 of 361), p = 0.002. Similarly when examining the history of preeclampsia in sisters, it was observed that 22.7% (57 of 251) of a sister of case versus 11.4% (26 of 228) of controls had a history of preeclampsia (P = 0.0011). We observed a decrease in free VEGF in the serum of patients (P <0.05) and increased soluble VEGF receptor. There was no association between polymorphisms in the VEGF gene and preeclampsia. The data obtained in this work validate that hypertensive disease in mothers and sisters with preeclampsia are risk factors for preeclampsia. The risk of illness in the family is higher according to disease severity. High incidence of preeclampsia can be assumed by the high incidence of this disease among the controls. Significant differences between the frequency of preeclampsia in mothers of cases and controls indicate familial factors. Work is being conducted with the to eventually perform genome wide association studies to identify susceptibility loci

Genome-Wide Survey of SNP Variation Uncovers the Genetic Structure of Cattle Breeds

The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.

Genetic association study between Interleukin 10 gene and dental implant loss

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A machine learning approach for genome-wide prediction of morbid and druggable human genes based on systems-level data

Background: The genome-wide identification of both morbid genes, i.e., those genes whose mutations cause hereditary human diseases, and druggable genes, i.e., genes coding for proteins whose modulation by small molecules elicits phenotypic effects, requires experimental approaches that are time-consuming and laborious. Thus, a computational approach which could accurately predict such genes on a genome-wide scale would be invaluable for accelerating the pace of discovery of causal relationships between genes and diseases as well as the determination of druggability of gene products.Results: In this paper we propose a machine learning-based computational approach to predict morbid and druggable genes on a genome-wide scale. For this purpose, we constructed a decision tree-based meta-classifier and trained it on datasets containing, for each morbid and druggable gene, network topological features, tissue expression profile and subcellular localization data as learning attributes. This meta-classifier correctly recovered 65% of known morbid genes with a precision of 66% and correctly recovered 78% of known druggable genes with a precision of 75%. It was than used to assign morbidity and druggability scores to genes not known to be morbid and druggable and we showed a good match between these scores and literature data. Finally, we generated decision trees by training the J48 algorithm on the morbidity and druggability datasets to discover cellular rules for morbidity and druggability and, among the rules, we found that the number of regulating transcription factors and plasma membrane localization are the most important factors to morbidity and druggability, respectively.Conclusions: We were able to demonstrate that network topological features along with tissue expression profile and subcellular localization can reliably predict human morbid and druggable genes on a genome-wide scale. Moreover, by constructing decision trees based on these data, we could discover cellular rules governing morbidity and druggability.

Genome-Wide Analysis of Differentially Expressed Genes During the Early Stages of Tomato Infection by a Potyvirus

Plant responses against pathogens cause up-and downward shifts in gene expression. To identify differentially expressed genes in a plant-virus interaction, susceptible tomato plants were inoculated with the potyvirus Pepper yellow mosaic virus (PepYMV) and a subtractive library was constructed from inoculated leaves at 72 h after inoculation. Several genes were identified as upregulated, including genes involved in plant defense responses (e. g., pathogenesis-related protein 5), regulation of the cell cycle (e. g., cytokinin-repressed proteins), signal transduction (e. g., CAX-interacting protein 4, SNF1 kinase), transcriptional regulators (e. g., WRKY and SCARECROW transcription factors), stress response proteins (e. g., Hsp90, DNA-J, 20S proteasome alpha subunit B, translationally controlled tumor protein), ubiquitins (e. g., polyubiquitin, ubiquitin activating enzyme 2), among others. Downregulated genes were also identified, which likewise display identity with genes involved in several metabolic pathways. Differential expression of selected genes was validated by macroarray analysis and quantitative real-time polymerase chain reaction. The possible roles played by some of these genes in the viral infection cycle are discussed.

A Genome-wide Screen for Neurospora crassa Transcription Factors Regulating Glycogen Metabolism

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Implementation of DNA markers to produce genomically - Enhanced EPDs in nellore cattle

Background: The sequencing and publication of the cattle genome and the identification of single nucleotide polymorphism (SNP) molecular markers have provided new tools for animal genetic evaluation and genomic-enhanced selection. These new tools aim to increase the accuracy and scope of selection while decreasing generation interval. The objective of this study was to evaluate the enhancement of accuracy caused by the use of genomic information (Clarifide® - Pfizer) on genetic evaluation of Brazilian Nellore cattle. Review: The application of genome-wide association studies (GWAS) is recognized as one of the most practical approaches to modern genetic improvement. Genomic selection is perhaps most suited to the improvement of traits with low heritability in zebu cattle. The primary interest in livestock genomics has been to estimate the effects of all the markers on the chip, conduct cross-validation to determine accuracy, and apply the resulting information in GWAS either alone [9] or in combination with bull test and pedigree-based genetic evaluation data. The cost of SNP50K genotyping however limits the commercial application of GWAS based on all the SNPs on the chip. However, reasonable predictability and accuracy can be achieved in GWAS by using an assay that contains an optimally selected predictive subset of markers, as opposed to all the SNPs on the chip. The best way to integrate genomic information into genetic improvement programs is to have it included in traditional genetic evaluations. This approach combines traditional expected progeny differences based on phenotype and pedigree with the genomic breeding values based on the markers. Including the different sources of information into a multiple trait genetic evaluation model, for within breed dairy cattle selection, is working with excellent results. However, given the wide genetic diversity of zebu breeds, the high-density panel used for genomic selection in dairy cattle (Ilumina Bovine SNP50 array) appears insufficient for across-breed genomic predictions and selection in beef cattle. Today there is only one breed-specific targeted SNP panel and genomic predictions developed using animals across the entire population of the Nellore breed (www.pfizersaudeanimal.com), which enables genomically - enhanced selection. Genomic profiles are a way to enhance our current selection tools to achieve more accurate predictions for younger animals. Material and Methods: We analyzed the age at first calving (AFC), accumulated productivity (ACP), stayability (STAY) and heifer pregnancy at 30 months (HP30) in Nellore cattle fitting two different animal models; 1) a traditional single trait model, and 2) a two-trait model where the genomic breeding value or molecular value prediction (MVP) was included as a correlated trait. All mixed model analyses were performed using the statistical software ASREML 3.0. Results: Genetic correlation estimates between AFC, ACP, STAY, HP30 and respective MVPs ranged from 0.29 to 0.46. Results also showed an increase of 56%, 36%, 62% and 19% in estimated accuracy of AFC, ACP, STAY and HP30 when MVP information was included in the animal model. Conclusion: Depending upon the trait, integration of MVP information into genetic evaluation resulted in increased accuracy of 19% to 62% as compared to accuracy from traditional genetic evaluation. GE-EPD will be an effective tool to enable faster genetic improvement through more dependable selection of young animals.