A diverse array of genetic factors contribute to the pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with variable clinical presentation frequently affecting the skin, joints, haemopoietic system, kidneys, lungs and central nervous system. It can be life threatening when major organs are involved. The full pathological and genetic mechanisms of this complex disease are yet to be elucidated; although roles have been described for environmental triggers such as sunlight, drugs and chemicals, and infectious agents. Cellular processes such as inefficient clearing of apoptotic DNA fragments and generation of autoantibodies have been implicated in disease progression. A diverse array of disease-associated genes and microRNA regulatory molecules that are dysregulated through polymorphism and copy number variation have also been identified; and an effect of ethnicity on susceptibility has been described.http://dx.doi.org/10.1186/1750-1172-8-2IS

The HapMap Resource is Providing New Insights into Ourselves and its Application to Pharmacogenomics

The exploration of quantitative variation in complex traits such as gene expression and drug response in human populations has become one of the major priorities for medical genetics. The International HapMap Project provides a key resource of genotypic data on human lymphoblastoid cell lines derived from four major world populations of European, African, Chinese and Japanese ancestry for researchers to associate with various phenotypic data to find genes affecting health, disease and response to drugs. Recent progress in dissecting genetic contribution to natural variation in gene expression within and among human populations and variation in drug response are two examples in which researchers have utilized the HapMap resource. The HapMap Project provides new insights into the human genome and has applicability to pharmacogenomics studies leading to personalized medicine

Chiari malformation type I: a case-control association study of 58 developmental genes

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI

Short stature investigation: clinical, laboratorial and genetic aspects concerning the trowth hormone insensitivity (GHI)

Neste artigo são descritos os aspectos clínicos, laboratoriais e genéticos da investigação da baixa estatura, dando ênfase para o diagnóstico da insensibilidade ao hormônio de crescimento (IGH). O paciente apresentado possuía características clínicas típicas de pacientes com IGH e em idade pré-púbere seus achados laboratoriais eram compatíveis com este diagnóstico (IGF-1 e IGFBP3 baixos, GH basal e pós-estímulo elevados). No entanto, quando avaliado durante a puberdade, as dosagens de IGF-1 e IGFBP-3 foram normais, dificultando o diagnóstico. O estudo molecular identificou mutação no exon 7 do gene do receptor do hormônio de crescimento (S226I). Discutiram-se os passos realizados para identificar a mutação e demonstrar que ela é responsável pelo fenótipo observado no paciente. Também será feita revisão dos casos de IGH descritos no Brasil e dos novos defeitos moleculares descritos nesta doença.It is reported in this study the clinical, laboratory and genetic aspects of short stature investigation with emphasis to the diagnostic approach of growth hormone insensitivity (GHI). This patient in case presented typical clinical features of GHI and his laboratory findings at prepubertal age were typical of those observed in GHI patients (low IGF-1 and IGFBP-3 levels, with high basal and stimulated GH levels). However, during the puberty, he presented normal IGFBP-3 and IGF-1 levels that hindered the diagnosis. The molecular study disclosed a mutation in exon 7 of growth hormone receptor gene (S226I). The steps that demonstrated the causative effect of this mutation are shown here, and also a review of Brazilian GHI cases is given and new molecular defects in this field are discussed as well.Conselho Nacional de Pesquisa (CNPq

Single-nucleotide variations and linkage disequilibrium patterns in three candidate genes for attention deficit hyperactivity disorder

"Allelic variations in the genes involving the dopaminergic system, particularly the dopamine transporter (DAT1/SLC6A3), dopamine receptor 4 (DRD4) and Catecol-O-Methyltransferase (COMT) genes have been associated with Attention Deficit Hyperactivity Disorder (AD/HD). However, the results of these studies have been variable and inconclusive in part due to the inconsistencies of experimental and statistical methodologies, phenotypic heterogeneity, low penetrance of the genes implicated, and population stratification. Genetic association studies based on linkage disequilibrium (LD) offer a promising approach to the study of common complex diseases. This study characterized LD patterns in three human populations (CEU, YRI, CHB+JPT) in the three genes mentioned above and identified factors affecting the inconsistencies of genetic association studies in AD/HD. We used the HapMap database and the Haploview program to evaluate linkage disequilibrium patterns of SNPs in these genes. The regression results suggest that there is a trend toward poorer capturing of rare SNPs, which would mean lesser detection of AD/HD associations if rare SNPs were causative on these genes. However, sparse sampling of tag SNPs in these genes (COMT and DAT1/SLC6A3) does not capture the other SNPs well and that a denser tag SNP set is needed to further test our results. The significant reductions of the r2 in the other two populations relative to the CEU supports the contention that associations on these genes varies between populations and suggests that prior assessment of tag SNPs using the HapMap is an essential step in the design of genetic association studies"--from author-supplied metadata

Inflammatory Proteins, Genetic Variation, and Environmental Influences on Health Care Associated Infection Development in Sepsis

The purpose of this study was to determine the impact of baseline systemic inflammation (pro‑inflammatory cytokine, anti‑inflammatory cytokine, and their ratio), genetic variability, and environment on the development of health care associated infections (HAI) among sepsis patients during their ICU stay (up to 28 days). Methods: A prospective observation study was conducted at the Veterans Affairs Medical Center in the Medical Intensive Care Unit over an 18 month period. A total of 78 patients were enrolled within 72 hours of presenting to the ICU with sepsis. Patient were excluded if they were receiving immunosuppressants (chemotherapy or greater than one mg/kg of prednisone or equivalent dose), immunosuppressed (AIDS, cancer), or had liver failure (Child Pugh category C or higher). Baseline plasma and buccal swabs were collected. Patients were followed prospectively through their ICU stay (or for a maximum of 28 days) for the development of HAI as defined by CDC guidelines. Primary variables included baseline IL‑6 and IL‑10 levels, IL‑6 SNP rs1800795, IL‑10 SNP rs1800896, APACHE II, invasive devices, and development of HAI. Results: A total of 17 HAI were identified with 64% caused by Candida. There were no significant differences in levels of pro‑inflammatory cytokine, anti‑inflammatory cytokine, or their ratio among subjects who did and did not develop at least one HAI during their ICU stay. There were also no significant differences in rs1800795 or rs1800896 genotypes for those who did and did not develop HAI; however, racial differences were detected in genotypes among white and black patients with sepsis who did and did not develop HAI. There was a significant difference in rs1800795 genotype among black patients with sepsis who did not develop HAI compared to whites patients with sepsis who did not develop HAI (p = 0.006). Specifically, black patients had a lower CG (17.4% vs. 42.1%) and higher GG (82.6% vs. 42.1%) than white patients. There were no racial differences when comparing white and black sepsis patients who developed HAI (p = 1.0). In a series of Cox regression analyses investigating timing to first HAI among those who did and did not develop HAI during ICU stay, the final model included only APACHE II, cumulative invasive device score, and IL‑6 rs1800795. Conclusion: This study provides evidence of a genetic risk for development of HAI. Despite best evidenced based practices some patients will develop HAI. Strict aseptic technique is essential to preventing infection. In addition to eliminating invasive devices as quickly as possible, patients with a high severity of illness may need to be isolated to lower their risk. Early administration of antibiotics not only provides prompt treatment for the initial infection but also lowers risk for subsequent infections

The development of a single nucleotide polymorphism database for forensic identification of specified physical traits

Magister Scientiae - MScMany Single Nucleotide Polymorphisms (SNPs) found in coding or regulatory regions within the human genome lead to phenotypic differences that make prediction of physical appearance, based on genetic analysis, potentially useful in forensic investigations. Complex traits such as pigmentation can be predicted from the genome sequence, provided that genes with strong effects on the trait exist and are known. Phenotypic traits may also be associated with variations in gene expression due to the presence of SNPs in promoter regions. In this project, the identification of genes associated with these physical traits of potential forensic relevance have been collated from the literature using a text mining platform and hand curation. The SNPs associated with these genes have been acquired from public SNP repositories such as the International HapMap project, dbSNP and Ensembl. Characterization of different population groups based on the SNPs has been performed and the results and data stored in a MySQL database. This database contains SNP genotyping data with respect to physical phenotypic differences of forensic interest. The potential forensicrelevance of the SNP information contained in this database has been verified through in silico SNP analysis aimed at establishing possible relationships between SNP occurrence and phenotype. The software used for this analysis is MATCH™. Data management and access has been enhanced by the use of a functional web-based front-end which enables the users to extract and display SNP information without running complex Structured Query Language (SQL) statements from the command line. This Forensic SNP Phenotype resource can be accessed at http://forensic.sanbi.ac.za/alecia_forensics/Index.htmlSouth Afric

Single nucleotide polymorphisms associated with the human electroencephalogram during desflurane anaesthesia

General anaesthesia is an induced state that enables a person to endure surgical procedures without pain or recollection. There is substantial individual variability in the response to anaesthesia and in order to avoid adverse effects caused by either under- or over-sedation, anaesthetic drug administration must be tailored to suit the individual patient. This requires a means to monitor the depth of general anaesthesia. The electroencephalogram (EEG) records the electrical activity of the brain and enables effects of anaesthetic drugs on brain functioning to be monitored. Quantitative EEG monitors, such as the Bispectral (BIS) index monitor, process the raw EEG and provide a numerical output that is often used to measure the depth of general anaesthesia during surgery. Due to a number of factors including clinical conditions and genetic variability in the EEG, the BIS value can at times be misleading. To identify genetic variations associated with EEG phenotypes relevant to anaesthesia monitoring, an association analysis was performed for 34 single nucleotide polymorphisms (SNPs) in a sample of 125 surgical patients undergoing general, gynaecological or orthopaedic surgery. During surgery, patients were anaesthetised with the volatile anaesthetic agent desflurane, the depth of anaesthesia was measured using BIS monitoring and the raw was also EEG recorded. SNP genotyping was performed for 13 SNPs in five candidate genes; SGIP1, GABRA2, CACNA1G, HCN1 and HCN2, using the polymerase chain reaction and restriction fragment length polymorphism analysis. An additional 21 SNPs in 15 genes involved in various inflammatory and other immune-related pathways were genotyped by Sequenom MassARRAY at the Australian Genome Research Facility. Six SNPs in five different genes were found to be associated with spindle amplitude (SGIP1, GABRA2, HCN1, IL1B and MYD88), and a further five SNPs were associated with either delta frequency (IL10), or end tidal desflurane concentration (ETDC) (CACNA1G, CRP, MYD88 and TGFB1). The strongest associations were identified for a single SNP located in the 3' UTR of MYD88 (rs6853). The rs6853 A/G genotype was associated with higher median spindle amplitude (p = 0.0040) and spindle amplitude relative to ETDC (p = 0.0006), and lower EDTC (p = 0.0095) than the A/A genotype. No rs6853 G/G homozygotes were identified in the study sample. MYD88 acts as an adaptor protein in the interleukin-1 receptor and toll-like receptor signalling pathways. Within the brain, cytokines are thought to act as neuronal modulators and influence neurotransmitter signalling and ion channel activity. The association of MYD88 with spindle amplitude, in conjunction with IL1B, suggests that cytokines may influence the EEG during general anaesthesia. Thus cytokine mediated regulation of neuronal activity is speculated to underlie the reported associations. All reported effect sizes were small (0.77- to 1.55-fold) and associated genes had four distinct types of function; ion channels, neurotransmitter signalling, endocytosis, and cytokine signalling. This suggests that numerous genes in different pathways, each with a small, possibly additive effect, are involved in regulating the EEG during general anaesthesia

A computational characterisation of the relationship between genome structure and disease genes

>Magister Scientiae - MScThis is a pilot study to investigate the relationship between disease gene status and the structure of the human genome with specific reference to regions of recombination. It compares certain characteristics of a control set of genes, with no reported association or function in any known disease, with a second set of well-curated genes with a known association to a disease. One of the benefits of recombination is the introduction of new combinations of genetic variation in the genome. Recombination hotspots are regions on the chromosome where higher than normal frequencies of breaking and rejoining between homologous chromosomes occur during meiosis. The hotspot regions exhibit both a non-random distribution across the human genome and varying frequencies of breaking and rejoining. The study analyzed a set of features that represent general properties of human genes; namely base composition (percentage GC content), genetic variation (single nucleotide polymorphisms - SNPs), gene length, and positional effect (distance from chromosome end), in both the disease-associated gene set and the control set. These features were linked to recombination hotspots in the human genome and the frequency of recombination at these hotspots. Descriptive statistics was used to determine differences between the occurrences of these features in disease-associated genes compared to the control set, as well as differences in the occurrence of these same features in subset of genes containing an internal recombination hotspot compared to the genes with no internal recombination hotspot. The study found that disease-associated genes are generally longer than those in the control set, which is consistent with previous studies. It also found that disease-associated genes are much more likely to contain a recombination hotspot than those genes with no disease association. The study did not, however, find any association between disease gene status and the other set of features; namely GC content, SNP numbers or the position of a gene on the chromosome. Further analysis of the data suggested that the increased probability of disease-associated genes containing a recombination hotspot is most likely an effect of longer gene length and that the presence of a recombination hotspot is not sufficient in its own right to cause disease gene status