Acquisition of complement factor H is important for pathogenesis of Streptococcus pyogenes infections: evidence from bacterial in vitro survival and human genetic association.

Streptococcus pyogenes (or group A streptococcus [GAS]) is a major human pathogen causing infections, such as tonsillitis, erysipelas, and sepsis. Several GAS strains bind host complement regulator factor H (CFH) via its domain 7 and, thereby, evade complement attack and C3b-mediated opsonophagocytosis. Importance of CFH binding for survival of GAS has been poorly studied because removal of CFH from plasma or blood causes vigorous complement activation, and specific inhibitors of the interaction have not been available.

Dopamine, working memory, and training induced plasticity: implications for developmental research.

Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also for improving WM capacity.

Research resource: interactome of human embryo implantation: identification of gene expression pathways, regulation, and integrated regulatory networks.

A prerequisite for successful embryo implantation is adequate preparation of receptive endometrium and the establishment and maintenance of a viable embryo. The success of implantation further relies upon a two-way dialogue between the embryo and uterus. However, molecular bases of these preimplantation and implantation processes in humans are not well known.

Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population.

Objective: A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356).

Methods: We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci.

Genetic background and the risk of otitis media.

Objective: Otitis media is a multifactorial disease where genetic background may have an important role. For genome-wide association studies, it is important to understand the degree of heritability. The objective of this study was to estimate the heritability of recurrent acute otitis media and chronic otitis media with effusion.

Molecular genetics and molecular biology of dyslexia.

Developmental dyslexia has been recognized as a distinct entity among learning disabilities as early as the late 1800s and its partially genetic nature has been firmly established by family and twin studies. The application of genetic mapping and molecular cloning methods has revealed specific genes that contribute to the genetic risk, but those known now do not yet suffice for explaining all of it. More importantly, the first genes, some of them found by the study of rare families, have indicated specific neurodevelopmental processes important for the development of dyslexia, including control of neuronal migration for the DYX1C1, DCDC2, and KIAA0319 genes, and a role of axonal and dendritic guidance suggested by the ROBO1 gene.

Co-localization of neural cell adhesion molecule and fibroblast growth factor receptor 2 in early embryo development.

During development there is a multitude of signaling events governing the assembly of the developing organism. Receptors for signaling molecules such as fibroblast growth factor receptor 2 (FGFR2) enable the embryo to communicate with the surrounding environment and activate downstream pathways. The neural cell adhesion molecule (NCAM) was first characterized as a cell adhesion molecule highly expressed in the nervous system, but recent studies have shown that it is also a signaling receptor.

Genome wide association study identifies KCNMA1 contributing to human obesity.

Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified.

The asthma candidate gene NPSR1 mediates isoform specific downstream signalling.

Background: Neuropeptide S Receptor 1 (NPSR1, GPRA, GPR154) was first identified as an asthma candidate gene through positional cloning and has since been replicated as an asthma and allergy susceptibility gene in several independent association studies. In humans, NPSR1 encodes two G protein-coupled receptor variants, NPSR1-A and NPSR1-B, with unique intracellular C-termini. Both isoforms show distinct expression pattern in asthmatic airways.

Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons.

DCDC2 is one of the candidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a.

Study of estrogen receptor-α and receptor-β gene polymorphisms on Alzheimer's disease.

Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk.

Genomic strategy identifies a missense mutation in WD-repeat domain 65 (WDR65) in an individual with Van der Woude syndrome.

Genetic variation in the transcription factor interferon regulatory factor 6 (IRF6) causes and contributes risk for oral clefting disorders. We hypothesized that genes regulated by IRF6 are also involved in oral clefting disorders. We used five criteria to identify potential IRF6 target genes; differential gene expression in skin taken from wild-type and Irf6-deficient murine embryos, localization to the Van der Woude syndrome 2 (VWS2) locus at 1p36-1p32, overlapping expression with Irf6, presence of a conserved predicted-binding site in the promoter region, and a mutant murine phenotype that was similar to the Irf6 mutant mouse.

Influence of the COMT genotype on working memory and brain activity changes during development.

Background: The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development.

Glucocorticoid receptor gene haplotype predicts increased risk of hospital admission for depressive disorders in the Helsinki birth cohort study.

Background: Although glucocorticoid receptors (GR) are involved in mediating hypothalamic-pituitary-adrenal-axis functioning, which is altered in acute depression, data on associations between GR gene (NR3C1) polymorphisms and depression are scarce. We examined if single nucleotide polymorphisms (SNPs) and their haplotypes spanning the entire NR3C1 are associated with depressive disorders and with self-reported depressive symptoms in adulthood.

Methods: We successfully genotyped 10 SNPs spanning the NR3C1, and performed SNP and haplotype analyses in 1,075 women and 928 men participating in the Helsinki birth cohort study.

Methylation of H19 and its imprinted control region (H19 ICR1) in Müllerian aplasia.

Severe hypomethylation of the H19 imprinted control region (ICR1) in two patients with Silver-Russell syndrome (SRS) who have genital malformations has encouraged us to study DNA methylation in a cohort of 83 patients with Müllerian aplasia (MA). Site-specific methylation analyses of H19 ICR1 by quantitative real-time polymerase chain reaction in 80 clinically well-diagnosed Finnish MA patients showed no association between hypomethylation and the MA phenotype, but studies of the H19 locus in 38 patients showed aberrant methylation in 3/16 studied sites.

Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity.

Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance.

Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies.

Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus.

Update on SLC26A3 mutations in congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl(-) /HCO 3- transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility.

A comprehensive analysis of the COL29A1 gene does not support a role in eczema.

Background: Based on a recent positional cloning approach, it was claimed that the collagen 29A1 gene (COL29A1), which encodes an epidermal collagen, represents a major risk gene for eczema underlying a previously reported linkage to chromosome 3q21. However, thus far, not a single replication attempt has been published, and no definitive functional data have been provided.

Objectives: We aimed to determine whether COL29A1 polymorphisms contribute to eczema susceptibility and whether COL29A1 expression is altered in eczema.

Swedish population substructure revealed by genome-wide single nucleotide polymorphism data.

The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays.

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes.

A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung.

Background: Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF).

Methods: We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies.

SNP variations in the 7q33 region containing DGKI are associated with dyslexia in the Finnish and German populations.

Four genes, DYX1C1, ROBO1, DCDC2 and KIAA0319 have been studied both genetically and functionally as candidate genes for developmental dyslexia, a common learning disability in children. The identification of novel genes is crucial to better understand the molecular pathways affected in dyslectic individuals. Here, we report results from a fine-mapping approach involving linkage and association analysis in Finnish and German dyslexic cohorts.

Polymorphisms of the ITGAM gene confer higher risk of discoid cutaneous than of systemic lupus erythematosus.

Background: Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.

Principal Findings: To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus.

Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.

A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.