Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8

<p>Abstract</p> <p>Background</p> <p>Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency.</p> <p>Methods</p> <p>We identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients.</p> <p>Results</p> <p>Of the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2, *DR7, *DR3(17), *B8, or *B44.</p> <p>Conclusion</p> <p>These findings suggest that TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles.</p> <p>Supported by NIH/USIDNET N01-AI30070, NIH R21 AI079741 and NIH M01-RR00032</p

Vitamin A deficiency and inflammatory markers among preschool children in the Republic of the Marshall Islands

BACKGROUND: The exclusion of individuals with elevated acute phase proteins has been advocated in order to improve prevalence estimates of vitamin A deficiency in surveys, but it is unclear whether this will lead to sampling bias. The purpose of the study was to determine whether the exclusion of individuals with elevated acute phase proteins is associated with sampling bias and to characterize inflammation in children with night blindness. METHODS: In a survey in the Republic of the Marshall Islands involving 281 children, aged 1–5 years, serum retinol, C-reactive protein (CRP), and α(1)-acid glycoprotein (AGP) were measured. RESULTS: Of 281 children, 24 (8.5%) had night blindness and 165 (58.7%) had serum retinol <0.70 μmol/L. Of 248 children with AGP and CRP measurements, 123 (49.6%) had elevated acute phase proteins (CRP >5 mg/L and/or AGP >1000 mg/L). Among children with and without night blindness, the proportion with serum retinol <0.70 μmol/L was 79.2% and 56.8% (P = 0.03) and with anemia was 58.3% and 35.7% (P = 0.029), respectively. The proportion of children with serum retinol <0.70 μmol/L was 52.0% after excluding children with elevated acute phase proteins. Among children with and without elevated acute phase proteins, mean age was 2.8 vs 3.2 years (P = 0.016), the proportion of boys was 43.1% vs. 54.3% (P = 0.075), with no hospitalizations in the last year was 11.0% vs 23.6% (P = 0.024), and with anemia was 43.8% vs 31.7% (P = 0.05), respectively. CONCLUSIONS: Exclusion of children with inflammation in this survey of vitamin A deficiency does not improve prevalence estimates for vitamin A deficiency and instead leads to sampling bias for variables such as age, gender, anemia, and hospitalization history

Genome-wide association study of bronchopulmonary dysplasia : a potential role for variants near the CRP gene

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [ OR] 3.2, p = 3.4 x 10(-6)). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 x 10(-4)) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 x 10(-5)), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.Peer reviewe

Interleukin-10 polymorphisms in Spanish IgA deficiency patients: a case-control and family study

BACKGROUND: IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Genetic and environmental factors are suspected to be involved in the development of the disease. Interleukin-10 (IL-10) is a cytokine with stimulatory activity on immunoglobulin production and it may be an important regulator in IgAD pathogenesis. The IL-10 gene contains several single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites located in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers are associated or linked to IgAD in Spanish patients. METHODS: We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring. RESULTS: The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls. CONCLUSION: Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility

Genomic view of the evolution of the complement system

The recent accumulation of genomic information of many representative animals has made it possible to trace the evolution of the complement system based on the presence or absence of each complement gene in the analyzed genomes. Genome information from a few mammals, chicken, clawed frog, a few bony fish, sea squirt, fruit fly, nematoda and sea anemone indicate that bony fish and higher vertebrates share practically the same set of complement genes. This suggests that most of the gene duplications that played an essential role in establishing the mammalian complement system had occurred by the time of the teleost/mammalian divergence around 500 million years ago (MYA). Members of most complement gene families are also present in ascidians, although they do not show a one-to-one correspondence to their counterparts in higher vertebrates, indicating that the gene duplications of each gene family occurred independently in vertebrates and ascidians. The C3 and factor B genes, but probably not the other complement genes, are present in the genome of the cnidaria and some protostomes, indicating that the origin of the central part of the complement system was established more than 1,000 MYA

Human Pentraxin 3 Binds to the Complement Regulator C4b-Binding Protein

The long pentraxin 3 (PTX3) is a soluble recognition molecule with multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. PTX3 interacts with recognition molecules of the classical and lectin complement pathways and thus initiates complement activation. In addition, binding of PTX3 to the alternative complement pathway regulator factor H was shown. Here, we show that PTX3 binds to the classical and lectin pathway regulator C4b-binding protein (C4BP). A PTX3-binding site was identified within short consensus repeats 1–3 of the C4BP α-chain. PTX3 did not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintained its complement regulatory activity when bound to PTX3 on surfaces. While C4BP and factor H did not compete for PTX3 binding, the interaction of C4BP with PTX3 was inhibited by C1q and by L-ficolin. PTX3 bound to human fibroblast- and endothelial cell-derived extracellular matrices and recruited functionally active C4BP to these surfaces. Whereas PTX3 enhanced the activation of the classical/lectin pathway and caused enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a were not increased. Furthermore, PTX3 enhanced the binding of C4BP to late apoptotic cells, which resulted in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9. Thus, in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage

High-Density SNP Mapping of the HLA Region Identifies Multiple Independent Susceptibility Loci Associated with Selective IgA Deficiency

Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10−57; OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10−17; OR = 4.28) and the DRB1*1501 (combined P = 2.24×10−35; OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example

The Discovery of LOX-1, its Ligands and Clinical Significance

LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and atherogenesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other atherogenic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, thrombogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardiovascular diseases. Further understandings of LOX-1 and its ligands as well as its versatile functions will direct us to ways to find novel diagnostic and therapeutic approaches to cardiovascular disease