ADAM33, a new candidate for psoriasis susceptibility

Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT) for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations). This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.     

Population analysis and determination of the ethnic background are necessary in the study of multifactorial diseases: A study using the Dagestan population as a model

Psoriasis, a multifactorial disease with genetic predisposition, has been used as an example to study the role of the ethnic background in multifactorial diseases in the Dagestan population. The individual information card (IIC) is proposed as the main tool for correct collection and processing of information. The results of the study demonstrate that the Dagestan population is a convenient and adequate model population for studying multifactorial diseases, such as psoriasis, and may serve as an object for studying the role of heredity in the etiologies and pathogeneses of this and other multifactorial diseases.     

Population analysis and determination of the ethnic background are necessary in the study of multifactorial diseases: a study using the Dagestan population as a model

Psoriasis, a multifactorial disease with genetic predisposition, has been used as an example to study the role of the ethnic background in multifactorial diseases in the Dagestan population. The individual information card (IIC) is proposed as the main tool for correct collection and processing of information. The results of the study demonstrate that the Dagestan population is a convenient and adequate model population for studying multifactorial diseases, such as psoriasis, and may serve as an object for studying the role of heredity in the etiologies and pathogeneses of this and other multifactorial diseases.     

Asthma: a major pediatric health issue

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Interactions between genes and environmental factors in asthma and atopy: new developments

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Genetic dissection of diseases: design and methods

The etiology of heritable diseases may be elucidated by localizing genes conferring susceptibility and by subsequent biological characterization of these genes. To localize genetic components for multifactorial traits, both hypothesis-driven candidate gene and hypothesis-free genome scan approaches have been applied. To date, only a handful of results have been reproduced in either a different cohort or model organisms. The integration of genetic approaches with high-throughput genomic techniques is very promising. Unfortunately, most genetic studies completely ignore strong nongenetic effects such as low education and poverty even though these factors are well-known to predict, for example, obesity. Thus, what are most needed in future research are statistical methods for discovering sets of susceptibility genes and environmental factors, as well as systematic verifications of the gene-environment-disease network.     

Interactive effect of two candidate genes in a disease: extension of the marker-association-segregation chi(2) method.

For elucidating the genetic component of multifactorial diseases, it is important to investigate the effect of several factors and the possible interaction between them. In particular, for many diseases it is interesting to study the interactive effect of two genes. In this context, the marker-association-segregation chi 2 method (MASC), initially proposed to detect the involvement of a candidate gene in multifactorial diseases, is developed here to investigate the involvement of two candidate genes and to model the joint effect of these two genes. In particular, it is possible to precisely determine whether the joint effect of both genes is multiplicative. This extension simultaneously uses information on two markers, one for each candidate gene, at both the population and the familial segregation level. We show here that there can be an important gai of power to detect the effect of a second gene in a disease when information is used simultaneously on two markers instead of studying each marker separately. This extension of MASC is then applied on a sample of insulin-dependent diabetes (IDD) families typed for the markers of two candidate regions: HLA and that of the insulin gene (INS). This analysis allows us to confirm the involvement of INS in IDD, and the best-fitting model is a multiplicative (noninteractive) effect of HLA and INS, with a biallelic locus for INS and a complementation model for HLA.     

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.     

A comparative analysis of the molecular genetic processes in the pathogenesis of psoriasis and Crohn’s disease

Molecular Biology - A comparative bioinformatics analysis of the molecular genetic processes in the pathogenesis of multifactorial diseases—psoriasis and Crohn’s disease—was...     

Candidate gene studies of diabetic retinopathy in human

Diabetic retinopathy (DR) is a multifactorial disease with complex pathophysiology. It is the main cause of blindness among the people in productive age. The purpose of this literature review is to highlight recent achievements in the genetics of diabetic retinopathy with particular focus on candidate gene studies. We summarized most of the available published data about candidate genes for diabetic retinopathy with the goal to identify main genetic aspects. We conclude that genetic studies reported contradictory findings and no genetic variants meet criteria of a diagnostic marker, or significantly elucidate the root of DR development. Based on these findings it is important to continue with the research in the field of DR genetics, mainly due to the fact that currently new possibilities and approaches associated with utilization of next-generation sequencing are available.     

Studies on the Nature and Management of Psoriasis

Prevalence of psoriasis in Caucasians is estimated as 2 to 3 percent. Sound epidemiologic studies on a worldwide basis are needed to secure accurate prevalence rates for comparative purposes.Utilizing Stanford''s psoriasis life histories records, the genetics of psoriasis has been explored by various means: statistical census data, pedigree analysis, and twin studies. This research suggests a multifactorial pattern of inheritance for psoriasis, implying that both genetic and environmental components are responsible for the manifestation of the disease.At present it is not possible to point to any single causative factor. Some of the suggested areas for research include study of uninvolved skin, growth control in the psoriatic lesion, viral causes, immunological aspects, and lipid metabolism.     

Breakthroughs in the search for dyslexia candidate genes

Four genes have recently been proposed as candidates for dyslexia: dyslexia susceptibility 1 candidate 1 (DYX1C1), roundabout Drosophila homolog 1 (ROBO1), doublecortin domain-containing protein 2 (DCDC2) and KIAA0319. Each gene is implicated in global brain-development processes such as neural migration and axonal guidance, with the exception of DYX1C1, the function of which is still unknown. The most immediate clinical prospect of the discovery of these genes is the possibility of early identification of dyslexia via genetic screening. However, research efforts have yet to identify a functional mutation in any of these genes. When causal variants are identified, they will need to be considered within a multifactorial framework, which is likely to involve gene-gene and gene-environment interactions, to make accurate predictions of diagnostic status.     

Genetic approaches to common diseases

Combined molecular and epidemiological studies are advancing our understanding of the genetic basis of multifactorial diseases. Several of the results obtained during the past year highlight methodological issues associated with these approaches. For example, the affected sib-pair method has been applied successfully to detect linkage between the angiotensinogen gene and susceptibility to hypertension, and a large multi-centre epidemiological study has demonstrated association of a polymorphism of the angiotensin-converting enzyme gene with increased risk of myocardial infarction. The study of Mendelian forms of multifactorial diseases has also led to many new results. These include the characterization of mutations in the glucokinase gene in maturity onset diabetes of the young, localization to chromosome 2 of a gene involved in familial colon cancer, and localization to chromosome 19 of a gene responsible for hemiplegic migraine. New insights have been provided into the genetics of multifactorial disorders such as diabetes and hypertension through the study of animal models. Localization of susceptibility loci in such models has recently led to the identification of new candidate genes that may be implicated in disease.     

On the genetic contribution to selected multifactorial diseases with autoimmune characteristics.

The genetics of multifactorial diseases characterized by autoimmune phenomena are elusive so far. Yet, it is clear that the genetic contribution to a given clinically defined autoimmune disease entity is mostly variable and highly complex. On the basis of two basically different model diseases, Wegener's Granulomatosis and multiple sclerosis, approaches are discussed to unravel at least certain genetic predisposition factors. Major difficulties in these analyses arise from (in)exact definition of the clinical phenotype (disease entity), the vast number of potential candidate genes, the small to modest contribution of each genetic variation to disease risk and the combinatorial possibilities.     

Genetics in Osteoarthritis

Osteoarthritis is a degenerative articular disease with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. Despite the multifactorial nature of this pathology, from the 50’s it´s known that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidate genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this disease are not known, however, which seems clear is that expression levels of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthritis.     

Association studies in consanguineous populations.

To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients.     

Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application

Hirschsprung's disease (HSCR) is a congenital disorder, defined by partial or complete loss of the neuronal ganglion cells in the intestinal tract, which is caused by the failure of neural crest cells to migrate completely during intestinal development during fetal life. HSCR has a multifactorial etiology, and genetic factors play a key role in its pathogenesis; these include mutations within several gene loci. These have been identified by screening candidate genes, or by conducting genome wide association (GWAS) studies. However, only a small portion of them have been proposed as major genetic risk factors for the HSCR. In this review, we focus on those genes that have been identified as either low penetrant or high penetrant variants that determine the risk of Hirschsprung's disease. J. Cell. Biochem. 119: 28–33, 2018. © 2017 Wiley Periodicals, Inc.     

Childhood absence epilepsy: genes, channels, neurons and networks

Childhood absence epilepsy is an idiopathic, generalized non-convulsive epilepsy with a multifactorial genetic aetiology. Molecular-genetic analyses of affected human families and experimental models, together with neurobiological investigations, have led to important breakthroughs in the identification of candidate genes and loci, and potential pathophysiological mechanisms for this type of epilepsy. Here, we review these results, and compare the human and experimental phenotypes that have been investigated. Continuing efforts and comparisons of this type will help us to elucidate the multigenetic traits and pathophysiology of this form of generalized epilepsy.