Rafael de Cid

Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.

Psoriasis is a common inflammatory skin disease with a prevalence of 2–3% in individuals of European ancestry. In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster. The absence of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated (P = 1.38E–08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P = 5.4E–04). LCE3C_LCE3B-del is tagged by rs4112788 (r 2 = 0.93), which is also strongly associated with psoriasis (P < 6.6E–09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.

Brain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia

BACKGROUND There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.

Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the basolateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.

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 (1.15-1.27)), and for the first time directly demonstrates the deletions association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

DNA Hypomethylation at ALOX12 Is Associated with Persistent Wheezing in Childhood

RATIONALE Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. OBJECTIVES To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks. METHODS Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) PROJECT: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. MEASUREMENT AND MAIN RESULTS Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms. CONCLUSIONS DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.

Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment†‡

A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance‐abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non‐synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive‐compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

SNP analysis to results (SNPator)

UNLABELLED Single nucleotide polymorphisms (SNPs) are the most widely used marker in studies to assess associations between genetic variants and complex traits or diseases. They are also becoming increasingly important in the study of the evolution and history of humans and other species. The analysis and processing of SNPs obtained thanks to high-throughput technologies imply the time consuming and costly use of different, complex and usually format-incompatible software. SNPator is a user-friendly web-based SNP data analysis suite that integrates, among many other algorithms, the most common steps of a SNP association study. It frees the user from the need to have large computer facilities and an in depth knowledge of genetic software installation and management. Genotype data is directly read from the output files of the usual genotyping platforms. Phenotypic data on the samples can also be easily uploaded. Many different quality control and analysis procedures can be performed either by using built-in SNPator algorithms or by calling standard genetic software. AVAILABILITY Access is granted from the SNPator webpage http://www.snpator.org.

Association of Early-life Exposure to Household Gas Appliances and Indoor Nitrogen Dioxide With Cognition and Attention Behavior in Preschoolers

The authors investigated the association of early-life exposure to indoor air pollution with neuropsychological development in preschoolers and assessed whether this association differs by glutathione-S-transferase gene (GSTP1) polymorphisms. A prospective, population-based birth cohort was set up in Menorca, Spain, in 1997-1999 (n = 482). Children were assessed for cognitive functioning (McCarthy Scales of Childrens Abilities) and attention-hyperactivity behaviors (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) at age 4 years. During the first 3 months of life, information about gas appliances at home and indoor nitrogen dioxide concentration was collected at each participants home (n = 398, 83%). Genotyping was conducted for the GSTP1 coding variant Ile105Val. Use of gas appliances was inversely associated with cognitive outcomes (beta coefficient for general cognition = -5.10, 95% confidence interval (CI): -9.92, -0.28; odds ratio for inattention symptoms = 3.59, 95% CI: 1.14, 11.33), independent of social class and other confounders. Nitrogen dioxide concentrations were associated with cognitive function (a decrease of 0.27 point per 1 ppb, 95% CI: -0.48, -0.07) and inattention symptoms (odds ratio = 1.06, 95% CI: 1.01, 1.12). The deleterious effect of indoor pollution from gas appliances on neuropsychological outcomes was stronger in children with the GSTP1 Val-105 allele. Early-life exposure to air pollution from indoor gas appliances may be negatively associated with neuropsychological development through the first 4 years of life, particularly among genetically susceptible children.

Missense mutations in the cystic fibrosis gene in adult patients with asthma

Asthma is a complex genetic disorder that affects 5% of adults and 10% of children worldwide. The complete characterization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified missense mutations in 15% of 144 unrelated adult patients with asthma, but in none of 41 subjects from the general population. The four more common mutations were analyzed in an extended sample consisting of 184 individuals from the general population and did not show a significant difference in frequency. The hyperfunctional CFTR M470 allele was detected in 90% of patients with CFTR missense mutations, but in 63% of subjects from the general population and 63% of asthma patients without CFTR mutations. None of the patients with missense mutations had the 5T allele of intron 8 of CFTR, responsible for low CFTR levels, while it was detected in 8% of asthma patients without CFTR mutations and in 9% of subjects from the general population. These findings suggest a putative role for a combination of CFTR missense mutations, including the M470 allele, in the genetic variability of asthma. Hum Mutat 14:510–519, 1999.

A pooling-based genome-wide analysis identifies new potential candidate genes for atopy in the European Community Respiratory Health Survey (ECRHS)

BackgroundAsthma and atopy are complex phenotypes with shared genetic component. In this study we attempt to identify genes related to these traits performing a two-stage DNA pooling genome-wide analysis in order to reduce costs. First, we assessed all markers in a subset of subjects using DNA pooling, and in a second stage we evaluated the most promising markers at an individual level.MethodsFor the genome-wide analysis, we constructed DNA pools from 75 subjects with atopy and asthma, 75 subjects with atopy and without asthma and 75 control subjects without atopy or asthma. In a second stage, the most promising regions surrounding significant markers after correction for false discovery rate were replicated with individual genotyping of samples included in the pools and an additional set of 429 atopic subjects and 222 controls from the same study centres.ResultsHomo sapiens protein kinase-like protein SgK493 (SGK493) was found to be associated with atopy. To lesser extent mitogen-activated protein kinase 5 (MAP3K5), collagen type XVIII alpha 1 (COL18A1) and collagen type XXIX alpha 1 (COL29A1) were also found to be associated with atopy. Functional evidences points out a role for MAP3K5, COL18A1 and COL29A1 but the function of SGK493 is unknown.ConclusionIn this analysis we have identified new candidate regions related to atopy and suggest SGK493 as an atopy locus, although these results need further replication.