Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10-6<P<10-4) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10-7 in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10-7 and P = 1.98×10-7 in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP. © 2014 Wu et al

Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts

We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a P-value &lt;10(-5) for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor POO effects play major roles in the etiology of OC in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or POO effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus, the most promising SNPs identified by this study may still be worth further investigation. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000302544200014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Genetics &amp; HereditySCI(E)9ARTICLE4784-794158

African ancestry is a risk factor for asthma and high total IgE levels in African admixed populations

Oliveira, Ricardo Riccio; Carvalho Filho, Edgar Marcelino “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”. Candelaria Vergara1, Tanda Murray2, Nicholas Rafaels1, Rachel Lewis1, Monica Campbell1, Cassandra Foster1, Li Gao1, Mezbah Faruque3, Ricardo Riccio Oliveira4, Edgar Carvalho4, Maria Ilma Araujo4, Alvaro A. Cruz5, Harold Watson6, Dilia Mercado7, Jennifer Knight- Madden8, Ingo Ruczinski9, Georgia Dunston3, Jean Ford2, Luis Caraballo7, Terri H. Beaty2, Rasika A. Mathias1, and Kathleen C. Barnes1,* - 1Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University (JHU), Baltimore, Maryland 2Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 3National Genome Center at Howard University, Washington, DC 4Servico de Imunologia, Hospital Universitario Professor Edgard Santos, Salvador, Bahia, Brazil 5ProAR – Nucleo de Excelencia em Asma, Federal University of Bahia and CNPq, Salvador, Bahia, Brazil 6Faculty of Medicine, University of the West Indies, Cave Hill Campus, Barbados 7Institute for Immunological Research, University of Cartagena, Cartagena, Colombia 8Tropical Medicine Research Institute, The University of the West Indies, Jamaica, West Indies 9Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MarylandSubmitted by Ana Maria Fiscina Sampaio ([email protected]) on 2017-05-26T16:43:15Z No. of bitstreams: 1 Vergara C African ancestry is a Risk....pdf: 387125 bytes, checksum: 44b9ae46aa441a6991c3d5f290b6f0b8 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2017-05-26T17:06:57Z (GMT) No. of bitstreams: 1 Vergara C African ancestry is a Risk....pdf: 387125 bytes, checksum: 44b9ae46aa441a6991c3d5f290b6f0b8 (MD5)Made available in DSpace on 2017-05-26T17:06:57Z (GMT). No. of bitstreams: 1 Vergara C African ancestry is a Risk....pdf: 387125 bytes, checksum: 44b9ae46aa441a6991c3d5f290b6f0b8 (MD5) Previous issue date: 2013Contract grant sponsor: National Institutes of Health; Contract grant number: HL087699; Contract grant sponsor:The National Heart, Lung, and Blood Institute (NHLBI). Contract grant sponsor: COLCIENCIAS; Contract grant number:680-2009. Contract grant sponsor: Health Research Council. Contract grant sponsor: Caribbean Cardiac Society. Contract grant sponsor: University Hospital of West Indies. Contract grant sponsor: The Cultural Arts Sports and Education (CHASE) Fund. Contract grant sponsor: National Health Fund. Contract grant sponsor:National Health Fund Phase 2, 2007–2008. Contract grant sponsor: Mary Beryl Patch Turnbull Scholar Program. Contract grant sponsor: Brazilian National Research Council (CNPq).Múltipla - ver em NotasCharacterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (β = 1.3, P = 0.04), Barbadians (β = 3.8, P = 0.03), and Brazilians (β = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels

ER stress impairs MHC Class I surface expression and increases susceptibility of thyroid cells to NK-mediated cytotoxicity.

We recently reported that, in thyroid cells, ER stress triggered by thapsigargin or tunicamycin, two well known ER stressing agents, induced dedifferentiation and loss of the epithelial phenotype in rat thyroid cells. In this study, we sought to evaluate if, in thyroid cells, ER stress could affect MHC class I expression and the possible implications of this effect in the alteration of function of natural killer cells, suggesting a role in thyroid pathology. In both, a human line of fetal thyroid cells (TAD-2 cells) and primary cultures of human thyroid cells, thapsigargin and tunicamicin triggered ER stress evaluated by BiP mRNA levels and XBP-1 splicing. In both cell types, TAD-2 cell line and primary cultures, major histocompatibility complex class I (MHC-I) plasmamembrane expression was significantly reduced by ER stress. This effect was accompanied by signs of natural killer activation. Thus, natural killer cells dramatically increased IFN-γ production and markedly increased their cytotoxicity against thyroid cells. Together, these data indicate that ER stress induces a decrease of MHC class I surface expression in thyroid cells, resulting in reduced natural killer-cell self-tolerance

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

BackgroundThe genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies.MethodsWe combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p&lt;5 × 10(-8)).FindingsAnalysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10(-14)), FAM13A (p=1·12 × 10(-14)), and HHIP (p=1·57 × 10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p&lt;0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10(-9)) and TGFB2 (overall joint meta-analysis p=8·3 × 10(-9)).InterpretationWe have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD.FundingUS National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs