Showing papers by "Florence Demenais published in 2014"

Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.

Abstract: Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

The effect on melanoma risk of genes previously associated with telomere length

Abstract: Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.

Abstract: The prevalence of asthma and obesity is increasing worldwide, and obesity is a well-documented risk factor for asthma. The mechanisms underlying this association and parallel time trends remain largely unknown but genetic factors may be involved. Here, we report on a common ∼0.45 Mb genomic inversion at 16p11.2 that can be accurately genotyped via SNP array data. We show that the inversion allele protects against the joint occurrence of asthma and obesity in five large independent studies (combined sample size of 317 cases and 543 controls drawn from a total of 5,809 samples; combined OR = 0.48, p = 5.5 × 10−6). Allele frequencies show remarkable worldwide population stratification, ranging from 10% in East Africa to 49% in Northern Europe, consistent with discordant and extreme genetic drifts or adaptive selections after human migration out of Africa. Inversion alleles strongly correlate with expression levels of neighboring genes, especially TUFM (p = 3.0 × 10−40) that encodes a mitochondrial protein regulator of energy balance and inhibitor of type 1 interferon, and other candidates for asthma (IL27) and obesity (APOB48R and SH2B1). Therefore, by affecting gene expression, the ∼0.45 Mb 16p11.2 inversion provides a genetic basis for the joint susceptibility to asthma and obesity, with a population attributable risk of 39.7%. Differential mitochondrial function and basal energy balance of inversion alleles might also underlie the potential selection signature that led to their uneven distribution in world populations.

Genetic heterogeneity of asthma phenotypes identified by a clustering approach

Abstract: The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account. Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474). The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p −7 ) were observed between “active adult-onset nonallergic asthma” and rs9851461 flanking CD200 (3q13.2) and between “inactive/mild nonallergic asthma” and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5×10 −7 −7 ) were observed between three single nucleotide polymorphisms (SNPs) in the ALCAM region (3q13.11) and “active adult-onset nonallergic asthma”. These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the “active allergic asthma” phenotype. Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.

Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure

Abstract: To the Editor: Complex diseases, including asthma, have genetic and environmental origins. Genome-wide association studies have identified multiple genes for the development of asthma, yet they only explain a limited proportion of asthma heritability. Interactions between genetic predisposition and exposure to passive smoking might explain in part the hidden heritability of childhood asthma. However, to date, this approach has not been reported for the discovery of interactions between genes and tobacco smoke exposure. We performed a genome-wide interaction study (GWIS) on childhood asthma to identify genes that interact with 2 well-known environmental risk factors for childhood-onset asthma: in utero and childhood tobacco smoke exposure. We meta-analyzed interaction results from 9 studies participating in the GABRIEL consortium1 including more than 6,000 subjects of European descent. We replicated our findings in 4 independent studies including more than 13,000 subjects. Childhood-onset asthma was defined as asthma diagnosed by a doctor before the age of 16 years, which is consistent with the definition in the GABRIEL consortium.1 In utero tobacco smoke exposure was defined as “exposure to maternal tobacco smoking at any time during pregnancy.” Childhood tobacco smoke exposure was defined as “exposure to passive tobacco smoking at any time from birth until 16 years of age.” Details on the number of subjects, the design of the individual studies, and outcome and exposure definitions are provided in Tables E1 to E4 in this article's Online Repository at www.jacionline.org. The effects of in utero tobacco smoke exposure and childhood tobacco smoke exposure were analyzed separately. All individual studies were analyzed by using a logistic regression model containing the genetic effect, the effect of tobacco smoke exposure, and an interaction term indicating the interaction between the genetic effect and tobacco smoke exposure. Further methodological considerations on GWISs and details on the statistical analyses are described in this article's Online Repository at www.jacionline.org. For in utero tobacco smoke exposure, the discovery genome-wide meta-analysis consisted of 2,654 cases and 3,073 control subjects derived from 7 studies (see Table E1). Overall, in utero tobacco smoke exposure increased the risk of childhood-onset asthma (see Fig E1 in this article's Online Repository at www.jacionline.org). A total of 536,705 single nucleotide polymorphisms (SNPs) were included in the interaction meta-analysis. Fig E2 in this article's Online Repository at www.jacionline.org shows the Manhattan plot. We identified 27 SNPs in the discovery sample with a P value of less than 10−4 based on the fixed effect model (Table I and see Table E5 in this article's Online Repository at www.jacionline.org). Findings did not reach genome-wide significance but were consistent over all studies included, and no significant heterogeneity across studies was present (P value Q-statistic < .05). Four of these SNPs on chromosome 10 were in high linkage disequilibrium with each other in the discovery meta-analysis (r2 = 0.82-0.96). The most prominent marker was located on chromosome 18 near EPB41L3 (Forest plot, see Fig E3 in this article's Online Repository at www.jacionline.org). Table E6 in this article's Online Repository at www.jacionline.org shows the associations in exposed and nonexposed subjects. EPB41L3 belongs to the protein 4.1 family of membrane-associated proteins, is involved in cell-cell junctions,2 and might play a role in apoptosis.3 The literature shows that in utero tobacco smoke exposure affects the expression of genes involved in biological processes, such as cell proliferation and apoptosis, and influences lung development of the child in general.4 Our data suggest that this effect of in utero smoke exposure might potentially occur through mechanisms involving EPB41L3 (see the additional text in this article's Online Repository). Table I Results of the GWIS of in utero tobacco smoke exposure and childhood-onset asthma For childhood tobacco smoke exposure, the discovery genome-wide meta-analysis consisted of 3,048 cases and 3,509 control subjects derived from 9 studies (see Table E1). Overall, childhood tobacco smoke exposure increased the risk of childhood-onset asthma (see Fig E1). A total of 538,233 SNPs were included in the interaction meta-analysis. Fig E4 in this article's Online Repository at www.jacionline.org shows the Manhattan plot. We identified 35 SNPs in the discovery sample with a P value of less than 10−4 based on the fixed effect model. Four of these SNPs were excluded because they showed heterogeneity, and the P value of the random effect was greater than 10−4. Findings did not reach genome-wide significance. Table II and Table E7 (see this article's Online Repository at www.jacionline.org) the results for the top SNPs. Seven SNPs on chromosome 5 (except rs2312164) were in high linkage disequilibrium with each other in the discovery studies (r2 = 0.83-1.00). Table II Results of the GWIS on childhood tobacco smoke exposure and childhood-onset asthma The most prominent marker was located on chromosome 6 in PACRG (parkin coregulated gene; Forest plot, see Fig E5 in this article's Online Repository at www.jacionline.org). Table E8 in this article's Online Repository at www.jacionline.org shows the associations in exposed and nonexposed subjects. PACRG is located next to and has an overlapping promoter region with parkin 2 (PARK2).5 The gene has been associated with leprosy and parkinsonian diseases and has an important role in motile cilia function and cilia morphogenesis.2,6 PACRG is relatively highly expressed in the trachea and nasal mucosa. Ciliary dysfunction might impair mucus clearance from the airways and has been shown to affect asthma severity. Our data suggest that changes in ciliary function particularly affect the development of asthma in children exposed to passive tobacco smoke. The genes that have been reported previously to interact with tobacco smoke exposure with respect to asthma development (ie, TNF,7 GSTP1,7 and ADAM338) were not among our most significant hits. This can be explained by the fact that the genetic variants in these candidate gene studies have a strong main effect on asthma development. Bouzigon et al9 showed a more pronounced effect of the 17q21 region on the development of early-onset asthma in children with early-life tobacco smoke exposure than in those without. The genetic effect of these markers in our GWIS showed a similar direction, but the interaction was not significant. This study on childhood asthma is the first hypothesis-free GWIS specifically aiming to identify SNPs that interact with tobacco smoke exposure in disease development. We found suggestive evidence for an interaction between rs8094633 on chromosome 18 near EPB41L3 and in utero tobacco smoke exposure and an interaction between rs1575472 on chromosome 6 in PACRG and childhood tobacco smoke exposure. The SNPs found have not been identified previously in general genome-wide association studies on childhood asthma. Interestingly, the SNPs interacting with in utero and childhood tobacco smoke exposure were different and were not involved in the same pathway (see Fig E6 in this article's Online Repository at www.jacionline.org). Interactions between these SNPs and tobacco smoke exposure in utero and in childhood might explain part of the missing heritability of asthma. Future research needs to confirm these findings and further unravel the biological pathways.

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Abstract: BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 � 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 � 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 � 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.

The nuclear factor I/A (NFIA) gene is associated with the asthma plus rhinitis phenotype.

Abstract: Background A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) showed strong evidence of linkage of the 1p31 region to the combined asthma plus allergic rhinitis (AR) phenotype. Objective Our purpose was to conduct fine-scale mapping of the 1p31 linkage region to identify the genetic variants associated with asthma plus AR. Methods Association analyses with the asthma plus rhinitis phenotype were first conducted in the EGEA family sample using the family-based association method (FBAT) and logistic regression. The test of homogeneity of association between asthma plus AR versus asthma alone or AR alone was also applied. Replication of EGEA findings was sought in French-Canadian and United Kingdom family samples. Results We found a significant association between asthma plus rhinitis and a 1p31 genetic variant ( P = 2 × 10 −5 for rs12122228, which reached the multiple testing–corrected threshold) in EGEA using FBAT. There was evidence of heterogeneity of association between asthma plus AR versus asthma alone or AR alone ( P = .03). A Meta-analysis of FBAT results from EGEA and French-Canadian families improved evidence for both association and heterogeneity ( P = 5 × 10 −6 and P = .008, respectively), whereas a meta-analysis of EGEA, French-Canadian, and United Kingdom samples based on logistic regression slightly increased the evidence for heterogeneity. Conclusion The single nucleotide polymorphism specifically associated to asthma plus rhinitis is located in the flanking 5′ untranslated region of the nuclear factor I/A (NFIA) gene, a strong candidate gene for asthma and AR.

Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Abstract: Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome-wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures. We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job-exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349. Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p = 0.009), in particular to latex (p = 0.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma. Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01.

KIT and melanoma predisposition in pigs: sequence variants and association analysis

Abstract: KIT mutations have been detected in different cancer subtypes, including melanoma. The gene also has been extensively studied in farm animals for its prominent role in coat color. The present work aimed at detecting KIT variants in a porcine model of cutaneous melanoma, the melanoblastoma-bearing Libechov Minipig (MeLiM). By sequencing exons and intron borders, 36 SNPs and one indel were identified. Of 10 coding SNPs, three were non-synonymous mutations, likely to affect the protein conformation. A promising variant, located in exon 19 (p.Val870Ala), was genotyped in a MeLiM × Duroc cross, and an association analysis was conducted on several melanoma-related traits. This variant showed a significant association with melanoma development, tumor ulceration and cutaneous invasion. In conclusion, although the KIT gene would not be a major causal gene for melanoma development in pig, its genetic variation could be influencing this trait.

George Bonney (1947–2013) Remembered

Abstract: Christopher Amos,1∗ Varghese George,2 Joan Bailey-Wilson,3 and Florence Demenais4,5 1Department of Community and Family Medicine, Dartmouth College, Hanover, New Hampshire, United States of America; 2Department of Biostatistics & Epidemiology, Georgia Regents University, Augusta, Georgia, United States of America; 3Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America; 4INSERM, U946, Genetic Variation and Human Diseases Unit, Paris, France; 5Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris, France