Marrakchi S.,University of Sfax |
Marrakchi S.,University of Paris Descartes |
Guigue P.,University of Paris Descartes |
Renshaw B.R.,Amgen |
And 28 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis. METHODS: We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function. RESULTS: We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin- 36-receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor-like 2 (interleukin-1 receptor- related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine- induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients. CONCLUSIONS: Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.) Copyright © 2011 Massachusetts Medical Society.
PubMed | University of Minnesota, Southwestern University, University of Ulsan, University of Colorado at Denver and 11 more.
Type: Journal Article | Journal: BMC genetics | Year: 2016
Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta =3.710(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P=1.310(-7) and DQB1*06:02 P=6.110(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q<0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q<110(-16)).We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
PubMed | Clinique Mutualiste de Bellevue, Institute Paoli Calmettes, Institute Bergonie, Institute National du Cancer and 14 more.
Type: | Journal: Nature communications | Year: 2016
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism.
Leutenegger A.-L.,French Institute of Health and Medical Research |
Leutenegger A.-L.,University Paris Diderot |
Sahbatou M.,Center dEtude du Polymorphisme Humain |
Gazal S.,French Institute of Health and Medical Research |
And 5 more authors.
European Journal of Human Genetics | Year: 2011
Inbreeding coefficients and consanguineous mating types are usually inferred from population surveys or pedigree studies. Here, we present a method to estimate them from dense genome-wide single-nucleotide polymorphism genotypes and apply it to 940 unrelated individuals from the Human Genome Diversity Panel (HGDP-CEPH). Inbreeding is observed in almost all populations of the panel, and the highest inbreeding levels and frequencies of inbred individuals are found in populations of the Middle East, Central South Asia and the Americas. In these regions, first cousin (1C) marriages are the most frequent, but we also observed marriages between double first cousins (2-1C) and between avuncular (AV) pairs. Interestingly, if 2-1C marriages are preferred to AV marriages in Central South Asia and the Middle East, the contrary is found in the Americas. There are thus some regional trends but there are also some important differences between populations within a region. Individual results can be found on the CEPH website at ftp://ftp.cephb.fr/hgdp-hbd/. © 2011 Macmillan Publishers Limited.
Terao C.,Kyoto University |
Yamada R.,Kyoto University |
Ohmura K.,Kyoto University |
Takahashi M.,Kyoto University |
And 13 more authors.
Human Molecular Genetics | Year: 2011
Rheumatoid arthritis (RA) is a typical complex trait and the major cause of chronic inflammation worldwide. Although multiple genetic loci have been shown for their association with the onset of RA, they cover only a part of its genetic components and are largely ethnicity-specific. To identify novel genetic factors related to the predisposition and prognosis of RA in Japanese, we conducted a large-scale genome-wide association (GWA) study. We performed a GWA analysis by scanning the genome of 1247 RA cases and 1486 controls for 277 420 single nucleotide polymorphisms (SNPs), followed by replication analysis using two independent sample sets consisting of 1865 cases and 1623 controls, and 2303 cases and 3380 controls. We identified two SNPs, rs2075876 and rs760426, in intron of the autoimmune regulator AIRE gene at chromosome 21q22 that showed strong associations with the disease (P = 3.6 3 10-9 and P = 4.4 3 10-8, respectively). Rs1800250, in exon7 of AIRE, was in strong linkage disequilibrium (r2 = 0.94) with rs2075876 and introduced an amino acid alteration (S278R) in the SAND domain of the AIRE protein. In silico analysis showed the decreased transcription of AIRE by the risk allele of rs2075876 compared with the alternative allele (P = 6.8 3 10-5). No correlation was observed between the rs2075876 genotype and quantitative traits reflecting the progression of RA. As AIRE is a key molecule which regulates the expression and presentation of self-antigens in thymic negative selection, its downregulation by genetic polymorphisms may result in the survival of auto-reactive T cells to trigger auto-inflammation in RA. © The Author 2011. Published by Oxford University Press. All rights reserved.
Prufer K.,Max Planck Institute for Evolutionary Anthropology |
Racimo F.,University of California at Berkeley |
Patterson N.,The Broad Institute of MIT and Harvard |
Jay F.,University of California at Berkeley |
And 50 more authors.
Nature | Year: 2014
We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans. © 2014 Macmillan Publishers Limited.
Touleimat N.,French Atomic Energy Commission |
Tost J.,French Atomic Energy Commission |
Tost J.,Center dEtude du Polymorphisme Humain
Epigenomics | Year: 2012
Background: Huge progress has been made in the development of array- or sequencing-based technologies for DNA methylation analysis. The Illumina Infinium® Human Methylation 450K BeadChip (Illumina Inc., CA, USA) allows the simultaneous quantitative monitoring of more than 480,000 CpG positions, enabling large-scale epigenotyping studies. However, the assay combines two different assay chemistries, which may cause a bias in the analysis if all signals are merged as a unique source of methylation measurement. Materials & methods: We confirm in three 450K data sets that Infinium I signals are more stable and cover a wider dynamic range of methylation values than Infinium II signals. We evaluated the methylation profile of Infinium I and II probes obtained with different normalization protocols and compared these results with the methylation values of a subset of CpGs analyzed by pyrosequencing. Results: We developed a subset quantile normalization approach for the processing of 450K BeadChips. The Infinium I signals were used as 'anchors' to normalize Infinium II signals at the level of probe coverage categories. Our normalization approach outperformed alternative normalization or correction approaches in terms of bias correction and methylation signal estimation. We further implemented a complete preprocessing protocol that solves most of the issues currently raised by 450K array users. Conclusion: We developed a complete preprocessing pipeline for 450K BeadChip data using an original subset quantile normalization approach that performs both sample normalization and efficient Infinium I/II shift correction. The scripts, being freely available from the authors, will allow researchers to concentrate on the biological analysis of data, such as the identification of DNA methylation signatures. © Future Medicine Ltd.
Okada Y.,RIKEN |
Okada Y.,University of Tokyo |
Kamatani Y.,Center dEtude du Polymorphisme Humain
Journal of Human Genetics | Year: 2012
Hematological traits are essential biomedical indicators that are widely used in clinical practice. The elucidation of the etiology that determines an individual's hematological traits would have a substantial impact. Hematological traits are known to be heritable, and it has been suggested that genetic factors contribute significantly to the inter-individual variance of these traits. Here, we review our current knowledge regarding the genetic architecture of hematological traits in humans, most of which has been obtained through recent developments in genome-wide association studies (GWAS). In addition to current knowledge, which is based on the hematological traits of the three major blood-cell lineages (white blood cells; WBC, red blood cells; RBC, and platelets; PLT), we propose future approaches that would be useful as a next step in the post-GWAS era. © 2012 The Japan Society of Human Genetics All rights reserved.
Osman W.,Tokyo Medical University |
Okada Y.,RIKEN |
Okada Y.,University of Tokyo |
Kamatani Y.,Center dEtude du Polymorphisme Humain |
And 3 more authors.
PLoS ONE | Year: 2012
We performed a genome-wide association study (GWAS) on levels of serum total protein (TP), albumin (ALB), and non-albumin protein (NAP). We analyzed SNPs on autosomal chromosomes using data from 9,103 Japanese individuals, followed by a replication study of 1,600 additional individuals. We confirmed the previously- reported association of GCKR on chromosome 2p23.3 with serum ALB (rs1260326, Pmeta = 3.1×10-9), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP (Pmeta = 1.2×10-14 and 7.1×10-24, respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (Pmeta = 7.2×10-15 and 7.5×10-10, respectively) as well as rs10007186 on 4q21.2 near ANXA3 (Pmeta = 1.3×10-9) also indicated significant associations. Interestingly, TNFRSF13B and TNFSF13 encode a tumor necrosis factor (TNF) receptor and its ligand, which together constitute an important receptor-ligand axis for B-cell homeostasis and immunoglobulin production. Furthermore, three SNPs, rs4985726, rs3803800, and rs11552708 in TNFRSF13B and TNFSF13, were indicated to be associated with serum levels of IgG (P<2.3×10-3) and IgM (P<0.018), while rs3803800 and rs11552708 were associated with IgA (P<0.013). Rs10007186 in 4q21.2 was associated with serum levels of IgA (P = 0.036), IgM (P = 0.019), and IgE (P = 4.9×10-4). Our results should add interesting knowledge about the regulation of major serum components. © 2012 Osman et al.
Okada Y.,RIKEN |
Okada Y.,University of Tokyo |
Takahashi A.,RIKEN |
Ohmiya H.,RIKEN |
And 10 more authors.
Human Molecular Genetics | Year: 2011
C-reactive protein (CRP) is a hallmark acute-phase reactant and is widely used as a blood marker for inflammation. Substantial roles of serum CRP levels in the pathogenesis of diseases have been suggested, and investigation of the mechanisms that regulate serum CRP levels would have a substantial clinical impact. Here, through genome-wide association and replication studies performed using 12 854 Japanese subjects, we identified a significant association between serum CRP levels and a single nucleotide polymorphism in the promoter region of interleukin-6 (IL6) (rs2097677, P = 4.1 × 10 -11), a typical pleiotropic pro-inflammatory cytokine. Our study also replicated the associations in the CRP (rs3093059, P = 3.5 × 10 -21) and HNF1A loci (rs7310409, P = 2.7 × 10 -8). Pleiotropic association analysis with hematological and biochemical traits using 30 466 Japanese subjects demonstrated that the CRP-increasing allele of rs2097677 in the IL6 locus was significantly associated with an increased white blood cell count, platelet count and serum globulin and a decreased mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (P < 5.0 × 10 -4), although no pleiotropic association was observed in the CRP or HNF1A locus (α = 0.01). Our study demonstrated the pivotal role of the IL6 locus in the regulation of serum CRP levels and inflammatory pathways. © The Author 2010. Published by Oxford University Press. All rights reserved.