Study of the Rheumatoid Arthritis genetic component from multiplex families
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ABSTRACT: Rheumatoid arthritis (RA) is a multifactorial disorder for which the genetic component is not fully understood. By studying families with multiple cases, we identified new high risk variants impacting functions dysregulated in RA.
Project description:Background and Aims: Evidence for a genetic contribution to eosinophilic esophagitis (EoE) exists from family and genome-wide association studies. Extensive investigation into rare variants contributing to EoE has not been performed. The Aim is to evaluate families with multiple cases of EoE by genomic and transcriptomic sequencing to identify genes predisposing to EoE. Methods: We whole exome sequenced (WES) distant relative pairs (e.g., cousins) in extended EoE pedigrees and other affected relatives to identify rare, shared, potentially pathologic variants. Whole-transcriptome sequencing by RNA-Seq was performed in nuclear families with multiple EoE cases. We compared the overlap of genes from DNA and RNA sequencing for relevance to disease manifestations. Results: WES was performed in 50 familial cases in 21 EoE extended pedigrees. We observed 219 rare, candidate predisposition variants in 210 genes with complete sharing among all affected family members. Transcriptome sequencing was performed for 43 EoE cases in 18 nuclear kindreds, including 6 relatives without EoE. We observed 10,070 total differentially expressed genes compared to controls. We identified three genes (MUC16, ADGRE1, and TENM3) with evidence of rare variant sharing and differential gene expression among all affected family members. We identified 43 other genes with partial sharing of rare variants among affected family members and with differential gene expression. Several genes identified as prominent in EoE were also differentially expressed in unaffected relatives. Conclusions: Multiple genes related to immune response, barrier dysfunction, and cell adhesion were identified in familial EoE cases and unaffected family members supporting a genetic familial predisposition and a possible multi-hit background to disease pathophysiology.
Project description:Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and SNP arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g. PARP1, CDKN2A) or co-segregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare co-segregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
Project description:Background: Pregnant and postpartum women are at high risk of developing active tuberculosis (TB), but transcriptional TB studies have excluded pregnant women. We identified differentially expressed genes (DEGs) in pregnant women who did and did not progress to active TB. Methods: We followed a cohort of pregnant Indian women with TB infection for one year postpartum, collecting blood at study entry, 6 weeks postpartum and active TB diagnosis. A prospective signature of risk was identified by comparing whole blood RNA sequencing data from women who developed active TB postpartum (cases) with those who remained healthy (controls). Results: We identified 9 cases and matched them to 18 controls by HIV status and gestational age. A gene set of risk was identified: Expression of KCNIP4 > 2.2 log CPM and S1PR4 < 7.3 log CPM indicated a high probability of developing active TB postpartum. SF3B4 (>4.3 log CPM) and PGAM1 (>6.6 log CPM) correctly classified postpartum cases and controls. Both pairs displayed high accuracy (AUC >0.9) and were unique from 36 published TB signatures.Conclusions: We identified two genes that prospectively differentiated pregnant women who developed active TB postpartum from those who did not. If validated, this signature could be useful in targeted TB prevention programs.
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
Project description:Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors (ICI). The high failure rate (up to 75%) warrants investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors (PARPi) in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a novel series of 35 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant (nonsense mutation; ENIGMA class 5) and one BRCA2 variant of unknown significance (VUS). The low frequency of BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants of the literature. Among the 204 MCC studied for molecular alterations of BRCA1/2, only two BRCA1 pathogenic nonsense mutations were identified (1%), while the vast majority of BRCA1/2 variants were missense mutations classified as VUS. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated-MCC, PARPi might be a valuable therapeutic option requiring validation by clinical trials.
Project description:Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set. We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.
Project description:Beckwith–Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies. We identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID. Our data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling.
Project description:<p>Studying families with multiple cases of coronary artery disease (CAD) or with early onset CAD in order to identify new genes involved in CAD in an autosomal dominant manner. After identifying these genes in families that pass on CAD in Mendelian inheritance, we want to pursue their role in the pathogenesis of CAD and their contribution in the general population.</p>
Project description:The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk since women with ER-negative index primaries are at high risk for subsequent ER-negative primary cancers. We performed random fine needle aspiration (rFNA) of the unaffected breasts of cases; samples from 30 subjects (15 ER-positive and 15 ER-negative cases matched for age, race and menopausal status), were used for Illumina expression array analysis. In this study, we have examined gene expression profiles in random fine needle aspirate (rFNA) samples from the contralateral breasts of women with new unilateral breast cancer (cases) to seek candidate panels of ER-specific risk biomarkers. On a discovery set of 30 women, we have identified gene expression differences in the contralateral breast that associate with ER+ or ER- index primary tumors.