👤 Stefanie Gilles

Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10 This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies. Show less

The melanocortin 4 receptor (MC4R) plays a role in energy homeostasis and represents a target for treating energy balance disorders. For decades, synthetic ligands have been derived from MC4R endogenous agonists and antagonists, such as setmelanotide used to treat rare forms of genetic obesity. Recently, animal venoms have demonstrated their capacity to provide melanocortin ligands with toxins from a scorpion and a spider. Here, we described a cone snail toxin, N-CTX-Ltg1a, with a nanomolar affinity for hMC4R but unrelated to any known toxins or melanocortin ligands. We then derived from the conotoxin the linear peptide HT1-0, a competitive antagonist of Show less

CMTM6 is a critical regulator of cell surface expression of PD-L1 in tumor cells, but little is known about the transcriptional regulation of CMTM6. Here we report that the expression of CMTM6 positively correlates with the epithelial to mesenchymal transition (EMT) score in breast cancer cell lines and with the major EMT marker Vimentin in triple-negative breast cancers (TNBC). We showed that CMTM6 is concomitantly overexpressed with PD-L1 in breast mesenchymal compared with the epithelial cells. Driving a mesenchymal phenotype in SNAI1-inducible MCF-7 cells (MCF-7 Show less

The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes. Show less