Genetic correlations between migraine and carpal tunnel syndrome.

BACKGROUND: Surgical deactivation of extracranial nerve trigger sites is now well-established as an effective treatment for migraine headache. Parallels have been drawn to median nerve decompression for carpal tunnel syndrome (CTS), and two previous studies have demonstrated an association between migraine and CTS. We sought to: (1) substantiate these findings in a considerably larger UK cohort, and; (2) investigate potential genetic associations between the two disorders. METHODS: Nested case-control studies were conducted in the UK Biobank cohort of 401,656 individuals. Odds ratios were calculated for the association between migraine and CTS in the overall cohort and sex-stratified subsets. Genetic correlation between migraine and CTS was interrogated by linkage disequilibrium score regression (LDSC), leveraging data from published genome-wide association studies. Regions of genetic overlap were identified by Multi-Trait Analysis of GWAS (MTAG) and Cross-Phenotype Association (CPASSOC). RESULTS: Migraine and CTS show a significant epidemiological association within UK Biobank (OR=1.14, 95% CI: 1.04-1.25, p=0.0058), which is specific to females (OR=1.15; 95% CI: 1.04-1.28, p=0.0057) and not males (OR=1.07; 95% CI: 0.82-1.40, p=0.61). Genetic analysis demonstrated a significant positive genetic correlation between the two disorders (rg=0.13, p=0.0039), and implicated the TRIM32 locus on chromosome 9 as a region of genetic overlap. CONCLUSIONS: This study replicates past reports of an epidemiological association between CTS and migraine, albeit in females only. This association is underpinned by a genetic correlation, with shared genetic susceptibility at the TRIM32 locus. Our data adds credibility to the notion that an element of entrapment neuropathy underlies migraine pathophysiology.

Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.

The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present LUXendin645, a far-red fluorescent GLP1R antagonistic peptide label. LUXendin645 produces intense and specific membrane labeling throughout live and fixed tissue. GLP1R signaling can additionally be evoked when the receptor is allosterically modulated in the presence of LUXendin645. Using LUXendin645 and LUXendin651, we describe islet, brain and hESC-derived ß-like cell GLP1R expression patterns, reveal higher-order GLP1R organization including membrane nanodomains, and track single receptor subpopulations. We furthermore show that the LUXendin backbone can be optimized for intravital two-photon imaging by installing a red fluorophore. Thus, our super-resolution compatible labeling probes allow visualization of endogenous GLP1R, and provide insight into class B GPCR distribution and dynamics both in vitro and in vivo.

Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking.

The high demand of the pharmaceutical industry for new modalities to address the diversification of biological targets with large surfaces of interaction led us to investigate the replacement of α-amino acid residues with ureido units at selected positions in peptides to improve potency and generate effective incretin mimics. Based on molecular dynamics simulations, N-terminally modified GLP-1 analogues with a ureido residue replacement at position 2 were synthesized and showed preservation of agonist activity while exhibiting a substantial increase in stability. This enabling platform was applied to exenatide and lixisenatide analogues to generate two new ureidopeptides with antidiabetic properties and longer duration of action. Further analyses demonstrated that the improvement was due mainly to differences in signal bias and trafficking of the GLP-1 receptor. This study demonstrates the efficacy of single α-amino acid substitution with ureido residues to design long lasting peptides.