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A genome-wide association study recently identified an MSH3/DHFR locus associated with Huntington’s disease progression. Flower, Lomeikaite et al. identify tandem repeat variants at this locus, and show that a three-repeat allele is associated with reduced somatic expansion, delayed onset and slower progression in Huntington’s disease and myotonic dystrophy type 1., The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

Objective Smoking during pregnancy causes risks to mother and infant health. We investigated the feasibility and likely success of SKIP-IT, a narrative and picture-based smoking cessation intervention delivered via text messages. Methods A feasibility and pilot trial. We aimed to recruit 70 pregnant women who smoked, randomised to usual care alone or usual care and the SKIP-IT intervention between 12 weeks of pregnancy and 6 weeks post due-date. Outcomes assessed were recruitment, retention, acceptability of, and engagement with the intervention, smoking behaviour, intentions, perceived risk, and self-efficacy. Results Of 312 women initially approached by smoking cessation services only 54 (17%) agreed to be contacted by the research team. Twenty were then either ineligible or uncontactable and 28 (82%) participated. Most women reported texts to be entertaining and helpful. The proportion of women not smoking at follow-up was lower in the intervention group, but numbers were too small to draw conclusions about effectiveness. Conclusion The intervention was acceptable, but difficulty in making initial and follow-up contacts meant our methods were unfeasible for a larger trial. Practice implications Digital Storytelling interventions could help women quit smoking, but further research is required to identify alternative methods for studies with pregnant women who smoke.

Informed consent form for the LACE trial. (PDF 29Â kb)

Participant information leaflet for the LACE trial. (PDF 467Â kb)