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A Genetic Association Study of Glutamine-Encoding DNA Sequence Structures, Somatic CAG Expansion, and DNA Repair Gene Variants, with Huntington Disease Clinical Outcomes
33 Pages Posted: 10 Sep 2019
More...Abstract
Background: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes.
Methods: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses.
Findings: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 x 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 x 10 6), MLH3 (pFDR = 8·0 x 10-4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines.
Interpretation: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders.
Funding Statement: This work was supported by an award to DGM from CHDI Foundation. TRACK-HD and Enroll-HD are supported by CHDI Foundation, a non-profit biomedical research organization exclusively dedicated to developing therapeutics for HD. SJT receives funding from the Medical Research Council UK, Wellcome Trust, Rosetrees Trust, Takeda Pharmaceuticals, Cantervale Limited, NIHR North Thames Local Clinical Research Network, UK Dementia Research Institute at UCL and CHDI Foundation. LJ and PH receive support from the MRC (MR/L010305/1) and CHDI.
Declaration of Interests: MC, AM, SAC, DJHM, AMA, MDF, AD, BRL, PH, and LJ have nothing to disclose. RAR reports personal fees from UniQure, outside the submitted work. DRL reports personal fees from Roche Pharmaceutical, Voyager, Teva Pharmaceutical, Wave Life Sciences, Takeda Pharmaceutical Company and Axon Advisors, and other from CHDI, outside the submitted work. SK reports and is employed by CHDI Management, Inc., as an advisor to the CHDI Foundation. SJT reports personal fees from Alnylam Pharmaceuticals, DDF Discovery, F. Hoffmann-La Roche, Genentech, GSK, Heptares Therapeutics, Takeda Pharmaceuticals, Teva Pharmaceuticals, Triplet Therapeutics, UCB Pharma and Vertex Pharmaceuticals, outside the submitted work. DGM reports other from CHDI Foundation, during the conduct of the study and personal fees from Vertex Pharmaceuticals, LoQus23 Therapeutics and Triplet Therapeutics, outside the submitted work.
Ethics Approval Statement: This study complies with all relevant ethical regulations. All participants were recruited with informed consent and all collaborating clinical sites are required to obtain and maintain local ethics committee approvals. The study was approved by TRACK-HD and Enroll-HD.
Keywords: genetic association study; somatic expansion; DNA repair; Huntington disease
Suggested Citation: Suggested Citation