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Genetic variation in Charcot-Marie-Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy.
Chen, Y, Fang, F, Kidwell, KM, Vangipuram, K, Marcath, LA, Gersch, CL, Rae, JM, Hayes, DF, Lavoie Smith, EM, Henry, NL, et al
Pharmacogenomics. 2020;(12):841-851
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Abstract
Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes (ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results:FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.
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FTO association and interaction with time spent sitting.
Klimentidis, YC, Arora, A, Chougule, A, Zhou, J, Raichlen, DA
International journal of obesity (2005). 2016;(3):411-6
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Abstract
BACKGROUND/OBJECTIVES Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS. SUBJECTS/METHODS We tested these hypotheses in two cohorts of the Framingham Heart Study (FHS) (Offspring: n=3430 and Third Generation: n=3888), and attempted to replicate our results in the Women's Health Initiative (WHI; n=4756). Specifically, we examined whether an association exists between FTO and self-reported TSS, and whether an interaction exists between FTO and TSS on BMI, while adjusting for several important covariates such as physical activity. RESULTS In FHS, we find a significant positive association between the BMI-increasing FTO allele and TSS. We find a similar trend in WHI. Mediation analyses suggest that the effect of FTO on BMI is mediated through TSS. In FHS, we find a significant interaction of FTO and TSS on BMI, whereby the association of TSS with BMI is greatest among those with more FTO risk alleles. In WHI, we also find a significant interaction, although the direction is opposite to that in FHS. In a meta-analysis of the two data sets, there is no net interaction of FTO with TSS on BMI. CONCLUSIONS Our study suggests that FTO exerts its effect on BMI, at least partly, through energy expenditure mechanisms such as TSS. Further research into the intersection of genetics, sedentary behavior and obesity-related outcomes is warranted.
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Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis.
Roostaei, T, Sadaghiani, S, Park, MT, Mashhadi, R, Nazeri, A, Noshad, S, Salehi, MJ, Naghibzadeh, M, Moghadasi, AN, Owji, M, et al
Neurology. 2016;(5):410-7
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Abstract
OBJECTIVE To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). METHODS We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. RESULTS Two SCN10A polymorphisms in high linkage disequilibrium (r(2) = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 × 10(-4); rs6801957: p = 0.0025). Patients with MS with rs6795970(AA) genotype performed significantly worse than rs6795970(G) carriers in MSFC (p = 1.8 × 10(-4)) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970(AA) carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants. CONCLUSIONS Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.