Rare variants in <i>MC1R/TUBB3</i> exon 1 are not associated with <scp>P</scp>arkinson's disease

Lorenzo‐Betancor, Oswaldo; Wszołek, Zbigniew K.; Ross, Owen A.

doi:10.1002/ana.24581

Cited by 10 publications

(19 citation statements)

References 6 publications

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“…Our initial investigation based on more than 120,000 US men and women demonstrated that red hair color and red hair‐associated MC1R p.R151C polymorphism (rs1805007) were associated with higher risk of PD . MC1R variants have since garnered considerable interest and debate over their significance in the PD and melanoma association . In a case–control study based on 870 PD cases in Spain, another red hair‐associated MC1R variant p.R160W (rs1805008) was found to be associated with higher PD risk .…”

Section: Introductionmentioning

confidence: 99%

Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis

Chen

Feng

Schwarzschild

et al. 2017

Ann Clin Transl Neurol

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Several studies have been conducted with mixed results since our initial report of increased Parkinson's disease risk in individuals with red hair and/or red hair‐associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta‐analysis of six publications on red hair, MC1R, and Parkinson's disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson's disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson's disease.

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Section: Introductionmentioning

confidence: 99%

Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis

Chen

Feng

Schwarzschild

et al. 2017

Ann Clin Transl Neurol

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“…87,88 Furthermore, the loss-of-function MC1R variant p.R151C was found to be associated with increased PD risk in individuals of Northern American ancestry. [90][91][92][93][94][95][96] Notably, all significant associations of MC1R-PD risk were conferred only by loss-of-function MC1R variants. [90][91][92][93][94][95][96] Notably, all significant associations of MC1R-PD risk were conferred only by loss-of-function MC1R variants.…”

Section: Melanoma-related Genes and Pdmentioning

confidence: 98%

“…79 Yet these MCIR variant-PD risk associations were not reproduced in ethnically diverse populations, including non-Hispanic North American Caucasian 89 and Caucasian and Chinese cohorts. [90][91][92][93][94][95][96] Notably, all significant associations of MC1R-PD risk were conferred only by loss-of-function MC1R variants. 79,87,88 One drawback of these studies is that no analysis of familial versus sporadic PD patients was carried out.…”

Section: Melanoma-related Genes and Pdmentioning

confidence: 98%

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

Inzelberg

Flash

Friedman

et al. 2016

Annals of Neurology

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The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

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“…Recently 3 studies using samples from a Chinese population (778 PD cases and 517 healthy controls of Chinese ethnicity from Singapore; Mayo Clinic, Jacksonville, Florida (889 PD case and 940 healthy controls; and the International Parkinson's Disease Genomics Consortium (5,944 PD cases and 4,642 controls have investigated the potential association between MC1R variants and PD. Foo et al genotyped 6 MC1R genetic variants: rs34090186, rs2228479, rs33932559, rs1805007, rs1805008, and rs885479 .…”

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confidence: 99%

“…Another 4 variants showed no association with PD . Lorenzo‐Betancor O et al sequenced the MC1R gene ( TUBB3 exon 1), and Lubbe et al performed a meta‐analysis . They found that rare variants including rs1805008 in MC1R exon 1 are not associated with PD susceptibility …”

mentioning

confidence: 99%

Lack of association between MC1R variants and Parkinson disease in European descent

Jiang

Liu

2016

Annals of Neurology

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by internal mammary artery ligation produced 65% to 91% subjective improvement in four uncontrolled trials, but later was found in two placebo-controlled trials to have no effect (see review 2 ). Similarly, the implantation of the internal mammary artery into the heart for revascularization in angina patients yielded subjective improvement in 85% of patients, but this was later shown to have no correlation with graft patency or cardiac revascularization. 2 Interestingly, some patients showed objective evidence of improved exercise tolerance or cardiac function with these procedures, suggesting that the placebo response can also affect physiological function. With respect to the study of shunting for iNPH by Kahlon and colleagues, 3 I apologize for misquoting the duration of the effect of the shunting (i.e., 96% of the operated patients did indeed report subjective improvement at 6 months, but around half that number at 5 years). However, it is important to recognize that the Kahlon study contained a very interesting "nocebo" group (neither the doctor nor the patient thought that the patient had been treated), that is, a set of patients who were referred for shunting, but did not meet criteria for either the lumbar infusion test or cerebrospinal fluid removal test, and therefore did not receive operations. Interestingly, at the 6-month follow-up, 10% of the nocebo patients had improved on a walking step test, 24% on a timed walking test, 48% on a reaction time test, and 28% on a memory test. At 5 years, 1 of the 4 nocebo patients who was followed up still showed improved walking and reaction times. So, the improvement in subjective or even objective performance after shunting procedures for iNPH must be compared to a noisy baseline, in which substantial numbers of unoperated patients may show improvement, and a very strong surgical placebo effect. Together, these can more than account for the results of the uncontrolled iNPH studies.As I stated in my editorial, no drug would ever be used without evidence for efficacy in a randomized, placebocontrolled, clinical trial, particularly if it had a known rate of serious adverse events of greater than 10% in the first 6 months. The same standard should be applied to shunting procedures for iNPH: There should be a moratorium on such procedures until such time as randomized, placebo-controlled studies, such as I outline in my editorial, have been done.

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Rare variants in MC1R/TUBB3 exon 1 are not associated with Parkinson's disease

Cited by 10 publications

References 6 publications

Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis

Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

Lack of association between MC1R variants and Parkinson disease in European descent

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