Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Role of ATP10B in Parkinson disease in a cohort from southern Spain.

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.

MUC1 expression in colorectal carcinoma: Clinicopathological correlation and prognostic significance / Expresión de MUC1 en el carcinoma colorectal: correlación clinicopatológica y valor pronóstico

Introduction: MUC1 overexpression has been linked to cancer development and has been associated with a higher stage at diagnosis and presence of lymph node or distant metastases. However, its prognostic significance is still unclear. We aimed to evaluate the relationship between MUC1 expression and prognosis of colorectal carcinoma. Materials and methods: Immunohistochemical expression of MUC1 in 96 colorectal carcinomas with analysis of potential prognostic influence. Results: 55.2% of patients were women and the mean age was 65.9 years. Tumors were more frequently located in rectum or sigmoid colon (60.4% and 21.9%). Most tumors were T3 (60.3%). 36.9% of patients showed lymph node metastases and 30.2% showed distant metastasis at the time of diagnosis. MUC1 was intensely positive in 46% and negative in 37.9% of tumors. Overall, 61% of patients recurred and 40.4% died during follow-up. 58.5% of tumors of surviving patients were intensely positive for MUC1 and 29.5% were negative, as compared with 28.5% (intense positivity) and 51.4% (negativity) in the group of patients who died (p=0.022). 65% of tumors of patients without recurrences showed intense positivity for MUC1 and 23% of them were negative as compared with 33.9% (intense positivity) and 47% (negativity) in the group of patients who recurred (p=0.019). Conclusions: Loss of MUC1 expression was more frequent in cases with disease recurrence or death, as compared with patients with stable disease, in whom intense positivity was more frequently seen. These findings disagree with the majority of previous studies, indicating the need for further investigation

Introducción: La sobreexpresión de MUC1 se ha asociado al desarrollo de cáncer, mayor estadio al diagnóstico y la presencia de metástasis ganglionares o a distancia. Sin embargo, su valor pronóstico es dudoso. Nuestro objetivo es evaluar la relación entre la expresión inmunohistoquímica de MUC1 y el pronóstico del carcinoma colorrectal (CRC). Material y métodos: Expresión inmunohistoquímica de MUC1 en 96 CRC y análisis de su influencia pronóstica. Resultados: El 55,2% de los pacientes eran mujeres, con edad media de 65,9 años. Los tumores se localizaban principalmente en recto o sigma (60,4 y 21,9%). El 60,3% de los CRC fueron estadio T3. El 36,9% de pacientes mostraron metástasis ganglionares y el 30,2% a distancia. MUC1 fue intensamente positivo en el 46% y negativo en el 37,9% de los casos. En el 61% de los pacientes se observaron recurrencias y el 40,4% falleció. Un 58,5% de tumores de pacientes vivos mostró positividad intensa y un 29,5% negatividad para MUC1, en comparación con un 28,5 y 51,4% de positividad intensa y negatividad en los pacientes que murieron (p=0,022). El 65% de los tumores de pacientes sin recurrencias fueron intensamente positivos para MUC1 y el 23% fue negativo, en comparación con un 33,9 y 47% de positividad intensa y negatividad en pacientes con recurrencias (p=0,019). Conclusiones: La pérdida de expresión de MUC1 fue más frecuente en pacientes con recurrencias o fallecidos que en pacientes estables. Estos resultados son contrarios a la mayoría de estudios previos y subrayan la necesidad de realización de más estudios

Diferentes caras de la distonía sensible a la levodopa / No disponible

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