VNTR polymorphism in the monoamine oxidase A promoter region and cerebrospinal fluid catecholamine concentrations in forensic autopsy cases

4557 Background: In patients with metastatic midgut carcinoid tumors increased serotonin secretion is related to the carcinoid syndrome and mortality. Free serotonin is taken up via the serotonin transporter (5-HTT) in the liver and the lung and metabolized to 5- hydroxyindolacetic acid (5-HIAA) by Monoamine Oxidase A (MAO-A). The 5-HTT gene has a functional polymorphism in the promoter region (5-HTTPLR), with a short (S, less active) and long (L) allele and a polymorphic region in the second intron with variable number tandem repeats (VNTR-2). The MAO-A gene contains a length polymorphism in its promoter region (MAOA-LPR). To determine the clinical effects of the serotonin metabolizing capacity of individual patients, the association between different genotypes and symptoms (flushes and diarrhea) and survival was studied. Methods: 107 patients with metastatic midgut carcinoid tumors were genotyped for 5-HTTPLR, VNTR-2 and MAO-A-LPR. Differences were tested using Chi-square test and survival according to genotypes was analyzed using Kaplan Meier survival curves and tested with a log rank test. The independent effect of genotypes on survival was studied with multivariate Cox regression analysis with adjustments for the urinary 5-HIAA level, age at presentation and the presence of liver metastases. Results: The various genotypic variants were not related to flushes or diarrhea. Patients with the SS variant of 5-HTTLPR had a shorter median survival (45 months, 95% Confidence Interval (CI) 0.50–90) compared to patients with the LS (113 months, 95% CI 53–172) and the LL variant (90 months, 95% CI 64–115) (P=0.02). After adjustment, survival in patients with the SS variant remained worse with an odds ratio of 0.43 (95% CI 0.23–0.83; P=0.009) and 0.63 (95% CI 0.33–1.11; P=0.1) compared to patients with the LS and the LL variant respectively. Survival was not influenced by the VNTR-2 or MAOA-LPR. Conclusions: The SS genotype of the 5-HTTLPR is independently associated with a worse survival in patients with metastatic midgut carcinoid tumors. No significant financial relationships to disclose.

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An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5′ end of the monoamine oxidase A gene

Human Molecular Genetics ◽

10.1093/hmg/1.3.187 ◽

1992 ◽

Vol 1 (3) ◽

pp. 187-194 ◽

Cited By ~ 31

Author(s):

Rudolf W. Hendriks ◽

Zheng-Yi Chen ◽

Heather Hinds ◽

Ruud K. B. Schuurman ◽

Ian W. Craig

Keyword(s):

Monoamine Oxidase ◽

X Chromosome ◽

Cpg Island ◽

X Chromosome Inactivation ◽

Differential Methylation ◽

Monoamine Oxidase A ◽

Chromosome Inactivation ◽

Vntr Polymorphism

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Molecular Changes Underlying Reduced Pineal Melatonin Levels in Alzheimer Disease: Alterations in Preclinical and Clinical Stages

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030833 ◽

2003 ◽

Vol 88 (12) ◽

pp. 5898-5906 ◽

Cited By ~ 143

Author(s):

Ying-Hui Wu ◽

Matthijs G. P. Feenstra ◽

Jiang-Ning Zhou ◽

Rong-Yu Liu ◽

Javier Sastre Toranõ ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Monoamine Oxidase ◽

Molecular Mechanisms ◽

Monoamine Oxidase A ◽

Mrna Levels ◽

Melatonin Rhythm ◽

Pineal Melatonin ◽

Preclinical Ad ◽

Highly Correlated

Abstract A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of β1-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.

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An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5′ end of the Monoamine Oxidase A gene

Human Molecular Genetics ◽

10.1093/hmg/1.8.662 ◽

1992 ◽

Vol 1 (8) ◽

pp. 662-662 ◽

Cited By ~ 6

Author(s):

R.W. Hendriks ◽

Z.-Y. Chen ◽

H. Hinds ◽

R.K.B. Schuurman ◽

I.W. Craig

Keyword(s):

Monoamine Oxidase ◽

X Chromosome ◽

Cpg Island ◽

X Chromosome Inactivation ◽

Differential Methylation ◽

Monoamine Oxidase A ◽

Chromosome Inactivation ◽

Vntr Polymorphism

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Post-Stroke Fatigue May Be Associated with the Promoter Region of a Monoamine Oxidase A Gene Polymorphism

Cerebrovascular Diseases ◽

10.1159/000450894 ◽

2016 ◽

Vol 43 (1-2) ◽

pp. 54-58 ◽

Cited By ~ 8

Author(s):

Smi Choi-Kwon ◽

Mihye Ko ◽

Sang-Eun Jun ◽

Juhan Kim ◽

Kyung-Hee Cho ◽

...

Keyword(s):

Monoamine Oxidase ◽

Promoter Region ◽

Tryptophan Hydroxylase ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Monoamine Oxidase A ◽

Potential Contribution ◽

Female Patients ◽

Post Stroke ◽

Mao A

Background: Post-stroke fatigue (PSF) is a common sequela of stroke. Despite reports of serotonergic involvement in the etiology of PSF, the potential contribution of serotonergic genes in the development of PSF needs to be investigated. Methods: A total of 373 patients, who experienced ischemic stroke for PSF, were evaluated 3 months after the stroke. PSF was assessed using the Fatigue Severity Scale. The genomic DNA collected and stored in a -70°C freezer was genotyped for 6 polymorphisms in genes associated with serotonin synthesis (tryptophan hydroxylase 1 (TPH1) A218C, TPH2 rs10879355, and TPH2 rs4641528), transport (the promoter region of the serotonin transporter protein), and catabolism (the 30-bp functional variable number tandem repeat) polymorphism in the promoter region of monoamine oxidase A (MAO-A). Results: Among the 373 patients, 164 (44%) had PSF. All patients were ethnic Koreans. Of the 6 polymorphisms examined, only one marker, that is, low-activity MAO-A was associated with PSF (p < 0.05) in female patients. Multiple logistic regression analyses showed that post-stroke depression (PSD; 95% CI 1.561-14.323, p = 0.006) and low MAO-A activity (95% CI 0.166-0.722, p = 0.005) were factors associated with PSF in female patients, whereas only PSD (95% CI 5.511-65.269, p = 0.000) was associated with PSF in male patients. Conclusions: Our findings suggest that PSF may be associated with a genetic polymorphism involving MAO-A, at least in female stroke patients.

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