Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome

Jiménez‐Jiménez, Félix Javier; Alonso‐Navarro, Hortensia; Martı́nez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán-Pascual, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo‐de‐la‐Fuente, Belén; Arroyo-Solera, Margarita; E, García-Albea; García‐Martín, Elena; Agúndez, José A. G.

doi:10.1007/s00702-014-1322-z

Cited by 26 publications

(19 citation statements)

References 17 publications

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“…An association was observed between NOS1 rs7977109 and RLS in a 3-stage design study, after correction for multiple testing [20]. However, the SNPs rs7977109 and rs693534 were not related to the risk of RLS in the Spanish population [21]. ADH enzyme, which participates in phase I of the metabolic pathways, was encoded by ADH1B gene.…”

Section: Discussionmentioning

confidence: 99%

“…For ADH1B, the association of 2 common SNPs (rs6413413 and rs1229984) with the risk for RLS or PD was investigated, and rs1229984 polymorphism was found associated with the risk not only for RLS [18] but also for PD in women [19]. For NOS1, 2 SNPs (rs7977109 and rs693534) have been found associated with German RLS, but only rs7977109 remained significant after correction of multiple testing, while neither of these 2 SNPs were related to RLS in Spanish population [20,21]. Jimenez-Jimenez et al [22] found an association between GABRR3 rs832032 and the risk for RLS, and also found an influence of GABRA4 rs2229940 on the age of onset of RLS as well.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Association Study of Restless Legs Syndrome in Chinese Population

Chen¹,

Luo²,

Li³

et al. 2019

Eur Neurol

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Backgrounds: Several recent case-control studies have suggested some candidate genes being responsible for causing the restless legs syndrome (RLS). However, the association between those genes and the risk for RLS among the Asian population has not been well investigated. Objectives: The aim of the study was to investigate the genetic risk factors of RLS among the Chinese Population. Methods: A total of 158 RLS patients and 229 controls were recruited and the diagnosis of RLS was based on the criteria of International RLS Study Group. Polymer chain reaction and sequencing were used to detect 14 single nucleotide polymorphisms (SNPs) in 9 genetic loci (heme oxygenase 1 [HMOX1], HMOX2, vitamin D3 [1, 25-dihydroxyvitamin D3] receptor gene [VDR], interleukin 17A [IL17A], IL1B, NOS1, alcohol-dehydrogenase [ADH1B], gamma-aminobutyrate acid receptors[GABRR3] and GABRA4). Results: Among 14 selected SNPs, the frequency of IL1B rs1143634C allelic variant was lower in RLS patients than that in controls. Moreover, after adjustment for age and sex, rs731236 of VDR were found associated with increased risk of RLS in the dominant model. However, none of those results survived Bonferroni correction. The effects of HMOX1 and HMOX2 gene on developing RLS were not seen after the inclusion of RLS patients with a low ferritin level. Conclusions: Our study failed to replicate the association between 9 candidate genetic loci (HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1, ADH1B, GABRR3 and GABRA4) and RLS in the Chinese population.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Association Study of Restless Legs Syndrome in Chinese Population

Chen¹,

Luo²,

Li³

et al. 2019

Eur Neurol

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“…Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by unpleasant sensations in the legs during periods of rest that create an irresistible urge to move the legs, leading to sleep disruptions (Allen et al., ). Two SNPs, one in intron 1 and one in intron 3 of nitric oxide synthase 1 ( NOS1 ), are reported to be associated with RLS in the German population, and the SNP in intron 1 is overrepresented in patients with a positive family history of RLS in the Spanish population (Jimenez‐Jimenez et al., ; Winkelmann et al., ). Consistently, a role for NOS1 in modulating sleep has been found in animal models.…”

Section: Sleep Disordersmentioning

confidence: 99%

The molecular genetics of human sleep

Zhang

2018

Eur J of Neuroscience

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It has been known for many years that genetic influences account for some of the individual differences in human sleep parameters, but the underlying molecular mechanisms remain unclear. With major advances of molecular biology and the recognition of heritable sleep behaviors in humans over the past 30 years, a number of genetic variants have been identified to be associated with human sleep timing, duration and quality, both in healthy individuals and under pathological conditions. Some of these variants were further validated and characterized in animal models, shedding light on the mechanism of how these variants likely alter sleep in humans, which may provide new insights into developing more effective treatments to improve human sleep.

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“…Several normoxic triggers of hypoxia response pathway activation, such as nitric oxide (NO), adenosine, and iron chelation have been described [40, 41]. There was a report in which individuals with RLS demonstrate allelic similarities on chromosome 12q (where the nNOS gene is located) [42], but these data have not been reproduced in specific studies [43] or GWAS analyses. The potential role of nitric oxide alterations in the pathophysiology of RLS is noteworthy, with respect to peripheral microcirculation.…”

Section: Introductionmentioning

confidence: 99%

Iron and restless legs syndrome: treatment, genetics and pathophysiology

Connor

Patton

Oexle³

et al. 2017

Sleep Medicine

103

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In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, either dietary or intravenous, can improve RLS symptoms. Therefore, we include a section on peripheral iron status and how peripheral status may influence both the RLS symptoms and treatment strategy. Given the impact of iron in RLS, we have evaluated genetic data to determine if genes are directly involved in iron regulatory pathways. The result was negative. In fact, even the HFE mutation C282Y could not be shown to have a protective effect. Lastly, a consistent finding in conditions of low iron is increased expression of proteins in the hypoxia pathway. Although there is lack of clinical data that RLS patients are hypoxic, there are intriguing observations that environmental hypoxic conditions worsen RLS symptoms; in this chapter we review very compelling data for activation of hypoxic pathways in the brain in RLS patients. In general, the data in RLS point to a pathophysiology that involves decreased acquisition of iron by cells in the brain. Whether the decreased ability is genetically driven, activation of pathways (eg, hypoxia) that are designed to limit cellular uptake is unknown at this time; however, the data strongly support a functional rather than structural defect in RLS, suggesting that an effective treatment is possible.

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Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome

Cited by 26 publications

References 17 publications

Genetic Association Study of Restless Legs Syndrome in Chinese Population

Genetic Association Study of Restless Legs Syndrome in Chinese Population

The molecular genetics of human sleep

Iron and restless legs syndrome: treatment, genetics and pathophysiology

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