Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome

Abstract

Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Heme-oxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS.We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls.The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs.The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population.

Genetic Association Study of Restless Legs Syndrome in Chinese Population

“…Since iron deficiency plays an important role in the pathogenesis of RLS, it is plausible that alteration in HMOX1 and HMOX2 gene could be related with RLS. This hypothesis is on the line of a previous study that suggested a weak association between HMOX1 polymorphism and the risk to develop RLS in the Spanish population [13].…”

“…Garcia-Martin et al [13] selected 4 single nucleotide polymorphisms (SNPs) in HMOX1 and HMOX2, and only HMOX1 rs2071746 turned out to be associated with the risk for RLS in the Spanish population. The fact that HMOX2 rs4786504C allele contributes to a more efficient breakdown of heme and that HMOX2 rs1051308 is associated with the risk of developing Parkinson's disease (PD) also make us wonder if HMOX2 could be a risk factor for Chinese RLS [14,15].…”

Delta‐amino‐levulinic acid dehydratase gene and essential tremor

“…In a previous study by our group, the frequencies of HMOX2 rs1051308A were higher in male patients with multiple sclerosis than in controls . This aside, a lack of a major association of this SNP with Parkinson's disease , restless legs syndrome and with age‐related macular degeneration has been reported.…”

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

“…We have previously reported association between HMOX1 rs2071746 variant and the risk for PD, ET, and restless legs syndrome 4 5 7 suggesting a possible link between these diseases. However, there are no clues on putative biological mechanisms underlying the association found.…”

“…Heme oxygenase occurs as 2 main isozymes, an inducible heme oxygenase-1 (HMOX1), and a constitutive heme oxygenase-2 (HMOX2), which are encoded by the genes designated, respectively, as HMOX1, HO-1 or HSP32 (gene identity 3162, chromosome 22q13.1) and HMOX2 or HO-2 (gene identity 3163, chromosome 16p13.3). Several recent studies have shown association between certain single nucleotide polymorphisms (SNPs) in the HMOX1 2 3 4 5 and HMOX2 4 6 genes and the risk for Parkinson’s disease (PD) 2 4 6 , essential tremor (ET) 5 , and restless legs syndrome 7 .…”