Sirtuin1 single nucleotide polymorphism (A2191G) is a diagnostic marker for vibration-induced white finger disease

Vibration-induced white finger disease (VWF) is an industrial injury that is triggered by the continued use of vibrating hand-held machinery. The disease is a widespread and officially recognized occupational disease affecting tens of thousands of employees. According to data that have been published by the Medical Research Council, around 2 million people in Britain are continuously subjected to potentially harmful levels of hand-arm vibration and around 300,000 people are anticipated to suffer from moderate to severe finger blanching (VWF) linked to such exposure, which may lead to considerable time off work, early retirement and considerable payouts from civil compensation schemes. In fact, a UK government fund that had been set up to cover claims by ex-coalminers who were exposed to the use of vibrating hand-held machinery had exceeded £100 million in payments by 2004[1].

VWF is characterized by vasospastic attacks and a cold sensation in the fingers followed by cyanotic discoloration or skin pallor (Figure1)[2–5]. In addition, the sensitivity in the affected fingers is usually reduced. As a consequence, some of the affected individuals have difficulty carrying out manual activities because of their limited fine motor skills. Attacks may be associated with a tingling sensation, feeling loss, stiffness and at times even severe pain. In an early stage of the disease, vasospastic attacks occur particularly under the influence of low temperature. In later stages of the disease, a cold ambient temperature is no longer required as a trigger to cause vasospasm. VWFmay be triggered by hand-operated technical tools and machines that cause high frequency vibration with an oscillation rate >50 Hz. The occurrence of the disease depends on the length and intensity of daily exposure to vibration. To date, little is known about individual susceptibility factors with respect to VWF.

The pathogenesis of this disease is currently unclear. Epigenetics is gaining increasing importance in the understanding of numerous diseases. Epigenetic pathways have recently been suggested to be important in the regulation of vascular gene expression in the pathophysiology of atherosclerosis[6, 7], the microvascular environment of tumors[8], cytokine-inducible gene expression in vascular endothelium[9], and in the developmental regulation of vascular remodeling[10, 11]. Chromatin-based regulatory mechanisms may therefore play a key role in the constitutive expression of endothelium-restricted genes[10].

A single nucleotide polymorphism (SNP) is defined as the difference between chromosomes in the base present at a particular site in the DNA sequence that naturally occurs within a population, and presents the most common type (90%) of genetic variation in humans[12]. Hopefully, increasing knowledge of an individual’s SNP genotype may contribute to the assessment of disease susceptibility and individualized treatment modalities[13].

Based on structural and functional similarities, mammalian histone deacetylases (HDACs) are grouped into four categories. There are three classes of non-sirtuin HDACs, comprising the yeast HDACright parietal dorsal 3 homologs (class I HDACs); class II HDACs, which share a significant degree of homology with the yeast HDA1; and the most recently described class IV HDACs, which comprise HDAC11-related enzymes. There is one class of sirtuin HDACs (class III HDACs), which are homologs to the yeast Sir2 protein.

The yeast Sir2 protein has seven human homologs (SIRT1-7), which play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging[14].

SIRT1, which is a member of the Sir2 family of NAD⁺-dependent HDACs, deacetylates histone H3 lysines 9 and 14 and specifically histone H4 lysine-16, while it hydrolyzes one molecule of NAD⁺ for every lysine residue that is deacetylated[14, 15]. Derivatives of the yeast Sir2 HDAC share a common catalytic domain, which is highly conserved in organisms ranging from bacteria to humans and which is composed of two distinct motifs that bind NAD⁺ and the acetyl-lysine substrate, respectively[14–17]. SIRT1 is known to directly modify chromatin and to silence transcription, to modulate the meiotic checkpoint, and as a probable antiaging effect, to increase genomic stability and to suppress recombinant DNA recombination[18, 19]. While, for yeast Sir2, no targets are known apart from histones, SIRT1 has a large and still growing list of targets,including p53 and forkhead transcription factors, which are mammalian homologs of Daf-16 and which are known to function as sensors of the insulin signaling pathway[14, 18].

To date, little is known about the pathogenesis of VWF. It is however widely accepted that both the nervous and the vascular systems are affected and that vasoconstrictive effects dominate over vasodilatative effects during a vasospastic attack. In this process, endothelium-dependent and endothelium-independent mechanisms regulating the vascular tone may be distinguished. The endothelium-dependent vascular regulation is based on the interplay of competing vasoconstrictive and vasodilatative substrates, of which nitric oxide (NO), a factor that significantly depends on the activity of the endothelial isoform of NO synthase (eNOS, synonym: NOS3), is a key player.

There is increasing evidence that epigenetic mechanisms play a key role in a number of vascular disorders[10, 20]. SIRT1 and eNOS co-localize and co-precipitate in endothelial cells, and SIRT1 deacetylates eNOS, thus stimulating eNOS activity, which subsequently increases endothelial NO[21]. Fully functional Sirt1 is essential in the regulation of endothelium-dependent vasodilation and may have profound effects not only on the control of the local vascular tone and systemic blood pressure, but also in the pathogenesis of VWF.

Our study shows an important, highly significant accumulation of the heterogeneous genotype of the Sirt1 SNP A2191G (Ile → Val) when compared with healthy controls (P <0.001).

We therefore claim the Sirt1₂₁₉₁ A/G genotype to be a risk factor for VWF, and that it may be used as a biological marker to facilitate the identification of risk populations who are being considered for exposure to potentially hazardous hand-held vibrating machinery. This may prevent thousands of employees from experiencing physical pain and disability, in addition to long-lasting administrative fights for VWF compensation, which frequently end unsettled and in great frustration.