Background

Emerging evidence suggests that environmental factors, including trace metal and metalloid exposure, may play a role in the development and pathogenesis of the myeloproliferative neoplasms (MPNs) essential thombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Traditional biomarkers are limited in their ability to capture long-term trace element exposure. Toenails reflect chronic exposure to elements due to their slow growth-rate and the independence of trace elements from metabolic activities after their incorporation into the keratin matrix. In an exploratory study, we sought to explore associations between trace metals and metalloids and MPNs.

Methods

Hallux clippings from participants in the United Kingdom's Myeloproliferative Neoplasms: An In-Depth Case-Control (MOSAICC) pilot study were collected between 2012-2014. Samples were cleaned, dried and acid-digested at 80°C prior to analysis using inductively coupled plasma-mass spectrometry (ICP-MS) for aluminium (Al), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd) and lead (Pb). Clinical, demographic and lifestyle data were collected using a combination of self-completed questionnaires (including the MPN Symptom-Assessment Form [MPN-SAF]), a telephone interview and abstraction of clinical and treatment data from medical records.

Statistical Analysis

Mean trace element concentration was compared between cases and controls (two-sample t-test). Backwards and ordered logistic regression analyses were used to assess the relationship between trace element concentration and MPN. Age, gender, alcohol intake, socioeconomic status and pack-years of smoking were included as potential confounders.

Results

In total, 95 MPN cases (n=32 PV, n=50 ET, and n=13 PMF) and 107 controls provided a toenail specimen. Cases were slightly older (mean age: 63.8 vs 60.9 years; p=0.087) and more likely to be male (42% vs. 38%; p=0.6).

There were significant differences in mean trace element concentrations (mg/kg) for Al (case: 11.8; control: 10.6; p<0.0001), V (case: 0.0104; control 0.0130; p<0.0001), Mn (case: 0.252; control: 0.214: p<0.0001), Fe (case: 9.77: control: 11.40; p<0.0001), Ni (case: 0.931; control: 1.34; p<0.0001), Cu (case: 4.06; control: 3.89; p<0.0001), Zn (case: 106; control: 113; p<0.0001), As (case: 0.152; control: 0.0581; p<0.0001), Se (case: 0.571; control 0.638; p=0.0002) and Pb (case: 0.222; control 0.288; p=<0.0001). There were no differences in mean trace element concentration (mg/kg) in Cr (case: 0.520; control: 0.671; p=0.07) or Cd (case: 0.0065; control: 0.0074; p=0.09).

Cases had a significantly lower Se concentration than controls (adjusted odds ratio [aOR] 0.0120, 95% confidence interval [CI] 0.0009,0.1406; p=0.0006). Se concentration was significantly lower than controls in PV (aOR 0.0088, 95% CI 0.0002,0.3505; p=0.0117) and ET (aOR 0.0036, 95% CI 0.0001, 0.0932; p=0.0007) but not PMF (p=0.559). Newly diagnosed MPN cases (≤ 1 year from diagnosis; n=23) had a significantly lower Se concentration compared to controls (aOR 0.0159, 95% CI 0.0002,0.8014; p=0.0449). Hydroxycarbamide (HU) treatment was associated with low Se concentration (n=78; aOR 0.0111, 95% CI 0.0006,0.1667; p=0.0017) compared with controls. There was no significant difference in Se concentration between HU naïve cases (n=17) or controls (OR 0.0368, 95% CI 0.0002,5.1135, p=0.2084). Se concentration was not affected by the duration of HU treatment (aOR 0.537, 95% CI 0.0166, 17.4700, p=0.727). Low Se concentration was correlated with a high MPN-SAF symptom score for pruritus (7-10; aOR 0.0150, 95% CI 0.0005-0.4911, p=0.0183). There were no associations observed between MPN and any other element when adjusted for potential confounders.

Conclusions

Se concentrations in toenails of MPN patients was substantially lower than in controls including in those recently diagnosed suggesting lower Se concentrations prior to diagnosis. The associations were not affected by time since diagnosis nor duration of HU treatment. Low Se concentration was correlated with increased symptom burden for pruritus. Further evaluation of the role of Se deficiency in the development and pathogenesis of MPN is warranted.

Disclosures

McMullin:AOP Health: Other: Clinical Trial Support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novatis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trials Support.

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2024
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