A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans.

Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Trace elements in whole blood in the general population in Trøndelag County, Norway: The HUNT3 Survey.

BACKGROUND: Biomonitoring of a cohort within a large health survey can provide reliable information on trace element status. The main aims of this study were 1) to determine the concentrations of 28 trace elements in whole blood samples from the general population of the Nord-Trøndelag region, Norway, and 2) to investigate how trace element concentrations vary with geographical area, lifestyle, and socio-demographic factors. METHODS: Whole blood samples were collected in the third survey of the Trøndelag Health Survey (HUNT3), a large population-based study in Norway. In total, 1011 whole blood samples from individuals aged 20-91 years were analyzed using high resolution inductively coupled plasma-mass spectrometry (HR-ICP-MS). We compared trace element concentrations (As, B, Be, Br, Ca, Cd, Cr, Cs, Cu, Ga, Au, In, Fe, Pb, Hg, Tl, Mg, Mn, Mo, Ni, Rb, Sc, Se, Ag, Sr, Sn, W and Zn) between three geographical areas (coastal, fjord/town, inland/mountain) using multivariable linear regression and assessed differences in trace element concentrations with socio-demographic and lifestyle factors using general linear models. RESULTS: Trace element concentrations were generally comparable to levels reported in other recent studies and suggest low exposure to toxic trace elements in the region. We found geographical differences in concentrations of 19 trace elements. As, Br, Hg, and Se concentrations were higher on the coast compared to the fjord/town and inland/mountain areas, suggesting that the marine environment is an important source of exposure for these trace elements. In addition, socio-demographic and lifestyle characteristics, particularly age and sex, were associated with differences in trace element concentrations. CONCLUSIONS: We report concentrations of 28 trace elements in the general population of a rural region with low exposure to pollution. Whole blood concentrations of trace elements varied with geographical area, the participants' lifestyle, and socio-demographic characteristics, highlighting the importance of considering these factors when evaluating trace element status in a population.

Trace Elements in the Large Population-Based HUNT3 Survey.

The Nord-Trøndelag Health Study (The HUNT Study) is a large health survey population study in the county of Trøndelag, Norway. The survey has been repeated four times in about 10-year intervals. In the HUNT3 survey (2006-2008), we collected 28,000 samples for trace element analysis. Blood samples from 758 healthy persons without known occupational exposure were selected for multielement analysis of a small sample of blood (0.25 mL). The aim of the study was to determine the minimum blood volume that can be used for the analytical procedure and to compare our results with previously published results of similar surveys in healthy populations. Samples were digested and the concentration of selected trace elements was determined by ICP-MS. We report results on essential elements (B, Co, Cu, Mn, Se and Zn) as well as non-essential elements (As, Be, Br, Cd, Cs, In, La, Pb, Hg, Nd, Ni, Nb, Pd, Pt, Sm, Ta and Sn). Results are similar to previous studies on the HUNT3 population, and with a few exceptions, our data compares very well with results obtained in recent studies from other countries. We wanted to test a minimum volume of blood in a large-scale analytical program. For a number of nonessential elements, our results were below the limit of detection. We suggest that future studies using similar ICP-MS equipment as analytical tool should use at least 0.5 mL of blood.

Trace element status in patients with type 2 diabetes in Norway: The HUNT3 Survey.

Several epidemiological studies have indicated that a number of trace elements may play a role in type 2 diabetes (T2D). We investigated the association between prevalent T2D and the concentrations of 25 trace elements in whole blood, and the relationships between T2D duration and blood levels of the trace elements that we found to be related to T2D prevalence. In this population based case-control study, 267 patients with self-reported T2D and 609 controls (frequency matched), were selected from the third Nord-Trøndelag Health Survey. Trace element blood levels were determined by high resolution inductively coupled plasma-mass spectrometry. Multivariable conditional logistic regression and multivariable linear regression were used to estimate associations. The prevalence of T2D was positively associated with boron, calcium and silver, and inversely associated with indium, lead and magnesium (Ptrend<0.05). We found no statistical evidence for associations between blood levels of arsenic, bromine, cadmium, cesium, chromium, copper, gallium, gold, manganese, mercury, molybdenum, nickel, rubidium, selenium, strontium, tantalum, thallium, tin and zinc and T2D prevalence. After corrections for multiple testing, associations remained significant for calcium and lead (Qtrend<0.05), and borderline significant for magnesium, silver and boron. With increasing disease duration, higher calcium levels were observed (P<0.05). This study suggests an association between prevalent T2D and blood levels of boron, calcium, indium, lead, magnesium and silver.

Trace elements in early phase type 2 diabetes mellitus-A population-based study. The HUNT study in Norway.

Differences in trace elements levels between individuals with type 2 diabetes and controls have been reported in several studies in various body fluids and tissues, but results have been inconsistent. In order to examine trace element levels in the early phase of type 2 diabetes, we investigated the association between whole blood levels of 26 trace elements and the prevalence of previously undiagnosed, screening-detected type 2 diabetes. The study was conducted as a case-control study nested within the third survey of the population-based Nord-Trøndelag Health Study (HUNT3 Survey). Among participants without previously known diabetes, 128 cases of type 2 diabetes were diagnosed in people with a high diabetes risk score (FINDRISC≥15), and frequency-matched for age and sex with 755 controls. Blood samples were analyzed by high resolution inductively coupled plasma mass spectrometry. Associations between trace element levels and the prevalence of previously undiagnosed type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for age, sex, body mass index, waist-to-hip ratio, education, income, smoking and family history of diabetes. The prevalence of previously undiagnosed type 2 diabetes increased across tertiles/quartiles for cadmium, chromium, iron, nickel, silver and zinc, and decreased with increasing quartiles of bromine (Ptrend<0.05). After corrections for multiple testing, associations for chromium remained significant (Qtrend<0.05), while associations for iron and silver were borderline significant. No associations were found for arsenic, boron, calcium, cesium, copper, gallium, gold, indium, lead, magnesium, manganese, mercury, molybdenum, rubidium, selenium, strontium, tantalum, thallium and tin. Our results suggest a possible role of bromine, cadmium, chromium, iron, nickel, silver and zinc in the development of type 2 diabetes.