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.publishedVersio

Utvalgte sporelementer hos personer med udiagnostisert type 2-diabetes mellitus og FINDRISC≥15.: En nøstet case-kontrollstudie fra den tredje Helseundersøkelsen i Nord-Trøndelag (HUNT3)

Prevalensen av type 2-diabetes øker raskt over hele verden, og har blitt et av samtidens største folkehelseproblem. Mange risikofaktorer for utviklingen av type 2-diabetes har blitt identifisert, men den nøyaktige etiologien bak type 2 diabetes er fortsatt ikke avklart. Sporelementer har viktige betydninger for human helse, både som essensielle og ikke-essensielle. Tidligere studier har rapportert endringer i sporelementnivå blant personer med type 2-diabetes, men studiene som har blitt utført, indikerer noe motstridende resultater. Målet med oppgaven har vært å undersøke sporelementstatus hos personer med type 2-diabetes, og assosiasjonen mellom 19 utvalgte sporelementer og forekomsten av type 2-diabetes. Personer med udiagnostisert type 2-diabetes (n=129) med FINDRISC≥15 fra HUNT3s understudium for diabetes (HUNT DE-PLAN) ble frekvensmatchet for alder og kjønn med personer uten diabetes (n=763). Assosiasjonen mellom sporelementer og forekomsten av type 2-diabetes ble vurdert ved kondisjonell logistisk regresjon og assosiasjonene ble justert for alder, kjønn, BMI, liv-hofte-ratio, yrke, områdetilhørighet, daglig røyking og familiehistorie for diabetes, i tillegg til sporelementspesifikke faktorer. Konsentrasjonen av sporelementer ble bestemt ved hjelp av HR-ICP-MS.Denne studien indikerer økende forekomst av diabetes over økende kvartiler/tertiler av jern, kadmium, krom og nikkel etter justering for BMI, liv-hofte-ratio, yrke, områdetilhørighet, daglig røyking og familiehistorie for diabetes (alle Ptrend 0,05. Forekomsten av type 2-diabetes antydes også å være assosiert med sink, Ptrend(lineær) <0,001, men etter justering ble Ptrend=0,061, selv om OR for fjerde kvartil =2,28 (95 % KI: 1,00 til 5,21).Denne studien antyder en mulig assosiasjon mellom jern, kadmium, krom, nikkel og sink og forekomsten av type 2 diabetes

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

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 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

Prediction of recurrence from metabolites and expression of TOP2A and EZH2 in prostate cancer patients treated with radiotherapy.

Funder: Nanne and Gullord's foundationBACKGROUND: The dual upregulation of TOP2A and EZH2 gene expression has been proposed as a biomarker for recurrence in prostate cancer patients to be treated with radical prostatectomy. A low tissue level of the metabolite citrate has additionally been connected to aggressive disease and recurrence in this patient group. However, for radiotherapy prostate cancer patients, few prognostic biomarkers have been suggested. The main aim of this study was to use an integrated tissue analysis to evaluate metabolites and expression of TOP2A and EZH2 as predictors for recurrence among radiotherapy patients. METHODS: From 90 prostate cancer patients (56 received neoadjuvant hormonal treatment), 172 transrectal ultrasound-guided (TRUS) biopsies were collected prior to radiotherapy. Metabolic profiles were acquired from fresh frozen TRUS biopsies using high resolution-magic angle spinning MRS. Histopathology and immunohistochemistry staining for TOP2A and EZH2 were performed on TRUS biopsies containing cancer cells (n = 65) from 46 patients, where 24 of these patients (n = 31 samples) received hormonal treatment. Eleven radical prostatectomy cohorts of a total of 2059 patients were used for validation in a meta-analysis. RESULTS: Among radiotherapy patients with up to 11 years of follow-up, a low level of citrate was found to predict recurrence, p = 0.001 (C-index = 0.74). Citrate had a higher predictive ability compared with individual clinical variables, highlighting its strength as a potential biomarker for recurrence. The dual upregulation of TOP2A and EZH2 was suggested as a biomarker for recurrence, particularly for patients not receiving neoadjuvant hormonal treatment, p = 0.001 (C-index = 0.84). While citrate was a statistically significant biomarker independent of hormonal treatment status, the current study indicated a potential of glutamine, glutamate and choline as biomarkers for recurrence among patients receiving neoadjuvant hormonal treatment, and glucose among patients not receiving neoadjuvant hormonal treatment. CONCLUSION: Using an integrated approach, our study shows the potential of citrate and the dual upregulation of TOP2A and EZH2 as biomarkers for recurrence among radiotherapy patients

Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

TMPRSS2-ERG has been proposed to be a prognostic marker for prostate cancer. The aim of this study was to identify changes in metabolism, genes and biochemical recurrence related to TMPRSS2-ERG by using an integrated approach, combining metabolomics, transcriptomics, histopathology and clinical data in a cohort of 129 human prostate samples (41 patients). Metabolic analyses revealed lower concentrations of citrate and spermine comparing ERGhigh to ERGlow samples, suggesting an increased cancer aggressiveness of ERGhigh compared to ERGlow. These results could be validated in a separate cohort, consisting of 40 samples (40 patients), and magnetic resonance spectroscopy imaging (MRSI) indicated an in vivo translational potential. Alterations of gene expression levels associated with key enzymes in the metabolism of citrate and polyamines were in consistence with the metabolic results. Furthermore, the metabolic alterations between ERGhigh and ERGlow were more pronounced in low Gleason samples than in high Gleason samples, suggesting it as a potential tool for risk stratification. However, no significant difference in biochemical recurrence was detected, although a trend towards significance was detected for low Gleason samples. Using an integrated approach, this study suggests TMPRSS2-ERG as a potential risk stratification tool for inclusion of active surveillance patients

A novel non-canonical Wnt signature for prostate cancer aggressiveness

Activation of the Canonical Wnt pathway (CWP) has been linked to advanced and metastatic prostate cancer, whereas the Wnt5a-induced non-canonical Wnt pathway (NCWP) has been associated with both good and poor prognosis. A newly discovered NCWP, Wnt5/Fzd2, has been shown to induce epithelial-to-mesenchymal transition (EMT) in cancers, but has not been investigated in prostate cancer. The aim of this study was to investigate if the CWP and NCWP, in combination with EMT, are associated with metabolic alterations, aggressive disease and biochemical recurrence in prostate cancer. An initial analysis was performed using integrated transcriptomics, ex vivo and in vivo metabolomics, and histopathology of prostatectomy samples (n=129), combined with at least five-year follow-up. This analysis detected increased activation of NCWP through Wnt5a/ Fzd2 as the most common mode of Wnt activation in prostate cancer. This activation was associated with increased expression of EMT markers and higher Gleason score. The transcriptional association between NCWP and EMT was confirmed in five other publicly available patient cohorts (1519 samples in total). A novel gene expression signature of concordant activation of NCWP and EMT (NCWP-EMT) was developed, and this signature was significantly associated with metastasis and shown to be a significant predictor of biochemical recurrence. The NCWP-EMT signature was also associated with decreased concentrations of the metabolites citrate and spermine, which have previously been linked to aggressive prostate cancer. Our results demonstrate the importance of NCWP and EMT in prostate cancer aggressiveness, suggest a novel gene signature for improved risk stratification, and give new molecular insight

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Background: Robust biomarkers that identify prostate cancer patients with high risk of recurrence will improve personalised cancer care. In this study, we investigated whether tissue metabolites detectable by high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) were associated with recurrence following radical prostatectomy. Methods: We performed a retrospective ex vivo study using HR-MAS MRS on tissue samples from 110 radical prostatectomy specimens obtained from three different Norwegian cohorts collected between 2002 and 2010. At the time of analysis, 50 patients had experienced prostate cancer recurrence. Associations between metabolites, clinicopathological variables, and recurrence-free survival were evaluated using Cox proportional hazards regression modelling, Kaplan–Meier survival analyses and concordance index (C-index). Results: High intratumoural spermine and citrate concentrations were associated with longer recurrence-free survival, whereas high (total-choline+creatine)/spermine (tChoCre/Spm) and higher (total-choline+creatine)/citrate (tChoCre/Cit) ratios were associated with shorter time to recurrence. Spermine concentration and tChoCre/Spm were independently associated with recurrence in multivariate Cox proportional hazards modelling after adjusting for clinically relevant risk factors (C-index: 0.769; HR: 0.72; P=0.016 and C-index: 0.765; HR: 1.43; P=0.014, respectively). Conclusions: Spermine concentration and tChoCre/Spm ratio in prostatectomy specimens were independent prognostic markers of recurrence. These metabolites can be noninvasively measured in vivo and may thus offer predictive value to establish preoperative risk assessment nomograms

Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT.

Funder: EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant 116074 The Royal Society (204623/Z/16/Z) United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron-related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron-binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI), and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257,953 individuals. We identify 123 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate recently published results using genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.Wellcome Trust and the Royal Society (204623/Z/16/Z). United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7). National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014