Genetic polymorphisms related to calcium homeostasis and thyroid function in association with the risk of osteoporosis and low energy fractures in the subjects > 65 years old. The Tromsø Study

Vitamin D lagring i fettvev og assosiasjon mellom vitamin D gener og lav bentetthetVi fant at vitamin D tilskudd, gitt over tid og lagret i fettvevet, forebygger vitamin D mangel i opp til ett år uten vitamin D tilskudd. I tillegg fant vi noen gener, relaterte til vitamin D og estrogen, gir litt økt risiko for å få benskjørhet.Vitamin D er en biologisk aktiv substans, som finnes i de fleste kroppsceller og vev hos mennesker. Vitamin D er viktig for benhelse, og man også vet at vitamin D er viktig for å vedlikeholde immunforsvar, muskelstyrke, utholdenhet. Den kan også minske betennelse i kroppen og slapphet. I Nord Norge har man ingen aktiv vitamin D produksjon i hud fra september til april, og grunnet lite soleksponering anbefales det å ta vitamin D tilskudd eller tran året rundt. Det er noe usikkert om man får like god effekt av vitamin D hvis den tas sjeldnere, men i høyere doser. I tillegg, er det lite data så langt hvordan vitamin D lagres i vevet. Våres forskning viste at vitamin D, gitt over tid, lagres i fettvev, og bidrar til å holde tilfredstillende vitamin D nivå i 1 år etter vitamin D tilskudd hadde blitt avsluttet. I våres studie var vitamin D tilskudd høyere enn det som anbefales å ta daglig for generell befolkning, og var gitt over 3 til 5 år. Vi målte vitamin D i fettvevet hos mennesker, og fant at den var høy ved avslutning av vitamin D tilskudd, og halverte ila. ett år. Videre, har vi funnet at noen typer av gener (genvariasjoner, genetiske polymorfismer), relaterte til vitamin D metabolisme og estrogen reseptor, er assosierte med risiko for lav bentetthet i Tromsø populasjon. Effekten av disse gener er liten, siden benskjørhet er en sammensatt tilstand hvor forskjellige andre risikofaktorer, slik som lav fysisk aktivitet, noen sykdommer og medikamentbruk, bidrar til utvikling av lav bentetthet.

Genetic polymorphisms related to calcium homeostasis and thyroid functionDuring the fourth Tromsø Study, blood tests for SNPs were drawn. Total amount of available SNP samples is above 11 000 samples. BMD was measured in the same subjects in 2001-2002, thus allowing us to relate different SNPs to delta BMD and conclude if genetic polymorphism is predicting for bone mass loss or gain.The Tromsø Study, conducted by the University of Tromsø in cooperation with the National Health Screening Service, is a longitudinal population-based multipurpose study focus in on life-style related diseases. The fourth survey was performed in 1994-95, fifth in 2001-2002 and the sixth in 2007-2008. During the fourth Tromsø Study, blood tests for SNPs were drawn. Total amount of available SNP samples is above 11 000 samples. BMD was measured in the same subjects in 2001-2002, thus allowing us to relate different SNPs to delta BMD and conclude if genetic polymorphism is predicting for bone mass loss or gain. This is a novel hypothesis and has not been explored yet. Outcomes: 1. Body composition data. Tromsø Study 2. BMD in three last Tromsø studies. 3. Delta BMD (BMD 2007- BMD 2001): to explore if the genetic predisposition have any association with longitudinal changes in BMD The first paper is already published and is available in pubmed. Doi: 10.1371/journal.pone.0145359 ABSTRACT Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population. METHODS AND FINDINGS: Measurements and DNA were obtained from the participants in the Tromsø Study in 1994-1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05-1.49) for T2D and 1.14 (1.02-1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints. CONCLUSIONS: The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed. The second paper is under revision and is submitted to Plos One. Ieva is also writing her Third paper and we have scheduled the Public defense of her PHD thesis to the fall 2017.

Vitamin D gener gir økt risiko for diabetes og hjerteinfarktVåres funn viser at det kan være gunstig å ha spesifikk vitamin D gen variant med tanke på utvikling av hjerte-kar sykdom og diabetes.Vi har sett på vitamin D gener av over 9000 mennesker som deltok i Tromsø undersøkelse i 1994-1995. Såkalt vitamin D reseptor (VDR) finnes i nesten alle kroppsceller, og man tror at den er ansvarlig for at vitamin D virker bl.a. i ben som benmasse besparende og i muskler som styrke fremmende. I cellekulturer ser man at VDR med tilført vitamin D kan beskytte både mot utvikling av hjertesvikt, hjerte-kar sykdommer og diabetes. Samtidig har man ikke funnet den samme effekt for mennesker, og man tror at individuelle gener kan forklare forskjellig respons for vitamin D. Vi har sett på syv forskjellige VDR gener og deres varianter, og fant at en gen variant øker livslang risiko å utvikle type 2 diabetes med 40 % og mulig risiko for hjerteinfarkt med 25 %. Siden risikoen for begge to sykdommer er sammensatt, kan genetisk testing i fremtiden bidra til å kartlegge og skreddersy individuell behandling. Det er første gang man har sett på dette genet i forbindelse med diabetes, og man trenger flere studier for å bekrefte funn og forstå virkningsmekanismen. Videre skal vi se på vitamin D relaterte gener og bentetthet; samt skal se på andre bentetthet relaterte gener. Også er det planlagt å se på vitamin D status og omsetning i fett vevet i mennesker som fikk enten placebo eller vitamin D tilskudd i 3-5 år i forbindelse med intervensjonsstudie for diabetes type II forebygging. Vitamin D status i serum og fett vevet blir fulgt opp over ett år etter avsluttet tilskudd. Til tiden er det uklart hvordan vitamin D lagres og utskilles fra fettvevet samt hvor fort den går ut fra kroppen.

Genetic polymorphisms realted til calcium homeostasis and thyroid function in association with the risk of osteoporosisWe analyze the vitamin D receptor related single nucleotide polymorphisms, as well as calcium and thyroid function related SNPs, and relation with bone mineral density, mortality, myocardial infarction, type II diabetes and several cancer forms as we have data from Tromsø Study.The vitamin D receptor single nucleotide polymorphism rs7968585 was analyzed as risk factor for low vitamin D, and in subgroups according to vitamin D levels and risk for outcomes such as type II diabetes, myocardial infarction, mortality and cancers. We have found association between some rs7968585 genotype variations and increased risk for myocardial infarction as well as diabetes type II. The article on this data is beeing written and the abstract was presented in The vitamin D workshop in London, April 2014. Vi chose to concentrate on vitamin D SNPs and those outcomes while awaiting when Institute of Community Medicine helps us with emerging of SPSS files. Afterwards we are planning to look at different SNPs and the BMD measurements from different localizations (vertebrae, lower and upper extremities) Abstrakt: Objective The aim of this study was to investigate if the SNP rs7968585 in the VDR gene predicts type 2 diabetes (T2D). Design and methods DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with T2D (endpoint register complete till the end of 2010), as well as a randomly selected control group. Serum 25(OH)D was measured and genotyping performed for VDR gene polymorphism rs7968585. Cox regression, adjusted for sex, age and body mass index, was used to study the hazard ratios (HR) for risk of T2D with the major homozygote of rs7968585 as reference and with observation time from birth until 2010. Results 1197 subjects were registered with T2D and 3586 were included as control subjects. Serum 25(OH)D did not differ significantly between subjects with T2D and controls, neither between the rs7968585 genotypes. In the Cox regression model, subjects with the minor homozygote genotype for rs7968585 had a HR of 1.30 (95% CI 1.08; 1.53) and subjects with the heterozygote genotype 1.21 (95% CI 1.05; 1.40) for risk of T2D with the major homozygote genotype as reference. Conclusions The VDR related SNP rs7968585 variations predict the occurrence of T2D and MI, which may indicate a role of vitamin D in the pathogenesis of T2D.