Bone mineral density is associated with vitamin D related rs6013897 and estrogen receptor polymorphism rs4870044: The Tromsø study
March
Bone mineral density is associated with vitamin D related rs6013897 and estrogen receptor polymorphism rs4870044: The Tromsø study
Ieva Martinaityte 1 2
Rolf Jorde 1 2
Nina Emaus 0 2
Anne Elise Eggen 2 3
Ragnar Martin Joakimsen 1 2
Elena Kamycheva 1 2
0 Department of Health and Care Sciences, UiT The Arctic University of Norway , Tromsø , Norway
1 Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway , Tromsø , Norway , 2 Division of Internal Medicine, University Hospital of North Norway , Tromsø , Norway
2 Editor: Karen Hind, Leeds Beckett University , UNITED KINGDOM
3 Epidemiology of chronic diseases research group, Department of Community Medicine, UiT The Arctic University of Norway , Tromsø , Norway
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Data Availability Statement: Because of ethical
and legal restrictions our data set is only available
upon request to the Tromsø Study. We are for
these restrictions not permitted to make the data
file publicly available. The Tromsø Study is
administrated by a working group (AU) and a
Scientific Board. The Tromsø Study is headed by
Professor Inger Njølstad, MD, PhD. In order to
obtain the data underlying the findings in our study
the enquiries should be sent by e-mail to:
or Kristin Sørensen may be
contacted by phone +47 776 45348. Application
Background
Bone mineral density (BMD) is determined by bone remodeling processes regulated by
endocrine, autocrine and genetic mechanisms. Thus, some studies have reported that BMD
is associated with single nucleotide polymorphisms (SNPs) associated with vitamin D
receptor (VDR), serum 25(OH)D levels and estrogen receptor 1 (ESR1), but without consensus.
Therefore, we aimed to map and compare the risk genotypes for forearm and total hip low BMD.
Methods and findings
Data were derived from a population-based study in northern Norway; the Tromsø Study.
Distal forearm BMD was measured with a single x-ray absorptiometric device, while total
hip BMD was measured with a dual-energy x-ray absorptiometric device. There were 7,317
and 4,082 successful analyses of distal forearm and total hip BMD, respectively, and at
least one SNP of interest. We evaluated plausible BMD modulating factors and
associations of BMD and SNPs related to vitamin D metabolism (FokI, Cdx2, BsmI, rs2298850,
rs10741657, rs3794060, rs6013897), ApaI-BsmI-TaqI haplotypes and ESR1 SNP
rs4870044.
Results
Age, BMI, physical activity and smoking were significantly associated with BMD. In a linear
regression model with adjustment for age and gender and with the major homozygote as
reference, rs6013897 had a standardized beta coefficient (β) of ±0.031 (P = 0.024) for total hip
BMD. β for ESR1 SNP rs4870044 was ±0.016 (P = 0.036) for forearm BMD and ±0.034 (P =
0.015) for total hip BMD. The other SNPs nor serum 25(OH)D were significantly associated
with BMD.
procedure is described in detail https://en.uit.no/
forskning/forskningsgrupper/sub?p_document_
id=453582&sub_id=71247. The Tromsø Study
requires the local (Norwegian) collaborator for
international researchers to apply. Though we are
not permitted to make the data file publicly
available, we are ready to consider collaboration
and apply for the access of data together with the
interested researchers.
Funding: We are indebted to the Norwegian
Insitute of Public Health for their participation in
collection of data in the fourth survey of the
Tromsø Study (http://www.fhi.no/artikler/?id=
28291), The Northern Norway Regional Health
Authority (https://forskningsprosjekter.ihelse.net/
prosjekt/SFP1215-14; IM grant No. SFP1215-14),
and The Research Council of Norway (https://www.
forskningsradet.no/prosjektbanken/#!/project/
213787/en; RJ grant 213787). The funding
institutions had no role in study design, data
analysis and interpretation, decision to publish, or
preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
Conclusions
Both forearm and total hip BMD were associated with ESR1 SNP rs4870044. Of the vitamin
D±related genes, only CYP24A1 gene rs6013897 was associated with total hip BMD, but the association was weak and needs confirmation in other studies. Serum 25(OH)D was not associated with BMD in our population, probably due to the generally sufficient vitamin D levels in the population.
Introduction
Osteoporosis, characterized by low bone mineral density (BMD), is a global health problem
[
1
]. BMD is a multifactorial trait and in 50±90% of cases is possibly determined by genetic
factors [
2,3
]. Every new identified factor may improve the prevention and treatment of bone loss,
with future individual-tailored approaches.
Vitamin D action in bone homeostasis is explained by the modulation of gene expression
and the activation of second-messenger systems when 1,25-dihydroxyvitamin D (1,25(OH)D)
binds to and activates the vitamin D receptor (VDR) [
4,5
]. VDR is found in all tissues involved
in vitamin D±related calc (...truncated)