Bone mineral density is associated with vitamin D related rs6013897 and estrogen receptor polymorphism rs4870044: The Tromsø study

PLOS ONE, Dec 2019

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. 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.

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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 - 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)


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Ieva Martinaityte, Rolf Jorde, Nina Emaus, Anne Elise Eggen, Ragnar Martin Joakimsen, Elena Kamycheva. Bone mineral density is associated with vitamin D related rs6013897 and estrogen receptor polymorphism rs4870044: The Tromsø study, PLOS ONE, 2017, Volume 12, Issue 3, DOI: 10.1371/journal.pone.0173045