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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Artikel i vetenskaplig tidskrift
Författare Anna-Lena Eriksson
John R B Perry
Andrea D Coviello
Graciela E Delgado
Luigi Ferrucci
Andrew R Hoffman
Ilpo T Huhtaniemi
M Arfan Ikram
Magnus K Karlsson
Marcus E Kleber
Gail A Laughlin
Yongmei Liu
Mattias Lorentzon
Kathryn L Lunetta
Dan Mellström
Joanne M Murabito
Anna Murray
Maria Nethander
Carrie M Nielson
Inga Prokopenko
Stephen R Pye
Leslie J Raffel
Fernando Rivadeneira
Priya Srikanth
Lisette Stolk
Alexander Teumer
Thomas G Travison
André G Uitterlinden
Dhananjay Vaidya
Dirk Vanderschueren
Joseph M Zmuda
Winfried März
Eric S Orwoll
Pamela Ouyang
Liesbeth Vandenput
Frederick C W Wu
Frank H de Jong
Shalender Bhasin
Douglas P Kiel
Claes Ohlsson
Publicerad i Journal of Clinical Endocrinology and Metabolism
Volym 103
Nummer/häfte 3
Sidor 991-1004
ISSN 0021-972X
Publiceringsår 2018
Publicerad vid Centre for Bone and Arthritis Research
Sidor 991-1004
Språk en
Länkar dx.doi.org/10.1210/jc.2017-02060
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Aromatase, genetics, Bone Density, genetics, physiology, Chromosomes, Human, X, Cohort Studies, Estradiol, blood, genetics, physiology, Estrone, blood, genetics, Female, Gene Expression Regulation, physiology, Genome-Wide Association Study, Genotype, Gonadal Steroid Hormones, blood, Humans, Insulin Resistance, genetics, physiology, Lumbar Vertebrae, physiology, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Testosterone, blood
Ämneskategorier Molekylär medicin (genetik och patologi)

Sammanfattning

Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

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