| 1. |
- Eriksson, Joel, et al.
(författare)
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Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Context Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden). 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs. BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site. 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42-0.09, p = 2.8*10(-3)). For a body weight reduction altering the BMI from 30 to 25 kg/m(2), the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349). Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.
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| 2. |
- Nielson, Carrie M., et al.
(författare)
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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2
- 2016
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 31:12, s. 2085-2097
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (β=0.22, p=1.9×10-8) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (β=0.09, p=1.2×10-10) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10-4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β=0.12, FDR p=1.7×10-3, functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence.
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| 3. |
- Abdulla, N., et al.
(författare)
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Epidemiology of hip fracture in Qatar and development of a country specific FRAX model
- 2022
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Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- A Summary Hip fracture data were retrieved from electronical medical records for the years 2017-2019 in the State of Qatar and used to create a FRAX (R) model to facilitate fracture risk assessment. Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi, and Kuwait but fracture probabilities varied due to differences in mortality. Objective This paper describes the epidemiology of osteoporotic fractures in the State of Qatar that was used to develop the country-specific fracture prediction FRAX (R) tool. Methods Hip fracture data were retrieved from electronic medical records for the years 2017-2019 in the State of Qatar. The age and sex specific incidence of hip fracture in Qatari residents and national mortality rates were used to create a FRAX (R) model. Fracture probabilities were compared with those from neighboring countries having FRAX models. Results Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi and Kuwait. In contrast, probabilities of a major osteoporotic fracture or hip fracture were lower in Qatar than in Kuwait but higher than those in Abu Dhabi and Saudi Arabia due to differences in mortality. Conclusion The FRAX model should enhance accuracy of determining fracture probability among the Qatari population and help guide decisions about treatment.
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| 4. |
- Al-Daghri, N. M., et al.
(författare)
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The application of FRAX in Saudi Arabia
- 2021
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Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- A Summary Assessment and treatment pathways based on age-specific intervention thresholds in Saudi Arabi can be used to identify patients at high risk of fracture and avoid unnecessary treatment in those at low fracture risk. Purpose Intervention thresholds for the treatment of osteoporosis have historically been based on the measurement of bone mineral density. The aim of the present study was to explore treatment paths and characteristics of women eligible for treatment in Saudi Arabia based on fracture probabilities derived from FRAX (R). Methods The approach to the setting of intervention and assessment thresholds used the methodology adopted by the National Osteoporosis Guideline Group for FRAX-based guidelines in the UK but based on the epidemiology of fracture and death in Saudi Arabia. The methodology was applied to women age 40 years or more drawn from a tertiary referral population for skeletal assessment. Missing data for the calculation of FRAX was simulated using data from the referral and FRAX derivation cohorts. Results Intervention thresholds expressed as a 10-year probability of a major osteoporotic fracture ranged from 2.0% at the age of 50 years increasing to 7.6% at the age of 70 years. A total of 163 of 1365 women (11.9%) had a prior fragility fracture and would be eligible for treatment for this reason. An additional 5 women were eligible for treatment in that MOF probabilities lay above the upper assessment threshold. A BMD test would be recommended for 593 women (43.4%) so that FRAX could be recalculated with the inclusion of femoral neck BMD. Of these, 220 individuals would be eligible for treatment after a BMD test and 373 women categorised at low risk after a BMD test. Conclusion Probability-based assessment of fracture risk using age-specific intervention thresholds was developed for Saudi Arabia to help guide decisions about treatment.
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| 5. |
- Auyeung, T. W., et al.
(författare)
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Sleep Duration and Disturbances Were Associated With Testosterone Level, Muscle Mass, and Muscle Strength-A Cross-Sectional Study in 1274 Older Men
- 2015
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610. ; 16:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Testosterone level follows a circadian rhythm. However, whether sleep duration and disturbances can affect testosterone level, muscle mass, and strength remains unknown. Objective: To examine the relationship of sleep duration and disturbances to testosterone level, muscle mass, muscle strength, and walking speed. Participants and methods: We recruited 1274 community-dwelling men older than 65 years of age. Their early morning testosterone level was assayed by mass spectrometry. A sleep questionnaire was administered to enquire about their reported sleep duration, prolonged sleep latency (>0.5 hour), and subjective insomnia complaint. Muscle mass was measured by dual-energy x-ray absorptiometry. Testosterone level, muscle mass, handgrip strength, and walking speed were tested against sleep duration and disturbances. Results: Testosterone increased with increasing sleep duration up to 9.9 hours, after which it decreased, giving rise to an inverted U-shaped relationship (P for quadratic trend < .05). A similar inverted U-shaped relationship occurred between sleep duration and muscle mass and function. Earlier go-to-bed time, despite being associated with a higher testosterone level (P < .05), was associated with weaker grip strength (P < .05). Earlier wake-up time was associated with higher muscle mass (P < .05) but neither grip strength nor walking speed. Neither prolonged sleep latency nor insomnia was associated with testosterone levels. However, prolonged sleep latency was associated with lower muscle mass (P < .05), weaker grip strength (P < .05), and slower walking speed (P < .001). Insomnia, on the other hand was associated with weaker grip strength (P < .05) and slower walking speed (P < .001) but not muscle mass. Conclusions: Sleep duration and disturbances can affect testosterone level, muscle mass, and its function. Whether optimization of sleep can ameliorate age-associated decline in sex hormone and muscle performance warrants further studies. (C) 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
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| 6. |
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| 7. |
- Axelsson, Kristian F, 1973, et al.
(författare)
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Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism
- 2022
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Ingår i: Jama Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Patients with primary hyperparathyroidism (pHPT) appear to have an increased risk of fractures and other comorbidities, such as cardiovascular disease, although results from previous studies have been inconsistent. Evidence of the association of parathyroidectomy (PTX) with these outcomes is also limited because of the lack of large well-controlled trials. OBJECTIVE To investigate whether untreated pHPT was associated with an increased risk of incident fractures and cardiovascular events (CVEs) and whether PTX was associated with a reduced risk of these outcomes. DESIGN, SETTING, AND PARTICIPANTS This cohort study included all patients who were diagnosed with pHPT at hospitals in Sweden between July 1, 2006, and December 31, 2017. Each patient was matched with 10 control individuals from the general population by sex, birth year, and county of residence. The patients were followed up until December 31, 2017. Data analyses were performed from October 2021 to April 2022. MAIN OUTCOMES AND MEASURES The primary outcomes were fractures, CVEs, and death. Cumulative incidence of events was estimated using the 1-minus Kaplan-Meier estimator of corresponding survival function. Cox proportional hazards regression models were used to calculate hazard ratios (HRs). RESULTS A total of 16 374 patients with pHPT were identified (mean [SD] age, 67.5 [12.9] years; 12 806 women [78.2%]), with 163 740 control individuals. The follow-up time was 42 310 person-years for the pH PT group and 803 522 person-years for the control group. Compared with the control group, the pH PT group had a higher risk of any fracture (unadjusted HR, 1.39; 95% CI, 1.31-1.48), hip fracture (unadjusted HR, 1.51; 95% CI, 1.35-1.70), CVEs (unadjusted HR, 1.45; 95% CI, 1.34-1.57), and death (unadjusted HR, 1.72; 95% CI, 1.65-1.80). In a time-dependent Poisson regression model, PTX was associated with a reduced risk of any fracture (HR, 0.83; 95% CI, 0.75-0.93), hip fracture (HR, 0.78; 95% CI, 0.61-0.98), CVEs (HR, 0.84; 95% CI, 0.73-0.97), and death (HR, 0.59; 95% CI, 0.53-0.65). CONCLUSIONS AND RELEVANCE Results of this study suggest that pHPT is associated with increased risk of fractures, CVEs, and death, highlighting the importance of identifying patients with this condition to prevent serious unfavorable outcomes. The reduced risk of these outcomes associated with PTX suggests a clinical benefit of surgery.
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| 8. |
- Axelsson, Kristian F, 1973, et al.
(författare)
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Eating disorders are associated with increased risk of fall injury and fracture in Swedish men and women
- 2022
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 33, s. 1347-1355
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Tidskriftsartikel (refereegranskat)abstract
- A Summary In this retrospective cohort study, men and women with eating disorders (n = 8867) had higher risk of injurious falls and hip fractures than age, sex, and county-matched controls (n = 88670). Introduction Eating disorders have been associated with decreased bone mineral density and increased fracture risk, but the association with fall injuries without fracture has not previously been investigated. Furthermore, fracture risk in men with eating disorders has been insufficiently studied. Methods In the present study, 8867 patients (9.4% men) with a diagnosed eating disorders and 88670 age-, sex-, and county-matched controls were investigated. Results The mean (standard deviation) age of the patients and controls was 41.6 (13.7) years and the follow-up time 9.6 (5.2, 14.4) years (median, interquartile range) for patients and 10.1 (5.5, 14.2) years for controls. The proportions of injurious falls without fracture (17.3% vs. 9.0%) and of hip fracture (1.6% vs. 0.7%) were substantially greater in patients with an eating disorder than in their corresponding population controls. In an unadjusted Cox proportional hazards model, individuals with an eating disorder had a higher risk of injurious falls without fracture (Hazard ratio (HR) 95% confidence interval (CI): 2.07 (1.96-2.18), and hip fracture (HR 2.30 (1.92-2.75)) than the risk observed in the controls. The HR for any investigated outcome associated with an eating disorder did not differ by sex or age (interaction term p > 0.10). The risk of injurious falls without fracture and hip fracture was increased in both women (HR 2.07 (1.95-2.19) and HR 2.41 (1.98-2.93), respectively) and men (HR 2.09 (1.76-2.49) and HR 1.84(1.12-3.02), respectively), with an eating disorder. Conclusion The risk of injurious falls without fracture and of hip fracture is increased in both women and men with eating disorders, indicating measures to prevent both falls and fractures are important in these patients, regardless of age and
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| 9. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 10. |
- Boonen, Steven, et al.
(författare)
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Preventing osteoporotic fractures with antiresorptive therapy: implications of microarchitectural changes.
- 2004
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Ingår i: Journal of internal medicine. - 0954-6820. ; 255:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Prospective studies have demonstrated that low bone mass correlates well with increased risk of osteoporotic fractures at various skeletal sites. Trials have likewise confirmed that enhancing bone mass with antiresorptive therapy reduces fracture incidence in individuals at risk. However, correlation of bone mineral density (BMD) increases with therapeutic risk reduction has proved less consistent than correlation of BMD decreases with greater fracture risk in the untreated. Indeed, various analyses have indicated that - even during treatment with potent bisphosphonates like alendronate and risedronate - BMD changes from baseline account for <30% of the reduction in vertebral fractures in treated women. It is clearly, therefore, that factors other than BMD are involved in the reduction of fracture risk achieved by antiresorptive therapies. According to recent micro-computed tomography imaging and other studies, antiresorptive therapy can help rebuild the microarchitecture of bone as well as strengthen the materials that go into it. When treating individuals with osteoporosis, these microarchitectural changes contribute to the reduction of fracture risk achieved by antiresorptive therapies.
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| 11. |
- Colldén, Hannah, et al.
(författare)
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Comprehensive Sex Steroid Profiling in Multiple Tissues Reveals Novel Insights in Sex Steroid Distribution in Male Mice
- 2022
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 163:3
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive atlas of sex steroid distribution in multiple tissues is currently lacking, and how circulating and tissue sex steroid levels correlate remains unknown. Here, we adapted and validated a gas chromatography tandem mass spectrometry method for simultaneous measurement of testosterone (T), dihydrotestosterone (DHT), androstenedione, progesterone (Prog), estradiol, and estrone in mouse tissues. We then mapped the sex steroid pattern in 10 different endocrine, reproductive, and major body compartment tissues and serum of gonadal intact and orchiectomized (ORX) male mice. In gonadal intact males, high levels of DHT were observed in reproductive tissues, but also in white adipose tissue (WAT). A major part of the total body reservoir of androgens (T and DHT) and Prog was found in WAT. Serum levels of androgens and Prog were strongly correlated with corresponding levels in the brain while only modestly correlated with corresponding levels in WAT. After orchiectomy, the levels of the active androgens T and DHT decreased markedly while Prog levels in male reproductive tissues increased slightly. In ORX mice, Prog was by far the most abundant sex steroid, and, again, WAT constituted the major reservoir of Prog in the body. In conclusion, we present a comprehensive atlas of tissue and serum concentrations of sex hormones in male mice, revealing novel insights in sex steroid distribution. Brain sex steroid levels are well reflected by serum levels and WAT constitutes a large reservoir of sex steroids in male mice. In addition, Prog is the most abundant sex hormone in ORX mice.
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| 12. |
- Colldén, Hannah, et al.
(författare)
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Dehydroepiandrosterone Supplementation Results in Varying Tissue-specific Levels of Dihydrotestosterone in Male Mice
- 2022
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 163:12
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Tidskriftsartikel (refereegranskat)abstract
- Dehydroepiandrosterone (DHEA), an adrenal androgen precursor, can be metabolized in target tissues into active sex steroids. It has been proposed that DHEA supplementation might result in restoration of physiological local sex steroid levels, but knowledge on the effect of DHEA treatment on local sex steroid levels in multiple tissues is lacking. To determine the effects of DHEA on tissue-specific levels of sex steroids, we treated orchiectomized (ORX) male mice with DHEA for 3 weeks and compared them with vehicle-treated ORX mice and gonadal intact mice. Intra-tissue levels of sex steroids were analyzed in reproductive organs (seminal vesicles, prostate, m. levator ani), major body compartments (white adipose tissue, skeletal muscle, and brain), adrenals, liver, and serum using a sensitive and validated gas chromatography-mass spectrometry method. DHEA treatment restored levels of both testosterone (T) and dihydrotestosterone (DHT) to approximately physiological levels in male reproductive organs. In contrast, this treatment did not increase DHT levels in skeletal muscle or brain. In the liver, DHEA treatment substantially increased levels of T (at least 4-fold) and DHT (+536%, P < 0.01) compared with vehicle-treated ORX mice. In conclusion, we provide a comprehensive map of the effect of DHEA treatment on intra-tissue sex steroid levels in ORX mice with a restoration of physiological levels of androgens in male reproductive organs while DHT levels were not restored in the skeletal muscle or brain. This, and the unexpected supraphysiological androgen levels in the liver, may be a cause for concern considering the uncontrolled use of DHEA.
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| 13. |
- Colldén, Hannah, et al.
(författare)
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Dietary Progesterone Contributes to Intratissue Levels of Progesterone in Male Mice
- 2023
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Ingår i: Endocrinology. - 0013-7227 .- 1945-7170. ; 164:8
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Tidskriftsartikel (refereegranskat)abstract
- Progesterone serum levels have been identified as a potential predictor for treatment effect in men with advanced prostate cancer, which is an androgen-driven disease. Although progesterone is the most abundant sex steroid in orchiectomized (ORX) male mice, the origins of progesterone in males are unclear. To determine the origins of progesterone and androgens, we first determined the effect of ORX, adrenalectomy (ADX), or both (ORX + ADX) on progesterone levels in multiple male mouse tissues. As expected, intratissue androgen levels were mainly testicular derived. Interestingly, progesterone levels remained high after ORX and ORX + ADX with the highest levels in white adipose tissue and in the gastrointestinal tract. High progesterone levels were observed in mouse chow and exceptionally high progesterone levels were observed in food items such as dairy, eggs, and beef, all derived from female animals of reproductive age. To determine if orally ingested progesterone contributes to tissue levels of progesterone in males, we treated ORX + ADX and sham mice with isotope-labeled progesterone or vehicle by oral gavage. We observed a significant uptake of labeled progesterone in white adipose tissue and prostate, suggesting that dietary progesterone may contribute to tissue levels of progesterone. In conclusion, although adrenal-derived progesterone contributes to intratissue progesterone levels in males, nonadrenal progesterone sources also contribute. We propose that dietary progesterone is absorbed and contributes to intratissue progesterone levels in male mice. We speculate that food with high progesterone content could be a significant source of progesterone in males, possibly with consequences for men undergoing androgen deprivation therapy for prostate cancer.
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| 14. |
- Colldén, Hannah, et al.
(författare)
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The gut microbiota is a major regulator of androgen metabolism in intestinal contents.
- 2019
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Ingår i: American journal of physiology. Endocrinology and metabolism. - 1522-1555. ; 317:6
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Tidskriftsartikel (refereegranskat)abstract
- Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.
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| 15. |
- Coviello, Andrea D, et al.
(författare)
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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p=1.8×10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4×10(-11)), GCKR (rs780093, 2p23.3, p=2.2×10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4×10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1×10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9×10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3×10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5×10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1×10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3×10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7×10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5×10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p=2.5×10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
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| 16. |
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| 17. |
- Dimai, H. P., et al.
(författare)
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Osteoporosis treatment in Austria-assessment of FRAX-based intervention thresholds for high and very high fracture risk
- 2022
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Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- A Summary The adoption of the management pathway proposed by the National Osteoporosis Guideline Group (NOGG), UK applied using the Austrian FRAX (R) tool in a referral population of Austrian women categorises 22-29% of women age 40 years or more eligible for treatment of whom 28-34% are classified at very high risk. Purpose The aim of this study is to provide a reference document for the further development of existing guidelines for the management of osteoporosis in Austria, considering FRAX-based intervention thresholds for high and very high fracture risk. Methods The model development was based on two Austrian hospital referral cohorts. Baseline information was collected to compute the 10-year probability (using the Austrian FRAX model) of a major osteoporotic fracture (MOF) and hip fracture both with and without the inclusion of femoral neck bone mineral density (BMD). Assessment thresholds for BMD testing were defined, as well as intervention thresholds. In addition, thresholds that characterise men and women at high and very high fracture risk were established. The management pathway followed that currently recommended by the UK National Osteoporosis Guideline Group (NOGG). Results The two cohorts comprised a total of 1306 women and men with a mean age of 66.7 years. Slightly more than 50% were eligible for treatment by virtue of a prior fragility fracture. In those women without a prior fracture, 22% (n = 120) were eligible for treatment based on MOF probabilities. Of these, 28% (n = 33) were found to be at very high risk. When both MOF and hip fracture probabilities were used to characterise risk, 164 women without a prior fracture were eligible for treatment (29%). Of these, 34% (n = 56) were found to be at very high risk. Fewer men without prior fracture were eligible for treatment compared with women. Conclusion The management pathway as currently outlined is expected to reduce inequalities in patient management. The characterisation of very high risk may aid in the identification of patients suitable for treatment with osteoanabolic agents.
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| 18. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 19. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:3, s. 1033-41
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids. OBJECTIVE: The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men. DESIGN: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 +/- 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 +/- 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 +/- 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry. RESULTS: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10(-6)). This association was confirmed both in the MrOS Sweden study (P = 9 x 10(-7)) and in the MrOS US study (P = 1 x 10(-4)). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10(-14)) and E1 (P = 8 x 10(-19)) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05). CONCLUSIONS: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.
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| 20. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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| 21. |
- Eriksson, Joel, et al.
(författare)
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Limited Clinical Utility of a Genetic Risk Score for the Prediction of Fracture Risk in Elderly Subjects
- 2015
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 30:1, s. 184-194
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Tidskriftsartikel (refereegranskat)abstract
- It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings, two genetic risk scores (GRS63 and GRS16) were developed. Our aim was to determine the clinical usefulness of these GRSs for the prediction of BMD, BMD change, and fracture risk in elderly subjects. We studied two male (Osteoporotic Fractures in Men Study [MrOS] US, MrOS Sweden) and one female (Study of Osteoporotic Fractures [SOF]) large prospective cohorts of older subjects, looking at BMD, BMD change, and radiographically and/or medically confirmed incident fractures (8067 subjects, 2185 incident nonvertebral or vertebral fractures). GRS63 was associated with BMD (3% of the variation explained) but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared with those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were found when the GRSs were added to a base model (age, weight, and height), and no significant improvements in C-statistics were found when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects. (c) 2014 American Society for Bone and Mineral Research.
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| 22. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 23. |
- Flehr, Alison, et al.
(författare)
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Development of a novel method to measure bone marrow fat fraction in older women using high-resolution peripheral quantitative computed tomography
- 2022
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 33:7, s. 1545-1556
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Tidskriftsartikel (refereegranskat)abstract
- Bone marrow adipose tissue (BMAT) has been implicated in a number of conditions associated with bone deterioration and osteoporosis. Several studies have found an inverse relationship between BMAT and bone mineral density (BMD), and higher levels of BMAT in those with prevalent fracture. Magnetic resonance imaging (MRI) is the gold standard for measuring BMAT, but its use is limited by high costs and low availability. We hypothesized that BMAT could also be accurately quantified using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: In the present study, a novel method to quantify the tibia bone marrow fat fraction, defined by MRI, using HR-pQCT was developed. In total, 38 postmenopausal women (mean [standard deviation] age 75.9 [3.1] years) were included and measured at the same site at the distal (n = 38) and ultradistal (n = 18) tibia using both MRI and HR-pQCT. To adjust for partial volume effects, the HR-pQCT images underwent 0 to 10 layers of voxel peeling to remove voxels adjacent to the bone. Linear regression equations were then tested for different degrees of voxel peeling, using the MRI-derived fat fractions as the dependent variable and the HR-pQCT-derived radiodensity as the independent variables. Results: The most optimal HR-pQCT derived model, which applied a minimum of 4 layers of peeled voxel and with more than 1% remaining marrow volume, was able to explain 76% of the variation in the ultradistal tibia bone marrow fat fraction, measured with MRI (p < 0.001). Conclusion: The novel HR-pQCT method, developed to estimate BMAT, was able to explain a substantial part of the variation in the bone marrow fat fraction and can be used in future studies investigating the role of BMAT in osteoporosis and fracture prediction.
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| 24. |
- Gavilanez, E. L., et al.
(författare)
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An assessment of intervention thresholds for high fracture risk in Chile
- 2023
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Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Assessment and treatment pathways using FRAX-based intervention thresholds in Chile can be used to identify patients at high risk of fracture and avoid unnecessary treatment in those at low fracture risk. Purpose: The aim of the present study was to explore treatment paths and characteristics of women eligible for treatment in Chile based on major osteoporotic fracture (MOF) probabilities derived from FRAX®. Methods: Intervention and assessment thresholds were derived using methods adopted by the National Osteoporosis Guideline Group for FRAX-based guidelines in the UK but based on the epidemiology of fracture and death in Chile. Age-dependent and hybrid assessment and intervention thresholds were applied to 1998 women and 1122 men age 50years or more drawn from participants in the National Health Survey 2016–2017. Results: Approximately 12% of men and women had a prior fragility fracture and would be eligible for treatment for this reason. Using age-dependent thresholds, an additional 2.6% of women (0.3% of men) were eligible for treatment in that MOF probabilities lay above the upper assessment threshold. A BMD test would be recommended in 5% of men and 38% of women. With hybrid thresholds, an additional 13% of women (3.6% of men) were eligible for treatment and BMD recommended in 11% of men and 42% of women. Conclusion: The application of hybrid intervention thresholds ameliorates the disparity in fracture probabilities seen with age-dependent thresholds. Probability-based assessment of fracture risk, including the use of the hybrid intervention thresholds for Chile, is expected to help guide decisions about treatment.
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| 25. |
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