A Variant In The Fat Mass And Obesity Associated (fto) Is Associated With Bone Mineral Density, But Not Forearm Fracture Risk In A Pediatric African-american Cohort

Background:There is an increased risk of low-trauma fracture as bone mineral density (BMD) decreases, however a large proportion of these fragility fractures occur in those without osteoporosis or osteopenia. The widely used FRAX tool uses femoral neck (FN) BMD, amongst other parameters, to predict fracture risk. In those with normal BMD, data is lacking on the weight these other parameters hold in predicting future risk. Indeed, FN BMD can be facultative in the estimation of risk when using FRAX.Objectives:To establish predictors of fragility fracture in a patient cohort referred for BMD estimation, subsequently found to have bilateral FN BMD of greater than 1.Methods:A cohort of patients in the North West of England referred between 2004 and 2014 for BMD estimation, with both left and right FN BMD of greater than 1 were identified. Patient parameters identified and analysed included age at scan, gender, BMD at left hip, body mass index (BMI), fat mass, family history of fracture, alcohol history of 3 or more units per day, smoking status, rheumatoid arthritis (RA), and steroid exposure. Patients with fragility fracture were compared with those without fracture. Chi-square test and T-test were applied to categorical and continuous data respectively. Further univariate and multivariate logistic regression models were fitted to determine parameters associated with future fracture risk.Results:619 patients with bilateral FN BMD of greater than 1 were identified and included in analysis. Mean age at scan was 54 years (SD 11.82) and 542 (87.56%) were female. 92 (14.86%) patients had a fragility fracture. Mean left FN BMD was 1.91 (SD 0.71), and mean right FN BMD was 1.92 (SD 0.68). Results of the univariate analysis are described in Table 1 below.Table 1.Logistic regression analysis of patient parameters with unadjusted and adjusted odds ratios for fragility fracturePredictorUnadjusted odds ratio (95% CI)Odds ratio adjusted for age (95% CI)Odds ratio adjusted for age and gender (95% CI)Age at scan (years)0.99 (0.98-1.01)--Gender1.37 (0.66, 2.84)1.34 (0.64, 2.80)-BMD at left hip0.34 (0.03, 4.05)0.37 (0.03, 4.37)0.50 (0.03, 7.67)BMI1.07 (1.03, 1.10)1.07 (1.03, 1.10)1.07 (1.03, 1.10)Fat mass1.00 (1.00, 1.00)1.00 (1.00, 1.01)1.00 (1.00, 1.01)Parent fractured hip0.99 (0.57, 1.70)0.97 (0.56, 1.68)0.94 (0.54, 1.64)Alcohol (3 or more units/day)1.16 (0.47, 2.86)1.16 (0.47, 2.87)1.16 (0.47, 2.89)Current smoker1.40 (0.89, 2.21)1.40 (0.89, 2.21)1.42 (0.90, 2.23)Rheumatoid arthritis0.83 (0.32, 2.19)0.85 (0.32, 2.24)0.86 (0.34, 2.27)Steroid exposure0.53 (0.30, 0.96)0.53 (0.30, 0.96)0.54 (0.30, 0.98)Conclusion:Steroid exposure and body composition parameters influence fracture risk in this group pf patients with normal BMD, further work will be done looking at the types of fractures and other parameters in this group of patients.Disclosure of Interests:Christopher Saleh: None declared, Marwan Bukhari Speakers bureau: Bristol-Myers Squib, UCB celltech, Roche/Chugai, Pfizer, Abbvie, Merck, Mennarini, Sanofi-aventis, Eli-Lilly, Janssen, Amgen and Novartis., Syed Mujtaba Bilgrami Speakers bureau: Pfizer

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MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk

Nature Communications ◽

10.1038/s41467-020-17315-0 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Ida Surakka ◽

◽

Lars G. Fritsche ◽

Wei Zhou ◽

Joshua Backman ◽

...

Keyword(s):

Bone Mineral Density ◽

Fracture Risk ◽

Bone Mineral ◽

Association Studies ◽

Forearm Fracture ◽

Risk Scores ◽

Health Study ◽

Loss Of Function ◽

Mineral Density ◽

Functional Variants

Abstract A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10−18), and increased osteoporosis (P-value = 4.2 × 10−5) and fracture risk (P-value = 1.6 × 10−5). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10−16, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.

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