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

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.

SUBMITTER: Surakka I

PROVIDER: S-EPMC7585430 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Surakka Ida I Fritsche Lars G LG Zhou Wei W Backman Joshua J Kosmicki Jack A JA Lu Haocheng H Brumpton Ben B Nielsen Jonas B JB Gabrielsen Maiken E ME Skogholt Anne Heidi AH Wolford Brooke B Graham Sarah E SE Chen Y Eugene YE Lee Seunggeun S Kang Hyun Min HM Langhammer Arnulf A Forsmo Siri S Åsvold Bjørn O BO Styrkarsdottir Unnur U Holm Hilma H Gudbjartsson Daniel D Stefansson Kari K Baras Aris A Abecasis Goncalo R GR Hveem Kristian K Willer Cristen J CJ

Nature communications 20201023 1

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.(Lys ...[more]

PMID: 33097703

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Project description:In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD.IntroductionHypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce.MethodsRetrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history.ResultsAnalysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations.ConclusionBMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis.Trial registration numberGerman register for clinical studies (DRKS00014022) DATE OF REGISTRATION: 02/10/2018 - retrospectively registered.

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

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

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