Elizabeth A Streeten

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (48)503.77 Total impact

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    ABSTRACT: More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
    Nature Communications 08/2015; 6:7756. DOI:10.1038/ncomms8756 · 10.74 Impact Factor
  • Elizabeth A Streeten
    Reviews in Endocrine and Metabolic Disorders 07/2015; DOI:10.1007/s11154-015-9317-0 · 3.81 Impact Factor
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    ABSTRACT: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly fire incidents have been monitored in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. An in-patient clinical surveillance protocol was performed on 35 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. Although urine U concentrations continue to be elevated in this group, illustrating on-going in situ mobilization of U from embedded fragments, no consistent U-related health effects have been observed. Now more than 20 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As tissue concentrations continue to accrue with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort. Am. J. Ind. Med. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Industrial Medicine 04/2015; 58(6). DOI:10.1002/ajim.22435 · 1.59 Impact Factor
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    ABSTRACT: Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14unaffected first degree family members. PQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in > 700 reference participants. We observed 4 fractures (3 femoral shaft) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (-1.51 vs. 0.17, p = 0.002), cortical area (-2.36 vs. 0.37; p < 0.001) and periosteal circumference (-1.86 vs.-0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (-0.69 vs 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects of bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG. Copyright © 2015. Published by Elsevier Inc.
    Bone 04/2015; 77. DOI:10.1016/j.bone.2015.04.007 · 4.46 Impact Factor
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    ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
    Nature 07/2014; 514(7520-7520):92-7. DOI:10.1038/nature13545 · 42.35 Impact Factor
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    ABSTRACT: We identified normal vs. abnormal 25-hydroxyvitamin D [25(OH)D] concentrations by examining the relation of 25(OH)D to non-bone-related measures (plasma glucose, insulin resistance, lipids, blood pressure, fitness, obesity, and regional adiposity) and asking whether there is a 25(OH)D concentration above and below which the relation between 25(OH)D and outcome changes. We examined the relation between 25(OH)D and outcome by race to see whether race-specific normal ranges are needed, and we examined the role of insulin-like growth factor-1 (IGF-1) in modulating the relation between 25(OH)D and outcome. In a cross-sectional study of 239 overweight and obese, sedentary postmenopausal women without diabetes (83 black, 156 white), outcome measures included plasma lipids, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), IGF-1, parathyroid hormone (PTH), aerobic fitness, body composition, subcutaneous abdominal and visceral fat, and blood pressure. We identified threshold effects in the association between 25(OH)D and these variables using piecewise linear regressions. We found that 25(OH)D was inversely related to fasting glucose, fasting and 2-h insulin, HOMA-IR, visceral abdominal fat, percentage fat, PTH, and triglycerides. Evidence for a threshold effect of 25(OH)D was found for 2-h glucose, 2-h insulin, fasting insulin, and HOMA-IR. There was no evidence suggesting the need for race-specific normal 25(OH)D concentrations. IGF-1 modulated the relation between 25(OH)D and outcome but only below, and not above, a threshold 25(OH)D concentration. Our findings suggest a threshold effect of 25(OH)D on glucose-insulin metabolism such that 25(OH)D ≥ ∼26 μg/L (65.0 pmol/L) supports normal glucose homeostasis and that the same cut point defining normal 25(OH)D concentration can be used in black and white women. This study was registered at clinicaltrials.gov as NCT01798030.
    Journal of Nutrition 04/2014; 144(5). DOI:10.3945/jn.114.190660 · 4.23 Impact Factor
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    ABSTRACT: Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 26,988 study subjects. Stage 1 meta-analyzed 7 GWA samples and 11,140 subjects for BMDs at the lumbar spine, hip, and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9,185 subjects, and by a Stage 3 de novo validation of 3 SNPs in 6,663 subjects. Combining evidence from all the stages, we have identified 2 novel loci that have not been reported previously at the genome-wide significance (GWS, 5.0x10(-8)) level: 14q24.2 (rs227425, p-value 3.98x10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, p-value 4.15x10(-9), CLDN14) in the female specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n=32,960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11), and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism, and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.
    Human Molecular Genetics 11/2013; 23(7). DOI:10.1093/hmg/ddt575 · 6.68 Impact Factor
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    ABSTRACT: Context:Although numerous epidemiologic studies have documented associations between osteoporosis and cardiovascular disease, the mechanisms underlying this association remain to be clarified. One hypothesis is that hyperlipidemia may be a common predisposing factor to both atherosclerotic heart disease and bone fragility.Objective:To evaluate this we compared bone mineral density (BMD) between subjects with and without the R3500Q APOB mutation, the cause of familial defective apolipoprotein B-100 which has been previously shown to markedly increase low density lipoprotein cholesterol (LDL-C). We hypothesized that R3500Q carriers would have lower BMD due to lifetime, elevated LDL-C.Design:A cross-sectional study in the Old Order Amish (OOA) population.Participants:The R3500Q APOB mutation is present at a high frequency (∼6% vs. < 0.5%) in the OOA population due to a founder effect. Therefore we conducted analysis on 1097 Amish individuals of whom 125 were R3500Q carriers.Main Outcome Measure:BMD was measured by dual-energy x-ray absorptiometry.Results:After adjusting for age, age(2), sex, BMI and family structure, carriers for the Q risk allele had significantly lower BMD than non-carriers at the femoral neck (p=0.037), lumbar spine (p=0.035) and whole body (p=0.016). Adjusting for LDL-C attenuated the association between R3500Q genotype and BMD but did not completely explain the relationship. Subgroup analyses showed no significant interactions with sex, age or presence of metabolic syndrome.Conclusion:These results utilize the unique genetic architecture of the OOA population to provide a novel line of evidence supporting a causal role for elevated LDL-C in lowering BMD.
    The Journal of Clinical Endocrinology and Metabolism 10/2013; 98(12). DOI:10.1210/jc.2013-2471 · 6.31 Impact Factor
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    Braxton D Mitchell · Elizabeth A Streeten
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    ABSTRACT: Osteoporotic fracture carries an enormous public health burden in terms of mortality and morbidity. Current approaches to identify individuals at high risk for fracture are based on assessment of bone mineral density and presence of other osteoporosis risk factors. Bone mineral density and susceptibility to osteoporotic fractures are highly heritable, and over 60 loci have been robustly associated with one or both traits through genome-wide association studies carried out over the past 7 years. In this review, we discuss opportunities and challenges for incorporating these genetic discoveries into strategies to prevent osteoporotic fracture and translating new insights obtained from these discoveries into development of new therapeutic targets.
    The Application of Clinical Genetics 10/2013; 6:75-85. DOI:10.2147/TACG.S52047
  • 05/2013; DOI:10.1530/boneabs.1.PP283
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    ABSTRACT: BACKGROUND: Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. AIM: To identify genetic variants associated with forearm BMD and forearm fractures. METHODS: BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. RESULTS: We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. CONCLUSIONS: These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.
    Journal of Medical Genetics 04/2013; 50(7). DOI:10.1136/jmedgenet-2012-101287 · 5.64 Impact Factor
  • Elizabeth A Streeten
    Endocrine Practice 03/2013; DOI:10.4158/EP12279.LT · 2.59 Impact Factor
  • Sruti Chandrasekaran · Nicoleta Ionica · Elizabeth A Streeten
    Endocrine Practice 03/2013; 19(2):377-8. · 2.59 Impact Factor
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    ABSTRACT: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10(-27)). The BMI allele score was associated both with BMI (p = 6.30×10(-62)) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary.
    PLoS Medicine 02/2013; 10(2):e1001383. DOI:10.1371/journal.pmed.1001383 · 14.00 Impact Factor
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    ABSTRACT: Objective: Distinguishing sHPT from eucalcemic primary hyperparathyroidism (EC-pHPT) is important. The objective of this study was to measure PTH-stimulated production of 1,25(OH)2D in early postmenopausal patients with idiopathic sHPT, who also fit the criteria for EC-pHPT, compared to age-matched controls.Methods: In this pilot case-control study, postmenopausal women aged 44-55 with normal serum calcium (Ca), glomerular filtration rate (GFR) ≥65 ml/min, 25(OH)D ≥ 75 nmol/L (30 ng/ml) were given an 8 hour infusion of PTH(1-34), 12 pmol/kg/hr. Patients (n=5) had elevated PTH, normal 1,25(OH)2D and no hypercalciuria. Controls (n=5) had normal PTH. At baseline, 4 and 8 hours serum Ca, creatinine (Cr), phosphorus (P), 1,25(OH)2D, FGF23, 24,25(OH)2D; urine Ca, P, Cr and cAMP/GFR were measured; FeCa, TMP/GFR were calculated.Results: Patients had lower 1,25(OH)2D levels (±SD) than controls at 4 (39.8±6.9 vs 58.8±6.7, p=0.002) and 8 hours (56.4±9.2 vs 105±2.3, p=0.003) of PTH infusion, attenuated after adjusting for higher BMI in patients (p=0.05, 0.04). 24,25(OH)2D levels were lower in patients than controls (1.9±0.6 vs 3.4±0.6, p=0.007). No differences were seen in: serum Ca, P; urine cAMP/GFR, TRP/GFR, FeCa, PTH suppression at 8 hours (patients 50%, controls 64%).Conclusions: Vitamin D sufficient patients who fit the criteria for EC-pHPT, had reduced PTH-stimulated 1,25(OH)2D compared to controls, partially attributable to their higher BMI. Other causes of reduced 1,25(OH)2D production ruled out were excessive catabolism of vitamin D metabolites, elevated FGF23 and CYP27B1 mutation. Elevated BMI and idiopathic reduced PTH-stimulated 1,25(OH)2D production should be considered in the differential of sHPT.
    Endocrine Practice 11/2012; 19(1):1-26. DOI:10.4158/EP12151.OR · 2.59 Impact Factor
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    ABSTRACT: We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)<P<5.9 × 10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
    PLoS Genetics 07/2012; 8(7):e1002745. DOI:10.1371/journal.pgen.1002745 · 8.17 Impact Factor
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    ABSTRACT: Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2012; 27(10):2051-64. DOI:10.1002/jbmr.1679 · 6.59 Impact Factor
  • 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS); 05/2012
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    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.
    Nature Genetics 04/2012; 44(5):491-501. DOI:10.1038/ng.2249 · 29.65 Impact Factor
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    ABSTRACT: EIF2AK3 is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Rare mutations in EIF2AK3 cause Wolcott-Rallison syndrome (OMIM 226980), an autosomal recessive disorder characterized by diabetes, epiphyseal dysplasia, osteoporosis, and growth retardation. To investigate the role of common genetic variation in EIF2AK3 as a determinant of bone mineral density (BMD) and osteoporosis, we sequenced all exons and flanking regions, then genotyped six potentially functional single nucleotide polymorphisms (SNPs) in this gene in 997 Amish subjects for association analysis, and attempted replication in 887 Mexican Americans. We found that the minor allele of a nonsynonymous SNP rs13045 had borderline associations with decreased forearm BMD in both discovery and replication cohorts (unadjusted p = 0.036 and β = -0.007 for the Amish; unadjusted p = 0.031 and β = -0.008 for Mexican Americans). A meta-analysis indicated this association achieved statistical significance in the combined sample (unadjusted p = 0.003; Bonferroni corrected p = 0.009). Rs13045 and three other potentially functional SNPs, a promoter SNP (rs6547787) and two nonsynonymous SNPs (rs867529 and rs1805165), formed two haplotypes: a low-BMD associated haplotype, denoted haplotype B [minor allele frequency (MAF) = 0.311] and a common haplotype A (MAF = 0.676). There were no differences in mRNA expression in lymphoblastoid cell lines between the two haplotypes. However, after treating lymphoblastoid cell lines with thapsigargin to induce ER stress, cell lines with haplotype B showed increased sensitivity to ER stress (p = 0.014) compared with cell lines with haplotype A. Taken together, our results suggest that common nonsynonymous sequence variants in EIF2AK3 have a modest effect on ER stress response and may contribute to the risk for low BMD through this mechanism.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2012; 27(2):331-41. DOI:10.1002/jbmr.549 · 6.59 Impact Factor

Publication Stats

2k Citations
503.77 Total Impact Points

Institutions

  • 2002–2015
    • University of Maryland, Baltimore
      • • Division of Endocrinology, Diabetes and Nutrition
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2013
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
  • 2001
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States