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Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

ABSTRACT: Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

SUBMITTER: Kung AW

PROVIDER: S-EPMC2820171 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

Kung Annie W C AW Xiao Su-Mei SM Cherny Stacey S Li Gloria H Y GH Gao Yi Y Tso Gloria G Lau Kam S KS Luk Keith D K KD Liu Jian-min JM Cui Bin B Zhang Min-Jia MJ Zhang Zhen-lin ZL He Jin-wei JW Yue Hua H Xia Wia-bo WB Luo Lian-mei LM He Shu-li SL Kiel Douglas P DP Karasik David D Hsu Yi-Hsiang YH Cupples L Adrienne LA Demissie Serkalem S Styrkarsdottir Unnur U Halldorsson Bjarni V BV Sigurdsson Gunnar G Thorsteinsdottir Unnur U Stefansson Kari K Richards J Brent JB Zhai Guangju G Soranzo Nicole N Valdes Ana A Spector Tim D TD Sham Pak C PC

American journal of human genetics 20100121 2

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta- ...[more]

PMID: 20096396

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Project description:BackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Project description:ImportanceDespite the reassuring emerging evidence on the lack of a causal relationship between sun protection and vitamin D deficiency, there is scarce data on whether multimodal sun protection is associated with reduced bone mineral density (BMD) and/or increased prevalence of osteoporotic bone fractures. This lack of data may lead to worry and decreased sun-protective behaviors on the part of patients.ObjectiveTo investigate the association of sun-protective behaviors with BMD z scores and the prevalence of osteoporotic fractures.Design, setting, and participantsThis population-based cross-sectional study included data from US adults who participated in the 2017 to 2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Data were analyzed between September and November 2020.Main outcomes and measuresDefinition of sun-protective behaviors (staying in the shade, wearing long sleeves, and sunscreen use), site-specific and total BMD, and osteoporotic fractures (hip, wrist, and spine) in the NHANES data.ResultsData from 3418 adults 20 years and older (average age, 39.5 [95% CI, 38.6-40.4] years; 1612 [47.2%] men and 1806 [52.9%] women) who completed the NHANES dermatology questionnaire were included in this study. The prevalence of frequent staying in the shade, wearing of long sleeves, and sunscreen use were 31.6% (95% CI, 27.8%-35.7%), 11.8% (95% CI, 10.6%-13.1%), and 26.1% (95% CI, 23.5%-28.8%), respectively. The use of individual sun-protective behaviors was not associated with diminished site-specific and total BMD z scores in the multivariate models (estimate, -0.23 [95% CI, -0.47 to 0.02], P = .18; -0.08 [-0.27 to 0.12], P = .72; and -0.10 [-0.32 to 0.13], P = .15 for frequent staying in the shade, wearing of long sleeves, and sunscreen use, respectively). Moderate to frequent staying in the shade was associated with reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19 [95% CI, 0.04-0.86], P = 0.02).Conclusion and relevanceIn this cross-sectional study, routine use of sun-protective behaviors among the US adult population was not associated with decreased BMD or increased risk of osteoporotic fracture. Sun protection may be associated with a modest decrease in the prevalence of osteoporotic fractures, possibly owing to risk-averse behaviors. These reassuring findings add to the growing body of evidence on the safety of sun protection, with no considerable negative association with bone health.

Project description:Introduction: Chronic pancreatitis (CP) can lead to malnutrition, an established risk factor for low bone mineral density (BMD) and fractures. This study aims to determine the prevalence of low BMD, assess fracture incidence and explore risk factors for fractures in patients with CP. Patients and methods: We performed a retrospective analysis of all patients treated for CP at Karolinska University Hospital between January 1999 and December 2020. Electronic medical records were retrieved to assess demographic, laboratory and clinical data. Patients subjected to dual-energy X-ray absorptiometry (DXA) were categorised as either low BMD or normal BMD. We investigated whether the rate of fractures, defined by chart review, differed between these groups using Cox regression, adjusting the model for age, sex and body mass index (BMI). Additional within-group survival analysis was conducted to identify potential risk factors. Results: DXA was performed in 23% of patients with definite CP. Some 118 patients were included in the final analysis. Low BMD was present in 63 (53.4%) patients. Mean age at CP diagnosis in the total cohort was 53.1 years and was significantly lower in patients with normal BMD than in patients with low BMD (45.5 vs. 59.8, p < 0.001). Significant differences were observed in smoking status and disease aetiology, i.e., a higher proportion of patients with low BMD were current or former smokers, with nicotine or alcohol being a more common cause of CP (p < 0.05). Total follow-up time was 898 person-years. Fractures were found in 33 (28.0%) patients: in 5 of 55 patients (16.7%) with normal DXA and in 28 of 63 patients (44.4%) with low BMD (adjusted hazard ratio = 3.4, 95% confidence interval (CI) = 1.2-9.6). Patients with at least 3 months of consecutive pancreatic enzyme replacement therapy (PERT) or vitamin D treatment had a longer median time to fracture after CP diagnosis. Conclusion: DXA was only performed in 23% of patients with definite CP in this study, indicating a low adherence to current European guidelines. A low BMD was found in 53.4% of patients with CP, and 44% of the patients with a low BMD experienced a fracture during follow-up. Moreover, the fracture rate in patients with low BMD increased compared to those with normal BMD.

Project description:SummaryWe tested whether two genetic variants were associated with BMD at multiple clinically relevant skeletal sites in Caucasians. We found that variant rs7776725 is consistently associated with hip, spine, wrist and whole-body BMD, which highlights the potential importance of this variant or linked variants for osteoporosis.IntroductionA recent genome-wide association study identified two single nucleotide polymorphisms (SNPs), rs7776725 and rs1721400, that were associated with bone mineral density (BMD) variation at the radius, tibia and calcaneus in a Korean population. In this study, we aimed to test whether the association of these two genetic variants can be replicated in Caucasians and whether their association with BMD can be extended to other clinically relevant skeletal sites.MethodsWe performed this study in two large cohorts of unrelated US Caucasians. Area BMD at the hip, spine, wrist (ultra-distal radius) and whole body were measured with Hologic dual-energy X-ray absorptiometer. SNPs were genotyped with Affymetrix human genome-wide genotyping arrays. Association analyses were performed using PLINK.ResultsWe detected highly significant association (combined p = 1.42 × 10(-16)) of rs7776725 with wrist BMD but only borderline association signal (combined p = 0.017) for rs1721400 with wrist BMD. In addition, we found that rs7776725 was associated with BMD at the hip, spine and whole body. At the FAM3C gene locus where rs7776725 was located, we identified several other SNPs (rs4727922, rs1803389, rs718766 and rs7793554) that were also associated with BMD.ConclusionsThis is the first follow-up association study of rs7776725 and rs1721400 with BMD. The rs7776725 showed consistent association with BMD at multiple clinically important skeletal sites, which highlighted the potential importance of rs7776725 or linked SNPs for risk of osteoporosis. Further in-depth re-sequencing studies and functional assays are necessary to elucidate the underlying mechanisms.

Dataset Information

Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

Publications

Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

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