Dataset Information

Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.

ABSTRACT:

Background

Osteoporosis 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.

Methods

In 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.

Findings

We 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.

Interpretation

Two 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.

SUBMITTER: Richards JB

PROVIDER: S-EPMC2679414 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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.