SUPR
Type 2 diabetes, glycaemic traits and bone health: a Mendelian Randomization study
Dnr:

simp2020001

Type:

SNIC SENS

Principal Investigator:

Adam Mitchell

Affiliation:

Uppsala universitet

Start Date:

2020-01-15

End Date:

2025-02-01

Primary Classification:

30211: Orthopaedics

Webpage:

Allocation

  • Castor /proj at UPPMAX: 128 GiB
  • Castor /proj/nobackup at UPPMAX: 128 GiB
  • Cygnus /proj/nobackup at UPPMAX: 128 GiB
  • Cygnus /proj at UPPMAX: 128 GiB
  • Bianca at UPPMAX: 2 x 1000 core-h/month

Abstract

Men and women with type 2 diabetes mellitus (T2DM) have higher risk of hip fracture, but the mechanisms are not fully understood. One such mechanism may be lower bone area. We have shown in a cross sectional study that men and women had a progressively lower bone area following the clinical cut-offs of fasting glucose, from normal fasting glucose (NFG) to impaired fasting glucose (IFG) to T2DM. Mendelian Randomization (MR) analysis is a form of instrumental variable analysis which uses genetic variation to investigate the causal relationships between potentially modifiable risk factors such as type 2 diabetes and health outcomes such as bone parameters within observational data. To this date, there have been two studies using MR methods to estimate the genetic effect of both T2DM and glucose levels on bone mineral density (BMD) and the risk of fracture. We intend to replicate the results found in one of these studies by showing the genetic effect of glucose on greater BMD but aim to add analysis on the genetic effect of glucose levels on bone area. We will conduct a two-sample MR with summary data on glucose related single nucleotide polymorphisms (SNP’s) from the MAGIC consortium GWAS in combination with data from the SMCC and UKBB. There are currently 37 glucose associated SNP’s that we will use for our analysis. For each SNP we will use regression models with outcomes (DXA total bone mineral density, DXA legs combined bone area, DXA leg bone density, Femur neck bone density, Femur shaft bone density, Femur total bone density and potentially ultrasound bone mineral density), adjusted for age, sex and 10 genetic principal components. Glucose concentrations in SMCC will be used for estimating the association between them and the SNP’s of interest for confirmation. There will be a number of sensitivity analysis conducted within this study using methods such as MR-Egger which is an approach to test for pleiotropy which relates to the effect of the genetic variants on other health outcomes. This study may highlight a mechanistic reason for why those with higher levels of glucose leading to a greater risk for T2DM have an increased risk of hip fracture. Therefore if we are able to determine those individuals with a genetic predisposition for higher glucose levels and T2DM it may be possible to intervene to ensure the expansion of bone area is not diminished. MR studies allow us to use observational data on large populations to answer causal questions by removing the common confounding problems in found in traditional epidemiological methods.