title: Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men.
abstract: BACKGROUND
  In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-κB cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.
  
  
  METHODS
  Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r(2)≥0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40-79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre.
  
  
  RESULTS
  We validated the associations between SNPs in GPR177 and BMD(a) previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD(a), increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD(a), vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS.
  
  
  CONCLUSIONS
  Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-κB signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.
authors: Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors: Delnaz
authors: D
authors: Roshandel
authors: Wendy
authors: W
authors: Thomson
authors: Stephen R
authors: SR
authors: Pye
authors: Steven
authors: S
authors: Boonen
authors: Herman
authors: H
authors: Borghs
authors: Dirk
authors: D
authors: Vanderschueren
authors: Ilpo T
authors: IT
authors: Huhtaniemi
authors: Judith E
authors: JE
authors: Adams
authors: Kate A
authors: KA
authors: Ward
authors: Gyorgy
authors: G
authors: Bartfai
authors: Felipe F
authors: FF
authors: Casanueva
authors: Joseph D
authors: JD
authors: Finn
authors: Gianni
authors: G
authors: Forti
authors: Aleksander
authors: A
authors: Giwercman
authors: Thang S
authors: TS
authors: Han
authors: Krzysztof
authors: K
authors: Kula
authors: Michael E
authors: ME
authors: Lean
authors: Neil
authors: N
authors: Pendleton
authors: Margus
authors: M
authors: Punab
authors: Frederick C
authors: FC
authors: Wu
authors: Kate L
authors: KL
authors: Holliday
authors: Terence W
authors: TW
authors: O'Neill
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000368:Aged; D000483:Alleles; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics*; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000000981:diagnostic imaging / Q000502:physiology; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D043562:Receptors, G-Protein-Coupled; D000097782:NF-kappaB-Inducing Kinase; C549111:WLS protein, human