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Biology subjects

Hartley, A.

Publications and source records attributed to Hartley, A..

2 recordsLinked to original sources

Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe

BackgroundPerinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.\n\nSettingCross-sectional study of CWH (6-16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.\n\nMethodsFrom Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.\n\nResultsThe 97 CWH were older (mean age 12.7 vs. 10.0 years) and therefore taller (mean height 142cm vs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score[&le;]-2) was more prevalent in CWH (35% vs. 5%, p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score [&le;]-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (both p[&le;]0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI -0.01, 0.67; p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33, p=0.001) and TBLH-BMCLBM Z-score (r=-0.23, p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.\n\nConclusionSize-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.

epidemiology

A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target

To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in >362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6x10-16; PGENE =8x10-17). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.

genetics