Ward, K. A. | bioRxiv Science

bioRxiv2022

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigated links between blood DNA methylation and child height in four LMIC cohorts (n=1927) and identified a robust association at three CpGs in the suppressor of cytokine signalling 3 (SOCS3) gene which replicated in a high-income country cohort (n=879). SOCS3 methylation (SOCS3m) - height associations were independent of genetic effects. Mendelian randomization analysis confirmed a causal effect of SOCS3m on height. In longitudinal analysis in a LMIC cohort, SOCS3m explained a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increased from birth to 21 years (2% to 18%). Childrens SOCS3m was associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirmed a regulatory effect of SOCS3m on gene expression. Our findings suggest that epigenetic modifications may play an important role in driving child height in LMIC.

genomics↗

bioRxiv2019

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[≤]-2) was more prevalent in CWH (35% vs. 5%, p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score [≤]-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (both p[≤]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↗