Abstract
BackgroundThe early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course.MethodsDNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women’s Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue.ResultsLower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6–7 years (p = 0.0001) and % fat mass at 6–7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6–7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults.ConclusionsThese data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.
Highlights
We found that SLC6A4 CpG methylation at Hg19 chr17:28561468 was associated with adiposity in adolescents (n = 812) and in adipose tissue from obese vs. lean adults (n = 81), suggesting that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course
Median maternal age at birth was 31.5 years, pre-pregnancy median body mass index (BMI) 24.3 kg/m2 and pregnancy weight gain 0.35 kg/week; 48% were in their first pregnancy and 12% smoked in late pregnancy
Examining the relationship between cord tissue SLC6A4 methylation at birth and infant/child adiposity, lower CpG1 (Hg19:28561601) and CpG2 (Hg19:28561578) methylation were associated with lower % fat mass age 6–7 years (CpG1, β = 0.118, p = 0.025; CpG2, β = 0.091 (0.0001, 0.183), p = 0.05, respectively) (Table 2), but were not associated with % fat mass at birth or 4 years or with total fat mass at birth, 4 or 6–7 years
Summary
The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course. Methods DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women’s Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue
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