Variability in newborn telomere length is explained by inheritance and intrauterine environment

Li Chen, Karen Mei Ling Tan, Min Gong, Mary F F Chong, Kok Hian Tan, Yap Seng Chong, Michael J Meaney, Peter D Gluckman, Johan G Eriksson, Neerja Karnani, Li Chen, Karen Mei Ling Tan, Min Gong, Mary F F Chong, Kok Hian Tan, Yap Seng Chong, Michael J Meaney, Peter D Gluckman, Johan G Eriksson, Neerja Karnani

Abstract

Background: Telomere length (TL) and its attrition are important indicators of physiological stress and biological aging and hence may vary among individuals of the same age. This variation is apparent even in newborns, suggesting potential effects of parental factors and the intrauterine environment on TL of the growing fetus.

Methods: Average relative TLs of newborns (cord tissue, N = 950) and mothers (buffy coat collected at 26-28 weeks of gestation, N = 892) were measured in a birth cohort. This study provides a comprehensive analysis of the effects of heritable factors, socioeconomic status, and in utero exposures linked with maternal nutrition, cardiometabolic health, and mental well-being on the newborn TL. The association between maternal TL and antenatal maternal health was also studied.

Results: Longer maternal TL (β = 0.14, P = 1.99E-05) and higher paternal age (β = 0.10, P = 3.73E-03) were positively associated with newborn TL. Genome-wide association studies on newborn and maternal TLs identified 6 genetic variants in a strong linkage disequilibrium on chromosome 3q26.2 (Tag SNP-LRRC34-rs10936600: Pmeta = 5.95E-08). Mothers with higher anxiety scores, elevated fasting blood glucose, lower plasma insulin-like growth factor-binding protein 3 and vitamin B12 levels, and active smoking status during pregnancy showed a higher risk of giving birth to offspring with shorter TL. There were sex-related differences in the factors explaining newborn TL variation. Variation in female newborn TL was best explained by maternal TL, mental health, and plasma vitamin B12 levels, while that in male newborn TL was best explained by paternal age, maternal education, and metabolic health. Mother's TL was associated with her own metabolic health and nutrient status, which may have transgenerational effects on offspring TL.

Conclusions: Our findings provide a comprehensive understanding of the heritable and environmental factors and their relative contributions to the initial setting of TL and programing of longevity in early life. This study provides valuable insights for preventing in utero telomere attrition by improving the antenatal health of mothers via targeting the modifiable factors.

Trial registration: ClinicalTrials.gov , NCT01174875. Registered on 1 July 2010.

Keywords: Inheritance; Intrauterine exposures; Newborn; Sex differences; Telomere length.

Conflict of interest statement

NK and YSC are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, EVOLVE Biosystems, DSM, and Danone. All other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Association studies of newborn telomere length. A Histogram of newborn telomere length. B Boxplots of sex and ethnicity (univariate P values). C, D Scatter plots of gestational age, maternal age, paternal age, and maternal telomere length (P values after adjusting for sex and ethnicity). E, F Effect size plot of factors significantly associated with newborn telomere length using all, female-only, and male-only subjects (error bar, 95%CI). Related to Table 2. E Categorical/ordinal variables. F Continuous variables
Fig. 2
Fig. 2
Association studies of maternal telomere length. A Histogram of maternal telomere length. B Boxplot of ethnicity and scatter plot of maternal age (univariate P values). C, D Effect size plot of significant factors associated with maternal telomere length after adjusting for age, ethnicity, and DNA extraction method (error bar, 95%CI). Related to Additional file 1: Table S6 (main model). C Continuous variables. D Categorical/ordinal variables
Fig. 3
Fig. 3
Schematic diagram summarizing the factors contributing to newborn TL variation

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