Prenatal famine exposure and estimated glomerular filtration rate across consecutive generations: association and epigenetic mediation in a population-based cohort study in Suihua China.

Wenbo Jiang,Yue Wang,Qiuying Dong,Tianshu Han,Xinyi Pei,Zehui Jiang,Ying Li,Wei Duan,Huanyu Wu,Wanying Hou,Yingying Chen,Changhao Sun

doi:10.18632/aging.103397

Abstract

Prenatal malnutrition could promote renal dysfunction in adulthood, but it is unclear whether the detrimental effect could be transmitted to the next generation. We investigated whether famine exposure was associated with variation of estimated glomerular filtration rate(eGFR) in two generations and explored the mediation role of methylation alterations. The longitudinal analysis included 2909 participants from Suihua rural area. F1 and F2 generations were divided into non-famine and famine group based on their birth year and exposure status of their parents, respectively. The eGFR was calculated by using the chronic kidney disease epidemiology collaboration equation. We applied mixed-effect models to investigate the association between famine and ΔeGFR and tested blood DNA methylomes in 46 families across two generations. The mediation-analysis models were utilized to examine the mediation effect of methylation alterations on the famine-ΔeGFR association.In mixed-effect models, famine exposure was associated with declined ΔeGFR level in F1(β:-8.32;95%CI:-11.51,-5.12) and in F2(β:-6.11;95%CI:-11.88, -0.43). Methylation850K BeadChip data showed only 19 of 961 F1 differentially methylated sites showed concordant alterations in F2. The mediation-analysis results showed methylation alterations on AGTR1 and PRKCA might mediate the famine-ΔeGFR association. Overall, prenatal famine exposure may have long-term effects on eGFR decline across consecutive generations which might be partly mediated by methylation alterations on AGTR1 and PRKCA.

Highlights

Early-life malnutrition is a long-standing public concern in developing countries which may elevate the abnormal development of various organs [1,2,3,4] including kidney [5] in later life
R^2~, the proportion of original variances that were explained by the omitted confounding. In this large longitudinal cohort study with 2909 participants across consecutive generations in Northern China, we novelly found that prenatal exposure to Chinese famine significantly decreased estimated glomerular filtration rate (eGFR) in adulthood in two consecutive generations
Two intriguing studies based on Chinese famine indicated famine exposure was linked to an enhanced risk (OR:1.54; 95% CI: 1.04, 2.28) of higher proteinuria level among women exposed to famine

Summary

Introduction

Early-life malnutrition is a long-standing public concern in developing countries which may elevate the abnormal development of various organs [1,2,3,4] including kidney [5] in later life. A somewhat limited number of longitudinal studies have shown that nutritional deprivation of intrauterine or early postnatal environment had severely deteriorated effects on the kidney function in adulthood [6]. Due to unavailable experimental data, the transgenerational effects on chronic kidney disease risk in adult offspring remain to be investigated. Famine provides a unique opportunity to explore the long-term association of prenatal malnutrition with renal function [2, 7]. The Great Chinese famine of 1959-1961 affected the whole nation and caused 30 million deaths and 30 million lost births during the period [8], and it was superimposed on widespread chronic undernourishment [9]. It offered a valuable opportunity to study the influence of the early-life famine on adult and offspring diseases [11]

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