Stunting is a global health problem that is common in low and middle-income countries where one third of children under 5 years of age are affected1. Africa has the highest rates of stunting and is the continent that has shown the least improvement in the prevalence of stunting in recent years2. Small mothers tend to give birth to small babies3, but the epigenetic mechanisms that underlie this correlation are poorly understood. This exploratory study of 30 imprinted genes in placentas from  mothers will test the hypothesis that genetic imprinting plays a role in the inter-generational transmission of stunting. The proposed study is innovative because it takes advantage of a prospective cohort study of a rural African population in which we are following 600 girls (F1 generation) from infancy, through childhood, to their first birth. Data are also being gathered on the parents (F0) and offspring (F2) of these subjects. We are in a unique position to combine these longitudinal data, spanning 3 generations, with the analysis of allele-specific expression of placental genes. [According to the conflict hypothesis4, growth inhibiting genes are repressed on the paternal alleles and growth promoting genes are repressed on the maternal alleles. The degree of imprinting varies between individuals and we hypothesize that this normal variation is the mechanism by which stunting is transmitted from one generation to the next.
Aim 1 will find out if maternal stunting is associated with higher levels of placental imprinting of growth promoting genes such as IGF2.
Aim 2 assesses the critical windows at which stunting matters, and the interaction between stunting and catch up growth.
Aim 3 will find out if increased repression of growth promoting genes in the placenta leads to offspring stunting, as measured by supine length at birth and at age one month.] The placental collections will be carried out by our Malian collaborators, including two mid-wives and a hospital assistant who reside permanently at the study site [in the District of Bandiagara in central Mali. This site is peaceful and more than 500 miles from Kidal, an area of political tension. The research team has field-tested all the protocols and collected 22 placentas, 5 of which have been analyzed by the PI's laboratory at the University of Michigan.] We will use a combination of PCR and deep sequencing to measure loss of imprinting with high accuracy. As stunting leads to a wide range of health problems from poor cognitive function to metabolic syndrome5, it is important to understand how it is transmitted to the next generation. The proposed study is basic science that is necessary for the eventual discovery of interventions and policies that prevent stunting and its adverse effects on the quality of life.
Stunting is a better predictor for impaired development (poor cognitive function and small organ size) than is body mass, and stunted children are at later risk for elevated glucose concentrations, high blood pressure, and harmful lipid profiles. The proposed study will test the hypothesis that the loss of imprinting in placental genes is a mechanism by which stunting is transmitted to the next generation. A better understanding of the etiology of stunting is an important step toward interventions and policy changes that will reduce the prevalence of stunting, and thereby prevent a variety of health problems in adult life.