Discrimination exposure and DNA methylation of stress-related genes in Latina mothers

Highlights

• DNA methylation of genes implicated in stress-related disorders predicts discrimination.

• Discrimination is inversely associated with NR3C1 and BDNF methylation over time.

• Discrimination is inversely associated with FKBP5 methylation at T1 but not at T2.

• BDNF data support the hypothesis of discrimination associated neuroplasticity.

Abstract

Latina mothers, who have the highest fertility rate among all ethnic groups in the US, are often exposed to discrimination. The epigenetic changes related to this discrimination are largely unknown. This study is the first to explore the relationship between discrimination and DNA methylation of stress regulatory genes in Latinas. Our sample was Latina women (n = 147) with a mean age of 27.6 years who were assessed at 24–32 weeks’ gestation (T1) and 4–6 weeks postpartum (T2) and reside in the U.S. Blood was collected at T1, and the Everyday Discrimination Scale (EDS) was administered at T1 and T2. DNA Methylation at candidate gene regions was determined by bisulphite pyrosequencing. Associations between EDS and DNA methylation were assessed via zero-inflated Poisson models, adjusting for covariates and multiple-test comparisons. Discrimination was negatively associated with methylation at CpG sites within the glucocorticoid receptor (NR3C1) and brain-derived neurotrophic factor (BDNF) genes that were consistent over time. In addition, discrimination was negatively associated with methylation of a CpG in the glucocorticoid binding protein (FKBP5) at T1 but not at T2. This study underscores associations between discrimination and epigenetic markers of DNA methylation in Latinas that warrant further investigation to better understand the biological pathways and psychopathological effects of discrimination on Latina mothers and their families.

Introduction

The accumulation of stress over the lifespan can contribute to biological vulnerability and directly affect health outcomes for mothers and their children. Latinas, who have the highest fertility rate among all ethnic groups and represent the largest minority group in the US (Center, 2015), are exposed to a multitude of stressful events and sociocultural factors, including discrimination (Ayón, 2015). Extant research in Latinas has largely focused on varied levels of exposure to risk and protective factors in the perinatal period including socio-determinants of health (e.g., socioeconomic background), prenatal care, social support, and stress. These factors, however, do not adequately account for all of the noted disparities in perinatal outcomes, such as perinatal depression and morbidity (Guintivano et al., 2017; Howell et al., 2017).

Discrimination has been defined as differential treatment based on: (1) race that disadvantages a racial/ethnic group and/or (2) inadequately justified factors other than race/ethnicity that disadvantages a racial/ethnic group (Council, 2004). A contributing factor in health disparities and social inequality, discrimination has been associated with several adverse physical and mental health outcomes in minority groups (Wallace et al., 2016; Williams and Mohammed, 2009). A recent meta-analysis of 150 studies demonstrated a statistically significant effect size of racial discrimination on health, with the largest effect on mental health (r = .20, 95% CI: .17, .24) (Carter et al., 2017). Earlier meta-analyses found similar associations (Lee and Ahn, 2012), and discrimination is a significant predictor of poor mental health in Black and Latino immigrants (Gee et al., 2006). A UK study concluded that cumulative exposure to racial discrimination has incremental long-term effects, and noted that assessing discrimination at only one time point may underestimate the adverse effects of discrimination on mental health (Wallace et al., 2016). Among Latinos, discriminatory experiences are specifically associated with decreased self-esteem and emotional stress, increased anxiety and depressive symptoms, and social isolation (Ayón, 2015). A recent nationally representative survey suggested that one in three Latinos report discrimination based on ethnicity, and one in five report that they have avoided seeking medical care or calling police authorities because they were concerned that they or a family member would experience discrimination (Health et al., 2017). Overall, these studies suggest that Latinos face discrimination across the US. Moreover, in the current political climate, discrimination against Latinos may be increasing (Almeida et al., 2016).

Several mechanisms for the adverse effects of discrimination on mental health have been described (Berger and Sarnyai, 2015). This study focuses on discrimination as a potent stressor that is associated with neuroendocrine dysregulation via epigenetic changes, which can ultimately be linked to deleterious health effects. Specifically, these epigenetic changes include DNA methylation of stress regulatory genes. DNA methylation is the addition of a methyl group, usually to cytosines within CpG dinucleotides, which when located in promoter regions generally represses gene expression. Stress reactivity has been hypothesized to mediate the impact of the social environment on health. Social adversity, in animal and human studies, has potent neuroendrocrine dysregulatory effects, resulting in altered stress response patterns. Specifically, exposure to various environmental stressors can alter responses of the hypothalamic–pituitary–adrenal axis (HPA) through potentially enduring changes in the transcriptional regulation of key genes. Through epigenetic modifications at key HPA-regulatory genes, stress response dysregulation is likely to contribute to stress-related health disparities and provide a link between the stressful social environment and disease development (Mitchell et al., 2016; Szyf, 2013).

Little is known about how perceived racial discrimination relates to DNA methylation patterning. A recent study reported an inverse relationship between perceived racial discrimination and DNA methylation at seven CpG sites (six genes related to tumor suppression protein-coding) in African-American women enrolled in a blood pressure study (Mendoza et al., 2018). To our knowledge, it is unknown if there are similar associations between discrimination and DNA methylation in Latinos. However, studies have reported dysregulation of the stress response in depressed Latina mothers (Lara-Cinisomo et al., 2017), supporting the rationale for the present investigation of discrimination and DNA methylation.

Two genes critically involved in the regulation of the stress response are the glucocorticoid receptor gene (NR3C1) (Herman et al., 2012) and the glucocorticoid receptor chaperone protein gene FKBP5, an important regulator of the stress response and glucocorticoid receptor sensitivity (Zannas et al., 2015). DNA methylation at key specific CpG sites within NR3C1 exon 1-F promoter has been associated with early adversity in a number of studies, supported by a meta-analysis (Palma-Gudiel et al., 2015). Early adversity has been associated with demethylation at two key CpGs within intron 7 of FKBP5 that appear to contribute to glucocorticoid resistance, higher cortisol levels, and prolonged recovery following exposure to stress, for review see Zannas and Binder (2014).

In addition, stress-induced neuroplasticity associated with altered HPA function is mediated by functional interactions between glucocorticoids and brain-derived neurotrophic factor (BDNF) (Numakawa et al., 2017), where methylation at a key promoter region IV has been linked to environmental stressors in humans and rodent models (Mitchelmore and Gede, 2014). Based on this integrated literature, we postulated that one biological mechanism related with discrimination is neuroendocrine-associated dysregulation via DNA methylation at previously described key CpG locis in stress regulatory genes. The current study investigated associations between methylation at specific CpG sites within the NR3C1, FKBP5, and BDNF genes and perceived discrimination during pregnancy and early postpartum in a population of Latina mothers. It was hypothesized that DNA methylation at key CpG sites within the NR3C1, FKBP5, and BDNF genes is inversely associated with perceived discrimination in Latinas in the U.S.