Our goal is to understand the potential independent and combined contributions of several critical pathways forhuman development to risks of orofacial clefts. These pathways include methyl group metabolism, oxidativestress, glycemic control, and the hypothalamic-pituitary adrenocortical (HPA) axis. Each of these pathwayshas evidence for its contribution to clefts. Here we propose two sets of analyses that will substantially extendour knowledge regarding the contribution of these pathways to clefts. First, we will explore nutrient exposuresthat regulate these pathways. Available evidence supports an association of nutritional status with clefts. Moststudies have investigated one or two nutrients at a time. We propose to extend current knowledge byexamining multiple nutrients simultaneously, and using an innovative pathway-focused analytic approach, asreflected in Aim 1 - Nutrient pathways and clefts: We will examine the association of risk of clefts withnutritional exposures that contribute to several specific mechanistic pathways, using data from a population-based case-control study we conducted in California. The pathways and exposures are as follows: 1)oxidative stress - nutrients that protect against oxidative stress ( - and -carotene, cryptoxanthin, cysteine,folate, lutein, lycopene, oleic acid, pro-vitamin A, vitamins C and E, zinc) or promote it (iron, saturated fat); 2)methyl group metabolism - betaine, choline, folate, methionine, riboflavin, vitamin B6, vitamin B12, zinc; and 3)glycemic control - dietary glycemic load; intake of glucose, sucrose, fructose, fiber. For our second Aim, wewill consider the HPA axis pathway. The HPA axis represents a complex feedback system by which the bodyresponds to stress. Experimental studies indicate that corticosteroids, a product of the stress response, causeclefts. Several studies in humans have examined clefts and stress, and most found an increased riskassociated with higher stress. Most of these studies have been quite limited in their assessment of stress.None of them have included measures of social support, an important potential buffer of the negative effects ofstress. To further extend our understanding of stress and clefts, we propose the following specific aim:
Aim 2 - Stress and clefts: We will examine the association of risk of clefts with maternal stressful life events andsocial support, using data from the National Birth Defects Prevention Study (NBDPS), a population-basedcase-control study. The proposed research will move forward our understanding of the causes of clefts and isinnovative and unique, the research team is highly experienced and successful in conducting epidemiologicresearch on birth defects, and the data to be used are population-based, rigorously collected, and high quality.

Public Health Relevance

The proposed research will improve our understanding of the causes of orofacial clefts. Its findings will contribute to the development of effective interventions or prevention messages, so that this common, costly outcome can be prevented.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
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Special Emphasis Panel (ZDE1-VH (07))
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Harris, Emily L
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Stanford University
Schools of Medicine
United States
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Carmichael, Suzan L; Ma, Chen; Tinker, Sarah et al. (2014) Maternal stressors and social support as risks for delivering babies with structural birth defects. Paediatr Perinat Epidemiol 28:338-44
Wallenstein, Matthew B; Shaw, Gary M; Yang, Wei et al. (2013) Periconceptional nutrient intakes and risks of orofacial clefts in California. Pediatr Res 74:457-65
Carmichael, Suzan L; Yang, Wei; Feldkamp, Marcia Lynn et al. (2012) Reduced risks of neural tube defects and orofacial clefts with higher diet quality. Arch Pediatr Adolesc Med 166:121-6