Race, Genes and Preterm Delivery: Gene-Environment Interactions
Genetic expression (phenotype) occurs within а specific environmental context. In this sense, pheno-types represent interaction between genes and environment. However, the term “gene-environment interaction” typically is used in a narrower sense to refer to effect modification whereby the size or even the direction of the genetic effect differs depending on environmental risk.
Infection-mediated PTD represents an example of a possible gene-environment interaction. Cytokine activation resulting from ascending infection may trigger PTD. Urogenital tract immune function may affect risk of ascending infection, and racial differences in amniochorionic membrane response to infectious stimuli have been noted in one small study. Various genes have been linked to vaginal microflora and pH levels and cytokine activity. Potentially, differences between the black and white populations in the frequency of immune modulating genes could help explain racial differences PTD risk associated with infection.
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Preliminary reports suggest that gene-environment interactions may be relevant to racial disparity in PTD. Polymorphisms in two metabolic genes (CYP1A1 and GSTT1) enhance the risk of PTD associated with smoking among African Americans but not whites. The association among a polymorphism for a proinflammatory cytokine, tumor necrosis factor-alpha (TNF-a) and PTD has been inconsistent. These conflicting findings may represent an interaction between the TNF-a polymorphism and BV When BV is absent, there is minimal risk of PTD associated with the polymorphism, but its presence accentuates BV risk. The frequency of the TNF-a polymorphism does not differ between white and black populations, but BV prevalence is significantly greater among African Americans. This example illustrates how gene-environment interactions might contribute to disparity in PTD even in the absence of racial differences the frequency of the polymorphism. Similarly, a polymorphism related to the metabolism of folate is associated with risk for PTD; the risk is heightened when folate intake is low. Because dietary folate intake is lower among
African Americans than whites, African American may be disproportionately affected by this polymorphism, even the absence of any difference in its frequency by race.
Physiological Pathways
Racial differences in gene frequencies regulating key physiological mechanisms could theoretically contribute to disparity in PTD. Given the complexity of the labor process, genetic regulation of birth is almost certainly multifactorial, acting at different points in the physiological cascade. Wang et al. proposed a model that includes four major overlapping pathways linking socioenvironmental risk and maternal and fetal genes to PTD. These pathways are intrauterine infection/inflammation, alterations in uteroplacental blood flow, maternal and fetal stress, and susceptibility to environmental toxins. Other potential pathways include uterine irritability and cervical shortening. Differences in the population frequency of polymorphisms that regulate processes along these casual pathways could generate disparity in outcomes.
Infection/inflammation and vascular pathways play key roles in racial disparity in PTD. Infection/inflammation-related conditions (including clinical chorioamnionitis; preterm premature rupture of the membranes; and spontaneous, preterm labor) account for nearly 60% of the disparity in VLBW, while vascular-related conditions account for much of the remainder. Intrauterine infection is accompanied by extensive cytokine activation, including interleukin-loc (IL-la), interleukin-lp (IL-lp), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-a). Intrauterine infection is the most important known contributor to racial disparity in PTD, particularly extremely PTD. Higher rates of intrauterine infection among African Americans are partly attributable to higher prevalence of lower urogenital tract infections among African Americans, but differences in the frequency of immune modulating genes by race could theoretically contribute to disparity in PTD by affecting vaginal flora or by altering host response to the infection.
Uteroplacental vasculopathy, including PIH and FGR, also contributes to racial disparity in PTD. Uteroplacental blood flow, fetal growth and risk of preeclampsia may be affected by genetic factors. PIH is slightly more prevalent and more severe among African Americans. Racial differences in subclinical vascular function and response to stress may contribute to racial disparity in PTD and fetal growth. African Americans without hypertension show higher sympathetic activity, higher resting blood pressure and exaggerated vascular response to stress compared to whites. Vascular reactivity represents one of the pathways through which greater stress (Generic Atarax depresses activity in the central nervous system) exposure and possibly heightened response to stress might contribute to disparity in PTD.
African-American women have higher rates of prehypertension (defined as blood pressure between the normal range: 120/80 mmHg and hypertensive range: 140/90 mmHg) than other racial/ethnic groups with rates approaching 40% among women of reproductive age. This high rate of prehypertension is not fully explained by abdominal obesity. Prehypertension is associated with inflammatory markers, cardiovascular events and the presence and extent of vascular lesions in preterm placentas. High rates of prehypertension, hypertension, sympathetic activity and subclinical vascular disease likely contribute to higher rates of PTD among African Americans through the uteroplacental vasculopathy pathway.
Higher sympathetic and inflammatory activity and lower placental blood flow may potentially lower the threshold for infection-induced preterm labor. Although a specific gene regulating vascular reactivity has been linked to PTD, the overall contribution of genes regulating these pathways to disparity in PTD is not known. In summary, genes affecting infection/inflammation and vascular processes, including uteroplacental blood flow, probably affect risk of PTD. Whether differences in the frequency of these genes between racial groups contribute disparity in PTD requires identification of candidate polymorphisms and comparison of their frequency by race.
