Hypertensive disorders of pregnancy are among the leading causes of maternal and neonatal morbidity and mortality worldwide.1 They constitute a clinical spectrum of conditions, including gestational hypertension, preeclampsia/eclampsia, and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Hypertensive disorders of pregnancy are etiologically heterogeneous, but they share overlapping clinical manifestations, risk factors, and perinatal outcomes.2 Women who develop and survive hypertensive disorders of pregnancy face future health complications including increased risk of vascular diseases and metabolic syndromes.3,4 Furthermore, the health of the child may be jeopardized because of intrauterine growth retardation, which frequently occurs from improper vascular endothelial development during placentation, systemic inflammatory response, and hypoxic conditions in the womb.3,5
Risk factors for hypertensive disorders of pregnancy identified to date include nulliparity, multifetal gestations, family history of preeclampsia, family history of cardiovascular disease, history of hypertensive disorders of pregnancy in prior pregnancies, obesity, higher maternal age, African race and ethnicity, and preexisting vascular or renal conditions such as chronic hypertension, pregestational diabetes, and nephropathy.4,6–10 Although the pathophysiology of hypertensive disorders of pregnancy remains unclear, it is well established that there is a genetic component influencing risk.4,5,7,11
Rates of hypertensive disorders of pregnancy vary by race and ethnicity, suggesting that genetic factors may be associated with risk. However, roles for sociodemographic and cultural factors cannot be dismissed. African American women of all socioeconomic backgrounds are reported to have a higher risk of preeclampsia and other gestational hypertensive disorders when compared with their non-Hispanic white and Hispanic counterparts.12–14 Latinas present higher rates of obesity, gestational diabetes, and insulin resistance compared with non-Hispanic white women, and they may progress more quickly from gestational hypertension to preeclampsia.14,15 Hypertensive disorders of pregnancy rates vary among diverse U.S. Latina populations, with some studies reporting higher rates than non-Hispanic white women15,16 and some reporting lower or comparable rates.12–15,17,18 Few studies have examined genetic and environmental risk factors associated with hypertensive disorders of pregnancy among Latinas.7,17
Latinos are a highly heterogeneous population in terms of sociodemographic characteristics, culture, and admixed genetic background. Additional diversity is introduced for foreign-born Latinos who differ in their acculturation and their countries of origin. At least three distinct racial/ethnic groups contribute to the admixed Latino gene pool: European (white), African, and Native American, with admixture proportions varying widely among countries depending on the history of migration patterns.19,20 These sources of heterogeneity may modify or confound the effects of hypertensive disorders of pregnancy risk factors among Latinas; therefore, consideration of these factors and the complex interaction among ancestry, culture, and environmental risk factors are essential for fully understanding hypertensive disorders of pregnancy risk among this growing population.19–21 We address this issue by examining the role of genetic ancestry and environmental risk factors among self-identified Latinas in a case-control study of hypertensive disorders of pregnancy in Los Angeles County.
Selection of Cases and Controls
As previously described,22,23 patients with hypertensive disorders of pregnancy (cases, n = 136) and patients without hypertensive disorders of pregnancy (controls, n = 169) were recruited retrospectively from delivery logs at the Los Angeles County + University of Southern California Women’s and Children’s Hospital from 1999 through 2006 (87 cases and 16 controls) and during their postpartum hospital stay from 2007 through 2008 (49 cases and 153 controls). Only women who identified as Hispanic or Latina and women who reported that they and their parents come from a country of Hispanic origin were eligible for this analysis (125 cases and 161 controls).
Detailed chart abstraction was performed to confirm diagnoses and characterize cases as well as to verify the absence of demonstrable hypertension among the controls. Preeclampsia was defined as blood pressure ≥140 (systolic) or ≥90 (diastolic) on two or more occasions at least 6 hours apart, in addition to proteinuria ≥300mg/dl in a 24-hour urine collection or +1 on a dipstick in women who were normotensive in early pregnancy (<20 weeks gestation).24 Severe preeclampsia was defined as blood pressure ≥160 (systolic) or ≥110 (diastolic) on two or more occasions at least 6 hours apart plus proteinuria ≥500mg/dl in a 24-hour urine collection or +3 on a dipstick. Gestational hypertension was defined as increased blood pressure (mild or severe, as defined above) without evidence of proteinuria. Eclampsia was defined as any hypertensive disorders of pregnancy accompanied by seizure in a woman without history of a seizure disorder. HELLP syndrome was defined as follows: (1) evidence of hemolysis (abnormal peripheral smear or lactate dehydrogenase levels ≥600); (2) alanine aminotransferase or aspartate aminotransferase levels ≥70 or both, and (3) platelets ≤100,000. Women with two of the three signs of HELLP syndrome were considered as having “partial HELLP syndrome.” Women with lupus, chronic renal disease, multiple gestation, or sickle cell disease/trait were excluded because the underlying etiology of hypertensive disorders of pregnancy in these women may differ.
All cases were initially diagnosed with preeclampsia by the attending physician. A maternal-fetal medicine specialist or fellow was on-site during all deliveries and aided in case diagnosis. Based on chart review, 39 of the 125 cases on did not have evidence of proteinuria and were thus reclassified as gestational hypertensive. Preeclampsia or eclampsia was diagnosed in 78 women; 6 were diagnosed with HELLP or partial HELLP and 2 with preeclampsia superimposed on chronic hypertension; 74% of women with gestational hypertension in this study had (1) signs/symptoms of more advanced disease, including increased liver enzymes, uric acid, or lactose dehydrogenase or decreased platelets for both; (2) symptoms of preeclampsia including headache, right upper quadrant pain, epigastric pain, or visual disturbances; or (3) a history of preeclampsia in a previous pregnancy. These signs and symptoms suggested that although nonproteinuric, the women had other criteria associated with preeclampsia but not currently part of the standard definition.23 Recently, the significance of proteinuria has been challenged as an essential criterion for preeclampsia (because it does not correlate well with clinical outcome), and an alternative menu of signs and symptoms in addition to hypertension has been suggested.25
Each participant completed an in-person questionnaire administered by a trained interviewer collecting information on demographic variables; pregnancy; medical history; reproductive history; lifestyle habits such as smoking (active/passive), alcohol use, supplement/medication use, and physical activity; and family history of hypertension, heart disease, kidney disease, cancer, blood clot/stroke, liver disease, and thyroid disease. The questionnaire was adapted to the Latino community,22 and women were given the choice of a Spanish or English version.
This study was approved by the University of Southern California Health Sciences Campus Institutional Review Board. All participants signed informed consent. Parental permission for participation was obtained for pregnant patients younger than 18 years of age at the time of recruitment.
Blood, mouthwash, buccal swabs, or saliva samples were collected from participants for DNA extraction (Oragene, DNA Genotek). DNA extraction from mouthwash specimens was completed using a phenyl-chloroform protocol,26 from buccal swabs and buffy coat using QIAamp DNA Mini kits (Qiagen, Valencia, CA), and from saliva samples using ethanol precipitation using the manufacturer’s protocol (DNA Genotek, Ottawa, Ontario, Canada).
Genotyping for Ancestry Informative Markers
A panel of 106 biallelic ancestry informative markers that distinguish European, African, and Native American ancestry was used to estimate genetic ancestry. The characteristics of this established panel of ancestry informative markers have been reported in previous studies.27,28 These selected markers are widely spaced throughout the genome, distributed well throughout the 22 chromosomes, and have large differences in allele frequencies among the ancestral populations (δ > 0.5) and therefore maximize the information acquired for more than one ancestral population pairing.27 Simulations show that ~100 markers are required to provide ancestry estimates that have correlation coefficients of >0.90 when compared with true ancestry.29 Allelic frequencies for the ancestral populations were obtained from a panel that included 42 Europeans (Coriell’s North American Caucasian panel), 37 West Africans (nonadmixed Africans living in London, UK, and South Carolina) and 30 Native Americans (15 Mayans and 15 Nahuas). Genotyping was performed at the Children’s Hospital Oakland Research Institute (Dr. Beckman’s laboratory) using a multiplex PCR coupled with single-base extension methodology with allele calls using a Sequenom analyzer. Further details of the ancestry informative markers genotyping platform used have been previously published.21 The average call rate was 95.8%. Removing eight markers that had call rates <90% increased the call rate to 97.7%.
Estimates of European, African, and Native American (Amerindian) genetic ancestry for each woman were obtained using 98 ancestry informative markers and the program STRUCTURE v.2.3.2. We ran STRUCTURE assuming genetic admixture occurring ~10 generations back30 with a prior that was set to assume independent allele frequencies among populations. To ensure convergence to the posterior distribution, 50,000 Markov Chain Monte Carlo replications were used after a burn-in length of 10,000.
Characteristics of cases and controls were compared using the Student’s t test for continuous variables and Fisher’s exact tests for categorical variables. We created composite variables for the participant’s personal and family histories of cardiovascular diseases such as chronic hypertension, heart disease, and blood clot/stroke with the following categories: no family history; at least one of these three conditions; and at least two of these conditions. A composite birthplace variable was created to capture the birthplace of the participant and her parents (participant parents): Mexico/Mexico; United States/Mexico; El Salvador/El Salvador; Guatemala/Guatemala; United States/Guatemala; United States/El Salvador; and Other country/Mexico. None of the participants had parents born in the United States. Because most of the women in the study population were Mexican-born Latinas with parents born in Mexico as well (n = 193), analyses were also performed and reported separately for this group.
In the initial analyses, we categorized each ancestry into quartiles based on the distribution among controls. Logistic regression was used to examine the relationship between ancestry and hypertensive disorders of pregnancy risk. Because the proportion of European, Native American, and African ancestry add up to 1, at most two ancestry variables can be used to characterize the genetic background of each woman. Furthermore, because European and Native American ancestry were highly inversely correlated (correlation coefficient = −0.88), only European and African ancestry were included in the models.
The following variables were included in the analysis to improve precision of the estimates, based on their possible or known role as risk factors for hypertensive disorders of pregnancy, and were included in the final model: age of participant at interview, prepregnancy body mass index (BMI), family history of preeclampsia (yes/no), nulliparity (yes/no), and composite variable for family history of cardiovascular diseases. Other precision variables considered but not included in the final model were as follows: family history of diabetes (yes/no); family history of any cancer (yes/no); participant’s personal history of diabetes (yes/no); and participant’s personal history of cardiovascular disease (composite variable), participant’s education level (seventh grade or less; completed eighth grade; 9–11 years [some high school]; high school diploma or equivalent [GED]; some college and higher), and household annual income (<$20,000; $20,000–$34,999; $35,000–$99,999; do not know/refused to answer).
Prepregnancy BMI (kg/m2) categories were based on cutoffs from World Health Organization classifications of BMI (adults with a BMI <23 are considered normal; ≥23 to <25 is considered within normal limits but potentially approaching overweight; a BMI of ≥25 to <30, overweight or preobese; and ≥30, obese).31 There were 10 women who did not have height information; the average of the heights of the study population was used to calculate the prepregnancy BMI for these women. The composite birthplace variable and birthplace of participant’s parents were considered potential confounders because they were associated with both genetic ancestry and hypertensive disorders of pregnancy among controls. However, they were not included in final models because their inclusion did not alter risk estimates >10%. A separate category was created for missing data for categorized variables with missing information. We performed sensitivity analyses excluding these categories.
To explore potential nonlinear relationships between ancestry and hypertensive disorders of pregnancy risk, we ran a second set of analyses using generalized additive models that extend generalized linear models to allow nonlinear functions of the covariates.32 Specifically, covariates enter the regression model as additive smoothing splines, whose degree of smoothness is determined by the data using cross-validation. We ran logistic regression generalized additive models with ancestry covariates entered as smoothing splines of the ancestry proportions. We evaluated additive effects of each ancestry and effects produced by the conjunction of two ancestries. This analysis included the same potential confounders used in the unconditional logistic model above.
We computed both crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Statistical analyses were performed using STATA 11 (StataCorp. 2009; Stata Statistical Software: Release 11, College Station, TX: StataCorp LP) and R (V2.11.1; http://www.R-project.org).
Table 1 shows the key demographic and other characteristics for women in our study. Cases were more likely than controls to report family history of preeclampsia, family history of at least one or two types of cardiovascular diseases, previous pregnancy affected by hypertensive disorders of pregnancy, and nulliparity before the birth.
Association Between Genetic Ancestry and Hypertensive Disorders of Pregnancy Risk
When considering each genetic ancestry component individually, cases showed higher European genetic ancestry and less Native American genetic ancestry than controls (Table 1). African ancestry was higher among cases than in controls, particularly among Mexican-born women with parents from Mexico (Mexico/Mexico).
When simultaneously examining European and African ancestry components (Table 2), we observed a U-shaped association between European genetic ancestry and risk of hypertensive disorders of pregnancy and a positive association between African ancestry and risk. The association between African ancestry and hypertensive disorders of pregnancy was slightly stronger when further adjusting models for age, nulliparity, prepregnancy BMI, family history of preeclampsia, personal history of hypertensive disorders of pregnancy, and family history of cardiovascular disease (for >7.2% vs. ≤2.3% African ancestry: OR = 2.6, 95% CI = 1.1–6.1).
Analyses were further done separately for each of the two main categories of hypertensive disorders of pregnancy (preeclampsia/eclampsia and gestational hypertension) compared with controls. The risk of preeclampsia/eclampsia (n = 77) was positively associated with higher proportion of African ancestry (highest quartile OR = 2.8 [95% CI = 1.1–7.6]). Similarly, the risk of gestational hypertension (n = 39) was also positively associated with higher proportion of African ancestry (highest quartile OR = 2.4 [0.6–9.0]) (data not shown). When further restricting analyses to women who were born in Mexico and whose parents were born in Mexico (Mexico/Mexico), increasing African ancestry was positively associated with risk of any hypertensive disorders of pregnancy (for >7.2% vs. ≤2.3% African ancestry, 4.3 [1.4–13]). Sensitivity analyses excluding women with missing information for any of the included variables did not change associations or magnitude of estimates.
Risk of hypertensive disorders of pregnancy increased linearly with increasing African and European ancestries, modeled jointly using generalized additive models and adjusting for potential confounders. Our models suggested that risk of hypertensive disorders of pregnancy may increase as Native American ancestry decreases and is displaced by European and African ancestries jointly. These results were seen among all Latinas in the study and in the “Mexico/Mexico” groups (Fig.). African ancestry showed a stronger positive association with risk in the “Mexico/Mexico” category, in both logistic regression analyses and the generalized additive model when taking European ancestry into account (data not shown).
Risk Factors Considering Genetic Ancestry
Table 3 shows the association between characteristics and Native American genetic ancestry among controls. Among women in the highest Native American ancestry quartile (>77%), 84% were born in Mexico compared with only 59% in the lowest quartile (0–48%). Most women born in the United States were in the lowest quartile of Native American ancestry (32%, compared with 8% in the highest quartile). Although numbers were low, women with the lowest Native American ancestry had the highest percentage of personal history of cardiovascular disease (10%, compared with 5% in the highest ancestry category).
Associations between hypertensive disorders of pregnancy and nongenetic risk factors did not greatly change when adjusted for genetic ancestry, suggesting that genetic admixture is unlikely to confound these associations. The analysis of interactions of ancestry with risk factors was limited by low numbers. Prepregnancy BMI seemed to be associated with hypertensive disorders of pregnancy only among women with higher African ancestry.
The panel of ancestry informative markers was selected simply for its ability to discriminate among Native American, European, and African ancestries. We performed additional analyses to confirm that the association with ancestry was not driven by any particular marker. We analyzed all single-nucleotide polymorphisms in our ancestral informative markers panel for association with the outcome, using models that adjusted for precision variables, confounders, and genetic ancestry, and using appropriate corrections for multiple testing (ie, a Bonferroni adjustment of the P value). We did not find any evidence of associations (data not shown).
To rule out the possibility that interactions with ancestry are driven by a specific interaction of a single-nucleotide polymorphism with environment, we analyzed each individual marker in our panel and environmental factors (prepregnancy BMI, family history of preeclampsia, family history of diabetes, family history and personal history of cardiovascular disease, family history of cancer, nulliparity, and income). We did not find evidence of any interactions of single-nucleotide polymorphisms and environment (data not shown).
Investigation of the lifestyle, cultural, and genetic heterogeneity of Latina populations in the United States may help explain inconsistent reports of hypertensive disorders of pregnancy rates among Latinas. Our study uses genetic markers to assess the diverse racial admixture of Latinas to determine whether differences in genetic ancestry are associated with hypertensive disorders of pregnancy risk. The results suggest that an increased proportion of both European and African ancestries may be associated with higher risk of hypertensive disorders of pregnancy among Latinas. Alternatively, an increase in Native American ancestry seems to be protective.
Our finding of an association between increasing African ancestry and risk of hypertensive disorders of pregnancy is consistent with reports showing African American women with the highest rates of hypertensive disorders of pregnancy in the United States. Researchers have reported that higher African ancestry is associated with higher risk of preterm delivery alone and preterm delivery complicated by hypertensive disorders of pregnancy.33 African Americans are primarily of African and European genetic ancestry.34 The joint effect of European and African ancestral components in association with risk of hypertensive disorders of pregnancy among our Latina population may also play a role in risk for African American women.
The observed association between African and European ancestries and hypertensive disorders of pregnancy risk could reflect the presence of susceptibility alleles in the African and European ancestral populations or ancestry could be a proxy for other factors correlated with ancestry, such as sociodemographics, culture, and lifestyle. In particular, we considered the fact that our study included both U.S.-born and immigrant Latinas. Exploratory analyses stratifying immigrant Latinas based on time of immigration showed a stronger association between risk and increasing African ancestry among women who migrated 10 years or more before their baby’s birth. Although limited by small numbers, these preliminary findings may suggest a role for acculturation in risk. Because there are likely unmeasured cultural and environmental factors, we cannot rule out the possibility that African and European ancestries may be acting as proxies for other factors that deserve further investigation.
The displacement of European and African ancestries with increasing Native American ancestry among our Latina population was associated with a decrease in risk of hypertensive disorders of pregnancy. However, hypertensive disorders of pregnancy have not been as carefully studied among Native Americans as in other U.S. ethnic groups. The increasing incidence of these disorders in the Southwestern Navajo population has been associated with obesity and diabetes.35 The increasing incidence of these comorbidities35,36 might mask the true relationship between Native American ancestry and risk. Our results on the association between Native American ancestry and nongenetic factors for controls show that participant’s place of birth and their genetic ancestry may play a role. Other genetic evaluations of hypertensive disorders of pregnancy risk among Native Americans, across the Americas, adjusting for associated risk factors, would be needed to validate our study results.
A large proportion of women in our study are of Mexican descent. Mexican Americans constitute the largest proportion of U.S. Latinos (67%).37 As a group, the Mexican population has a relatively low average African ancestry (means of 0.04 [standard deviation = 0.03]38 and 0.03 [0.02]39 among Mexican-Americans). The increased risk of hypertensive disorders of pregnancy seen with small increases of African ancestry among Mexican Latinas raises a concern that the association might be because of errors in the estimation of the admixture proportions rather than to true differences. However, such errors in estimation are presumably nondifferential between cases and controls and would introduce bias toward the null.
Our study includes one of the largest populations of Latinas ascertained to study hypertensive disorders of pregnancy risk. Subjects were ascertained at a large hospital in Los Angeles County, home to a large and diverse population of Latinos in the United States. Extensive medical chart extraction allowed for reliable confirmation of diagnosis and ascertainment of patient medical history, prenatal care, and laboratory results recorded during the pregnancy. Careful evaluation of other markers of disease (increased liver enzymes, persistent headache, etc) was completed during chart review, which helped to better characterize the case population and demonstrate disease severity, even among those classified as having gestational hypertension. Finally, estimations of genetic ancestry proportions were acquired using a panel specifically designed for Latino populations.
Limitations include small numbers for stratified analysis by disorder subtypes and limited power to detect interactions. The inclusion of women with gestational hypertension is expected to bias the estimates toward the null; however, excluding them from the analysis did not substantially change the effect estimates. In addition, information of the genetic ancestry of fathers was not obtained in this study, although the majority were Latinos. Their genetic ancestry may be important if risk was jointly determined by genetic traits present in the mother and father, as proposed in previous studies.23,40
Genetic ancestry may yield valuable information about risk factors for hypertensive disorders of pregnancy among Latino populations. In particular, our results suggest a possible role for protective alleles present in the Native American ancestral population or a possible role for other protective factors that strongly correlate with Native American ancestry. Whether this association is explained mostly by genetic traits or by interaction between genetics and cultural or environmental factors remains to be demonstrated. Future investigation into risk factors among Latinas may benefit from considering genetic ancestry as a potential effect modifier.
We are grateful to the women and their children who participated in this study. We also thank Aida Lozada for recruiting most of the women in the study.
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