Genetic determinants of cardiovascular disease in Hispanics ...

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Compared with other population groups in the United States, epidemiologic data suggest that Hispanic Americans are at a disproportionate risk for CVD.
Genetic Determinants of Cardiovascular Disease in Hispanics Krista Casazza, PhD, RD, and José R. Fernández, PhD

Corresponding author José Fernández, PhD Department of Nutrition Sciences, University of Alabama at Birmingham, Webb 449A, 1530 Third Avenue South, Birmingham, AL 35294, USA. E-mail: [email protected] Current Cardiovascular Risk Reports 2009, 3:175–180 Current Medicine Group LLC ISSN 1932-9520 Copyright © 2009 by Current Medicine Group LLC

Cardiovascular disease (CVD) affects many people in the United States. Compared with other population groups in the United States, epidemiologic data suggest that Hispanic Americans are at a disproportionate risk for CVD. The etiology of this disparity is complex, with genetic, behavioral, cultural, and other environmental factors acting in an independent, interactive, and/or synergistic fashion. Because many complex conditions mediate risk of CVD, including diabetes, obesity, and hyperlipidemia, genes associated with these conditions have been considered as possible contributors to CVD in Hispanics. In addition, the diversity of background and heritage within this population creates a plethora of environmental determinants that interact with behaviors, cultural practices, and genetic makeup to influence disease risk. In this review, we explore the recent literature on genetic determinants of CVD and explain that effective efforts to reduce CVD disparities in Hispanics in the United States will require an understanding of the interactions of genes, the environment, and health-related practices.

Introduction As a complex condition, cardiovascular disease (CVD) is partially influenced by genes. Concordance in twin studies, clustering in families, and lifetime risk analyses [1–3] have supported a genetic predisposition to CVD. However, scientific evidence supports the influence of physiologic and socioenvironmental factors that independently or synergistically influence the development of this condition [4–6,7•]. Because these influences differ among individuals, it is not surprising that the prevalence of CVD differs according to racial/ethnic populations in the United States.

Research has demonstrated that Hispanic Americans are disproportionately affected by CVD relative to their European American counterparts. Evidently, these disparities in disease prevalence respond to the effect of genetic, physiologic, and socioenvironmental factors accounting for phenotypic variation among individuals. However, the genetic architecture of CVD has not been thoroughly examined in Hispanic Americans. Perhaps there are two major reasons for this lack of examination. First, there is a great deal of genetic, cultural, and environmental diversity among individuals categorized as Hispanics. Second, the interplay of physiologic aspects, genetic contributors, and environmental factors underlying CVD and related comorbidities (ie, obesity, hypertension, dyslipidemia, stroke, and diabetes mellitus type 2) is so complex that disentangling their effects becomes experimentally and statistically cumbersome. Regardless of these challenges, it is evident that an understanding of the complex actions and interactions between biologic and nonbiologic aspects of CVD is essential for elucidating the underlying mechanisms associated with its progression, particularly in diverse populations. Herein we critically evaluate the recent literature on genetic determinants of CVD in Hispanics, taking into account other factors that also may contribute to disease risk in this population.

Adiposity The footprint of many of the aspects of CVD is fi rmly embedded in obesity status. A major risk factor for the development of CVD may rely not only on excess fat accumulation but also, and possibly more importantly, on the distribution of the fat throughout the body. It is believed that storage of fat, particularly in the intraabdominal compartment, is more metabolically efficient than storage of energy as glycogen in muscle and liver [8]. Because intra-abdominal fat has been shown to have high metabolic activity in terms of both lipogenesis and lipolysis, its accumulation can impact cardiometabolic risk factors. Although Hispanic Americans have greater fat accumulation, specifically in the abdominal compartment [9,10•,11], the mechanisms driving fat accrual in this population are poorly understood. Genetic loci have been recently identified as contributors to adverse fat accumulation, linking adipose tissue and its secretory products to adverse cardiometabolic outcomes.

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Peroxisome proliferator activator receptor gamma (PPAR-γ), which is primarily expressed in adipose tissue, has received much attention because it is believed to be a pivotal regulator of adipogenesis due to its role in converting unspecialized cells to adipocytes. PPAR-γ is also involved in the control of energy balance and both lipid and glucose homeostasis. Negative regulation of adipogenic transcription factor(s) due to the action of PPAR-γ may be related to the accumulation of intra-abdominal adiposity. In Hispanics, several transcriptional factors have been identified as regulators of the PPAR-γ expression, but evidence of a relationship has not been established. An association between the Pro12Ala variant of PPAR-γ and obesity has been reported by several researchers in various non-Hispanic populations [12–14], but the results have been somewhat inconsistent in Hispanics. For example, Black et al. [15••] demonstrated that the Pro12Ala allele of PPAR-γ (present in about 10% of their sample of Mexican Americans) may play a role in obesity as well as the regulation of insulin sensitivity in Mexican Americans at risk for type 2 diabetes. Importantly, however, there was an observed difference in the effect of the polymorphism on two populations of Mexican Americans. In a study by Nelson et al. [16] evaluating fat accumulation and distribution in Hispanics from Colorado, no association was detected between possession of the Pro12Ala variant allele of the PPAR-γ and body mass index or waist circumference, even after controlling for diet and physical activity. Previously, in the San Luis Valley Diabetes Study [17], the C161T variant of PPAR-γ but not Pro12Ala was associated with obesity or metabolic outcomes in Hispanics. The authors therefore hypothesized that PPAR-γ variants may be in linkage disequilibrium with unidentified functional variations in PPAR-γ or in a linked gene. This may account for some of the inconsistencies in the Pro12Ala association studies, because allele frequency and linkage disequilibrium of other polymorphisms in the region could vary in different populations (even within the same ethnic group). It is also plausible that the differences in published associations of PPAR-γ in Hispanics could be attributed to the interaction of the polymorphism with different ancestral genetic backgrounds (genetic admixture) in the populations tested, particularly when taking into account the heterogeneity existing within Hispanics.

Lipid Profiles Although the relationship is highly plausible, the link between blood lipids and CVD has not been clearly established. Research has documented that fat accumulation results in aberrations in the lipid profi le via increased free fatty acid mobilization, increased free fatty acid flux to the liver, increased triglyceride concentrations, decreased high-density lipoprotein cholesterol, and decreased hepatic insulin clearance [18–22]. About half of the variability in these adverse lipid profi les is determined by genetic factors. Studies have shown that genetic polymorphisms that

affect the transcription of key enzymes involved in lipolysis and the release of fatty acids into circulation vary in frequency among populations. Several genes, such as the apolipoprotein A5 (APOA5), apolipoprotein B (APOB), apolipoprotein E (APOE), and cholesterol ester transfer protein (CETP) genes, and fatty acid binding protein (FABP2) have been reported to be related to the lipid profi les in African Americans and European Americans, but only APOA5, APOE, CETP, and FABP2 have been investigated in Hispanics. Studies in Hispanics have not been replicated and typically are limited by the heterogeneity of the Hispanic population. For example, Tsai et al. [23] genotyped several gene variants of the CETP gene and did not fi nd any association with lipid profi les among Hispanics from six US communities (or any other population). In another study that aimed to identify genetic determinants in Caribbean Hispanics, Liao et al. [24••] identified 19 single nucleotide polymorphisms at 10 genes that were significantly related to lipid profi les (P < 0.01), with the APOA5, APOB, and cytochrome p450 polypeptide 7A1 genes accounting for the largest proportion of variation in lipid profi les. Further, Martinez-Lopez and colleagues [25•] demonstrated in 114 obese Mexicans that the proportion of adverse lipid profi les with the T54 allele of the FABP2 gene was higher than that detected in the general population, indicating that a genetic predisposition due to a variant in the FABP2 gene may lead to a greater incorporation of fatty acids from the diet. Although evidence is only beginning to accumulate, there may be some indication of a genetic predisposition toward adverse lipid profi les in Hispanics; however, to what extent aberrations in the lipid profi le increase the predisposition to CVD risk warrants further investigation. Another plausible mechanism by which lipids could exert an effect on CVD is the accumulation of excess triglycerides in the liver. Long-term accumulation of liver triglycerides can in turn lead to nonalcoholic fatty liver disease, which is highly associated with CVD. Hispanics have a higher prevalence of the disorder than European Americans and African Americans. In a study to identify genetic contributions to nonalcoholic fatty liver disease, Romeo et al. [26] conducted a genomewide survey of nonsynonymous sequences using 2270 markers. Only one variant (PLPLA3 [rs738409]) was strongly associated with hepatic fat content. The frequency of the allele was the highest among individuals of Hispanic ancestry. The PNPLA3 variant also was associated with elevated serum alanine aminotransferase and aspartate aminotransferase concentrations in Hispanics only. These fi ndings represent interesting topics for investigators interested in exploring the relationships between lipid profiles and CVD.

Inflammation Inflammation, which consistently has been shown to play a role in the atherogenic process, contributes to CVD risk.

Genetic Determinants of Cardiovascular Disease in Hispanics

Higher levels of cytokines, or proinflammatory markers, have been associated with adiposity, suggesting a mediating of inflammatory markers in the association between adiposity and CVD development and progression. It is not clear whether variation in genes coding for inflammatory markers accounts for racial/ethnic differences in risks associated with body fat accumulation and CVD. Recent evidence in Mexican Americans shows an association between risk for CVD and C-reactive protein, an inflammatory marker closely associated with release of multiple cytokines from adipose tissue, particularly intra-abdominal adipose tissue [27]. C-reactive protein is one of many components of a low-grade acute-phase inflammatory response, and low-grade inflammation that accompanies cytokine release has been shown to contribute to impaired lipid and glucose homeostasis. More recently, leukotrienes have been implicated as an inflammatory component associated with atherosclerosis. The initial enzymatic step in the leukotriene pathway is the oxidation of arachidonic acid to leukotriene A4 by 5-lipoxygenase, which is encoded by the ALOX5 gene. The first study evaluating the role of ALOX5 in the atherosclerotic pathway in rodents was conducted by Assimes et al. [28,29•], and this was followed by a human study identifying a nearly perfect correlation with the ALOX5 variant and heart disease in Hispanic and European Americans. However, in an effort to replicate these findings, no association between polymorphisms of the ALOX5 pathway and CVD in Hispanic or European Americans was found. Nevertheless, it is evident that variations in inflammatory markers or in genes that regulate the inflammatory pathway may represent a direct or indirect causal relationship between fat accumulation, cardiometabolic perturbations, and genetic predisposition.

Diabetes Of all the comorbidities associated with cardiovascular conditions (ie, obesity, impaired lipid metabolism, inflammation), type 2 diabetes is the most highly correlated with CVD. Although it is not clear which precedes the other [30], progression of type 2 diabetes and insulin resistance clearly underlies the pathogenesis of CVD [31]. Over the past 2 years, genomewide association studies have led to the discovery of a number of genetic regions associated with type 2 diabetes in Hispanics. A genomewide scan revealed that fasting serum glucose mapped to a region on chromosome 13q, a region that previously has been identified as being associated with obesity and diabetesrelated phenotypes [32]. Data from 644 Mexican Americans revealed evidence of significant genetic influence on variation in insulin dynamics and a relationship between insulin action and CVD risk factors [31]. Linkage for insulin resistance was also identified on chromosome 12q24. The strongest of the associations with type 2 diabetes has been seen in the transcription factor 7–like 2 locus (TCF7L2) gene, but the relationship has been noted among predominantly European-derived populations.

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However, the few studies evaluating this region in Hispanics offer promising results. In an evaluation of previously associated variants with measures of glucose homeostasis in Hispanic Americans, Palmer et al. [33,34••] noted significant evidence of association between single-nucleotide polymorphisms of TCF7L2 variants and insulin secretion, suggesting a possible role for this gene in the pathogenesis of type 2 diabetes. Similarly, Watanabe et al. [35] demonstrated that TCF7L2 was associated with gestational diabetes and interacts with adiposity to alter insulin secretion in Mexican Americans. Lehman et al. [36] provided evidence that variation in the TCF7L2 genomic region may affect the risk of type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in European-derived populations. Another region of possible interest when exploring CVD risk in Hispanic Americans is chromosome 20q12. This region exhibited a logarithm of odds score of 2.8 with diabetes status and harvests a genotype–phenotype association with microalbuminuria [37], a condition with a higher prevalence in Hispanic Americans with type 2 diabetes. Due to the close relationship between type 2 diabetes and CVD, genetic association studies exploring the connection among genetics, Hispanic ethnicity, and type 2 diabetes are also relevant to the exploration of genetic contributors to the pathogenesis of CVD.

Behavioral Influences and Environmental Factors As a complex condition, CVD responds to environmental contributors as well as genetic factors. The level of diversity in individuals of Hispanic/Latino descent has been an understudied issue in this community. Hispanic Americans descend from various countries characterized by autochthonous dietary preferences, cultural differences, and behavioral practices. Scientific evaluation of this uniqueness is challenging, particularly because in many contexts the line that separates the defi nition between gene and environment is not clearly delineated. For example, it is generally accepted that food intake is regulated by the environment and occurs as a condition of learned behavior. However, this simplified view diminishes the substantial role of the central nervous system (CNS) in the regulation of food intake. The CNS responds to various afferent hormonal signals (eg, insulin, leptin) generated in proportion to adipose tissue mass. In addition, negative feedback from short-term signals is provided to the CNS by gut hormones (eg, ghrelin), influencing meal size and satiety. It has recently been confi rmed that there is a genetic influence to eating in the absence of hunger that may contribute to obesity and resultant adverse cardiovascular health. Fisher and colleagues [38] have provided evidence that eating in the absence of hunger among Hispanics is under significant genetic control, particularly in overweight Hispanic children. They suggested that the underlying common genetic pathways include hormonal signals to the CNS from insulin, leptin, and ghrelin.

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Interestingly, these fi ndings underscore the role of genetic susceptibility, particularly among certain racial/ethnic groups, on aspects related to CVD that have been traditionally viewed as environmental/behavioral practices controlled by an individual’s choices or will. Other studies also have indicated a genetic influence on physical activity in Hispanics, with estimates suggesting about 30% heritability [39]. A genomewide scan in the population identified a highly significant linkage signal on chromosome 18q that influenced sedentary behavior in Hispanic American children [40]. These results indicate that there is a genetic component to physical activity behaviors. Additionally, the region that was identified flanks the melanocortin 4 receptor (MC4R) candidate gene, which has been shown to influence CNS regulation of food intake [41]. Further understanding of the extent to which behavioral practices are mediated by genetic predisposition is paramount; it will significantly contribute toward the design of intervention strategies to fight CVD and its related comorbidities, particularly in populations that have been underrepresented in research. Limited data exist demonstrating a role of gene–environment interactions in CVD outcomes in Hispanic Americans. Of all CVD comorbidities, obesity is perhaps the most environmentally studied, and the definition of what type of “environment” is measured ranges from behavior to neighborhoods to family settings to schools. Of most hope are studies in children in which the environmental exposures are reduced in comparison with those of adults and the contributions of smoking and alcohol are minimized. Data from our ongoing study of multiethnic children 7 to 12 years old have shown Hispanic American children to have greater adiposity, higher fasting glucose levels, higher triglyceride concentrations, and lower highdensity lipoprotein cholesterol levels than their European American and African American counterparts [42]. When we preliminarily evaluated the contributions of perceived parental responsibility in children’s feeding practices among Hispanics, parents of Hispanic American children were more likely to exhibit parental encouragement of eating without hunger (P < 0.01) and less restriction of calorie-dense foods (P < 0.01). It is evident that parental involvement, which is considered an environmental influence, might have an impact on CVD risk that is initiated at early stages of development within members of the Hispanic community. The extent to which these environmental contributions might be influenced by a genetic predisposition to behavioral engagement needs further study. The influence of the environment on CVD risk factors has also been explored by considering migration patterns. Hispanics born in the Unites States are at higher risk for CVD disease mortality relative to native-born Hispanics and European Americans [43], suggesting that the increased prevalence and acceleration of metabolic and vascular complications of CVD in this group can be partly explained by recent socioenvironmental changes in lifestyle, particularly diet and physical activity. Lifestyle

patterns often differ substantially between Hispanic and other racial/ethnic groups, particularly among recent immigrants, and likely contribute to cardiac disease risks. This topic deserves exploration.

Genetic Ancestral Background The historical intermating of European colonizers with indigenous Americans and the occasional introduction of African slaves in some areas of Central and South America originated the multiple subgroups that constitute the Hispanic population. This intermixing of people translated into a great deal of variability of genetic ancestry among individuals of Hispanic descent. Therefore, accounting for such variability in genetic background is relevant for the proper understanding of genetic contributors to CVD and avoiding the cost of false positives due to population stratification in genetic association studies. Ancestry informative markers have been used to obtain estimates of genetic admixture among Hispanic individuals, and recent research has shown that within this category there is great variability of ancestry [44,45••]. Differences in genetic makeup may not confer an identical risk of disease in all populations, and research has demonstrated associations of genetic ancestral background with outcomes related to CVD, such as diabetes [46] and obesity-related concerns [44,47] in Hispanics. Preliminary data from our laboratory suggest that, when analyzed according the genetic admixture, total and intra-abdominal fat accumulation is significantly greater in children with greater proportions of Native American genetic admixture. Based on studies evaluating the role of admixture ancestry in genetic associations [45••,48], it appears that some if not all of the lack of replication of true genetic association in outcomes related to CVD among Hispanics may be due to the inability to detect the interaction between genetic polymorphism and ancestral background in this heterogeneous group.

Conclusions It is evident that the relationship between ethnicity, genetic variation, and environmental influences in health outcomes is complex, and CVD is no exception. In the Hispanic population, evidence supports a genetic predisposition to traits that confer CVD risk; however, the extent to which genes contribute to the heritability of CVD and the mechanisms underlying these contributions are not completely clear. The genetic evidence presented herein supports the notion that cumulative effects of multiple genetic variants could contribute to interindividual variability in CVD risk. As with every complex health outcome, the contributions of genes to this interindividual variation is triggered by environmental factors, many of which still need to be defi ned and identified. The diversity and heterogeneity of individuals categorized as Hispanics in biomedical research is evident. Many

Genetic Determinants of Cardiovascular Disease in Hispanics

of the studies addressing genetic influences in CVD have been conducted in Mexican or Mexican American populations. The need to explore the genetic and environmental determinants that account for such heterogeneity within Hispanics and, furthermore, the extent to which these determinants influence health outcomes is evident. At this point, the use of ancestry informative markers and admixture estimations as tools to account for the genetic aspects of Hispanic heterogeneity has proven to be effective and seems promising in overcoming issues of population stratification and genetic variability. This genetic admixture approach is promising in reducing the bias that accompanies the stereotypical classification of individuals, particularly those who belong to newly formed population subgroups. As members of the “traditional” racial/ethnic groups continue to intermix, individuals in the population will become more admixed and the commonality of the criteria underlying the identification of a “population” (particularly racial and/or ethnic) will become less defined. The study of health disparities has relied in part on the commonality of social and cultural factors shared by individuals self-categorized into racial/ethnic groups. In moving toward the understanding and eradication of disparities in disease risk, it is imperative to develop experimental designs that carefully study the factors underlying these disparities. In an era in which genotyping has become widely accessible, it is evident that understanding the complexity of the interrelationship between the environment and genetic variation in Hispanics and other underrepresented groups is paramount toward the reduction of CVD in the Hispanic population.

Acknowledgment This work has been supported in part by National Institutes of Health grants R01-DK067426, P30-DK56336, and M01-RR-00032.

Disclosure No potential confl icts of interest relevant to this article were reported.

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