Current Opinion in Lipidology:
Genetics and molecular biology: Edited by Jose M. Ordovas and E. Shyong Tai
Hypoalphalipoproteinemia in populations of Native American ancestry: an opportunity to assess the interaction of genes and the environment
Aguilar-Salinas, Carlos Aa; Canizales-Quinteros, Samuelb; Rojas-Martínez, Rosalbac; Mehta, Roopaa; Villarreal-Molina, Ma Teresab; Arellano-Campos, Olimpiaa; Riba, Laurab; Gómez-Pérez, Francisco Ja; Tusié-Luna, Ma Teresab
aDepartamento de Endocrinología y Metabolismo del Instituto Nacional de Ciencias Médicas y Nutrición ‘Salvador Zubirán’
bUnidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México
cInstituto Nacional de Salud Publica, Cuernavaca, Morelos, México
Correspondence to Carlos A. Aguilar-Salinas, Departamento de Endocrinología y Metabolismo del Instituto Nacional de Ciencias Médicas y Nutrición ‘Salvador Zubirán’, Vasco de Quiroga 15, Mexico D.F.14000, México Tel: +52 55 55133891; fax: +52 55 55130002; e-mail: firstname.lastname@example.org
Purpose of this review: Our aim is to review the environmental and genetic factors associated with hypoalphalipoproteinemia in populations of Native American ancestry. We examine the strength of the association and outline the population-specific genetic factors that lead to a higher susceptibilty for this condition.
Recent findings: Low HDL is the most common lipid abnormality in populations of Native American ancestry. Population-based surveys carried out in Latin America and in Mexican Americans shows that 40–60% of adults have hypoalphalipoproteinemia. The contribution of this trait to the metabolic syndrome is greater in individuals with Native American ancestry than in other ethnic groups. Several environmental factors have contributed to this phenomenon (i.e. high dietary content of carbohydrates and fat due to cultural factors and a growing incidence of obesity). In addition, results from recent genetic studies show that certain hypoalphalipoproteinemia susceptibility alleles are ethnic specific for Native Americans. The variant R230C of the ATP-binding cassette transporter subfamily A member 1 gene (ABC-A1) is common among mestizos (10.9% in Mexican mestizos) and its presence has a significant negative effect on HDL cholesterol levels (−4.2%). An additional noteworthy finding is that the R230C variant appears to be specific for the Amerindian populations. Its allele frequency is 0.28 in Mayans, 0.214 in Purepechas, 0.203 in Yaquis and 0.179 among Teenek. In contrast, the C230 allele has not been found in African, European, Chinese or South Asian populations.
Summary: The assessment of the genetic and environmental determinants of hypoalphalipoproteinemia in populations of Native American origin provides an opportunity to assess the population-specific interactions between genes and the environment
Among ethnic groups, there are notable differences in the prevalence of hypoalphalipoproteinemia (defined as HDL cholesterol <40 mg/dl) . Asians and Indigenous American populations consistently have the lowest concentrations of HDL cholesterol both in population-based surveys and in cross-sectional studies. Hispanics are the fastest growing minority in the USA; from 1990 to 2000 this population increased by 58%, more than four times the national average of 13% . Hispanics will constitute up to a quarter of the US population by the year 2050. This ethnic group has a higher prevalence of diabetes, incidence of stroke and premature cardiovascular death than other populations . In this review, we examine the evidence regarding the increased susceptibility of Hispanic populations for hypoalphalipoproteinemia and discuss the contribution of genetic factors for this phenotype. The Native American ancestry of Hispanic populations provides an opportunity to assess the population-specific interactions between genes and the environment.
The epidemiological evidence
In the Global Burden of Disease Study, 31% of all deaths in 2000 in Latin American countries were attributed to cardiovascular diseases. The WHO predicts that the cardiovascular mortality rate in Latin America will increase by more than 60% between 2000 and 2020; in the developed world this figure is estimated to be 5% . In the USA, cardiovascular mortality is the leading cause of death in Hispanic men and women . The same is true for various Latin American populations . The association between atherogenic dyslipidemias (evaluated by the ratio apolipoprotein B/apolipoprotein A-I) and cardiovascular events has been confirmed in Latin American individuals ; the strength of the relationship is similar to that found in other areas of the world [8•]. Several groups have recognized that the expression of lipid abnormalities in Hispanics differs when compared with other ethnic groups [9,10]. Hypoalphalipoproteinemia is the most frequently found cardiovascular risk factor and its prevalence is higher than that seen in non-Hispanic individuals living in the same environment. The most recent NHANES data (1999–2002) show that the mean HDL cholesterol levels were lowest in Mexican Americans (45 ± 0.39 mg/dl in men and 52.9 ± 0.47 mg/dl in women) than in any other ethnic group . This difference was 5.6 mg/dl compared with non-Hispanic Blacks and 2.3 mg/dl compared with non-Hispanic Whites. The difference remains statistically significant among women (but not men) of different ethnic groups after adjusting for age. The low-HDL cholesterol levels reported in Hispanics in NHANES 1999–2002 are in accordance with the findings of NHANES 1988–1994. The same phenomenon has been reported in the US studies involving Hispanic adults and elders. In both the San Luis Rio Valley Study and the San Antonio Heart Study, lower HDL cholesterol levels were found in Mexican American participants compared with Caucasian controls [12,13]. Bermudez et al.  reported the same observation when comparing 490 Hispanic and 163 non-Hispanic White elders. The HDL cholesterol concentrations were statistically lower in Hispanics even after adjusting for age, sex, years-of-education, smoking status, waist circumference, BMI, and use of antihyperlipidemic drugs. A summary of several studies that have reported mean HDL cholesterol levels in adults from different ethnic backgrounds is shown in Table 1. Thus, hypoalphalipoproteinemia appears to be a phenotypic trait associated with Hispanic ethnicity.
The susceptibility of Hispanic populations to hypoalphalipoproteinemia has been detected in several Latin American population surveys. The prevalence of low HDL cholesterol has been described in two Mexican population-based surveys [19,20]. The National Survey of Chronic diseases (1993–1994) included results from 15 607 adults aged 20–69 years from 417 cities in Mexico . Of the 2256 individuals who provided fasting blood samples, the mean concentration of HDL cholesterol was 38.3 ± 9.5mg/dl. Close to 50% of the study group (58.8% in men and 40.8% in women) were found to have hypoalphalipoproteinemia (HDL cholesterol <35 mg/dl). If the low HDL cholesterol is defined as a concentration below 40 mg/dl in both genders, this figure jumps to 61%. Sixty-two percent of those with low-HDL cholesterol had hypertriglyceridemia (>150 mg/dl) and the remaining 38% had isolated hypoalphalipoproteinemia. These results were replicated in a second population-based survey carried out six years later. The Mexican National Health USA Survey (2000) included results from approximately 44 000 individuals over the age of 20  from both urban and rural regions. Of these, 2351 persons provided fasting blood samples for lipid analysis. Here again the mean concentration of HDL cholesterol was low, 38.4 mg/dl (95%CI = 37.2, 39.5). Hypoalphalipoproteinemia (HDL cholesterol <40 mg/dl) was the most prevalent dyslipidemia, present in 64.7% (95%CI = 58.7–70.8) of women and 61.4% (95%CI = 54.4–68.3) of men. Remarkably, the prevalence of hypoalphalipoproteinemia was not significantly different between adults living in rural or urban settings (for women 63.1 vs. 66.3%, for men 59.2 vs. 63.7% respectively).
The prevalence of hypoalphalipoproteinemia in Mexican adults is higher than that found in Caucasians. Using 1999–2000 NHANES data, with less strict thresholds (as defined by the National Cholesterol Education Program (NCEP) less than 40 mg/dl for men and <50 mg/dl for women), hypoalphalipoproteinemia was present in 36.6 and 43.4% of Hispanic men and women, respectively . Even higher percentages have been found in studies from the UK and the Netherlands [26,27]. The high figures reported for Mexico have only been superseded by the estimates reported for an urban cohort in Turkey (82% of men and 50% of women using the NCEP criteria).
The findings of the two Mexican National Surveys coincide with the results of the Mexico City Diabetes Study. In 1990–1992, 2282 adults (aged 35–64 years) from six low-income neighborhoods in Mexico City were enrolled in this study. Follow up results for the period 1997–1999 (n = 1754) have been published . The prevalence of low-HDL cholesterol (<40 mg/dl in men and <50 mg/dl in women) increased from 88.6% (95%CI 86.3–90.5) to 92.1% (95%CI 89.9–93.9) in men and from 94.4% (95%CI 92.9–95.5) to 96.6% (95%CI 95.3–97.5) in women. In addition, the cardiovascular risk profile of individuals in the 1990–1992 Mexico City Study has been compared with that of the Mexican-American participants in the San Antonio Heart Study . Individuals from Mexico City had significantly lower HDL cholesterol (P < 0.001) and higher triglyceride levels (P < 0.001) than their Texan counterparts. These results probably reflect differences in dietary habits between the two populations; the Mexico City inhabitants consuming a diet lower in fat but higher in carbohydrates. This highlights the influence of environmental factors on the expression of a particular genetic trait.
Surveys carried out in other Latin American countries are in accordance with the increased susceptibility of Hispanic individuals for low-HDL cholesterol and metabolic-syndrome traits. Studies performed in Colombia , Venezuela , Argentina , El Salvador , Brazil  and simultaneously in seven Latin American cities [34•], primarily to measure the prevalence of the metabolic syndrome, have reported a high prevalence of hypoalphalipoproteinemia. In particular, a Brazilian population-based study measured the prevalence of diabetes and related-risk factors among 1494 adults (18–59 years) living in the small community of Bambuí : using the NCEP criteria, a prevalence of 50% was reported.
Hence, low-HDL cholesterol is common in Hispanic populations. Clearly, further population-based studies and national surveys are necessary, especially as Latin American populations are undergoing an epidemiological transition [35•].
Factors influencing low-HDL cholesterol in Hispanic populations
The high prevalence of hypoalphalipoproteinemia encountered in Hispanics is a result of the interaction of environmental and genetic factors. On average, US Hispanics have lower intakes of total fat and higher intakes of carbohydrates compared with the US Caucasians . The same is true for the food pattern reported in México and other Latin American countries [37•]. Furthermore, Hispanics have a high prevalence of obesity, hypertriglyceridemia and the metabolic syndrome traits, all of which have a negative effect on HDL cholesterol concentrations . These associations complicate the identification of an independent contribution of ethnicity to the pathogenesis of this condition. However, there are two observations that suggest that Hispanic ancestry predisposes to low-HDL cholesterol. Firstly, in the USA metabolic syndrome cases, Hispanics (especially women) are the group with the highest prevalence of hypoalphalipoproteinemia . The prevalence is higher still in Mexican adults; in the Mexico City Study, hypoalphalipoproteinemia is a constant feature of the metabolic syndrome (men 88.6% and women 94.2%). This percentage is significantly greater than that found in Caucasians from San Antonio (58.4%) and from Spain (30.8%) . Secondly, 18.6% of Mexican adults have isolated hypoalphalipoproteinemia, a condition in which low-HDL cholesterol is not related to hypertriglyceridemia. The prevalence in young men (23.1%) is similar to that observed in men aged 50–59 years (26.5%). In addition, 43% of this group are lean and without markers of insulin resistance . These two observations endorse the search for a genetic predisposition for low-HDL cholesterol in this population.
The term Hispanic refers to people born in a country that was ‘conquered’ by Spaniards and for whom Spanish is the mother tongue . Significant genetic (in particular variability in genetic admixture) and cultural diversity is evident in this ethnic group. Even the Native American ancestry cannot be considered a homogeneous genetic background . However, if a genetic predisposition for hypoalphalipoproteinemia exists, it should be associated with the Native American heritage. Several groups have studied the lipid profile of American Indians from Canada, the USA, México and South America [42–44]. Most reports found low mean HDL cholesterol levels in these groups living in their natural settlements. However, a remarkable increment (∼31%) in HDL cholesterol occurs when they are exposed to a high-fat diet (from 32 to 42 mg/dl), as have been reported in Tarahumara and Pima Indians . More recent reports including indigenous populations living in Northern Mexico have found a high prevalence of hypoalphalipoproteinemia (53.8% in men and 39.5% in women, using the NCEP criteria) . This data supports the contention that the susceptibility for hypoalphalipoproteinemia in Hispanics may come from their Native American heritage.
HDL-genetic studies in hispanics
Twin studies suggest that close to 50% of the variation of HDL cholesterol levels are genetically determined . More than 50 genes have been reported to be associated with HDL based on human and animal studies . The genes encoding apolipoprotein AI, lecithin:cholesterol acyltransferase, cholesterol ester transfer protein, hepatic lipase and the ATP binding cassette protein A1(ABCA1) are key players in HDL metabolism and variations of these genes have been shown to alter HDL cholesterol levels . The number of identified loci and genes has recently increased as a result of the publication of five high-density genome-wide association studies [49•–53•]. However, the pathophysiological mechanism by which the majority of the genes and loci are linked with variations in HDL cholesterol levels remain unknown. Despite the large number of identified loci, the SNPs that meet the genome-wide level of significance, including the previously identified genes, explain only 5–8% of the interindividual variation in HDL cholesterol . Current knowledge of the genetics of HDL accounts for only a small fraction of the total-genetic contribution.
The evidence discussed earlier originates primarily from Caucasian cohorts. Hispanics have been included in only one of the five genome-wide scans cited earlier. The majority of the genetic studies including Hispanics or Native Americans have focused on other metabolic syndrome traits [55,56]. However, there are several reports describing loci that affect HDL cholesterol levels in Mexican-Americans and in kindred from Mexico [57,58]. Also, several groups have analyzed the effects of CETP, LPL, LIPC, ABCG5/G8 and APOC3 variants on HDL levels in multiethnic cohorts including Hispanics or Native Americans [59,60••].
Certain population-specific genes may alter the disease susceptibility of Hispanics by influencing lipid profiles, for example, the ϵ2 allele of APOE is very rare in Native American populations ; in Latin American cohorts, the prevalence of the ϵ2 allele is a marker of admixture with Europeans. A more noteworthy allele is the (Arg230Cys) variant of the ABC-A1 gene. Villarreal-Molina et al. [60••,61•] have shown that this variant is strongly associated with hypoalphalipoproteinemia in two different Mexicans cohorts. The R230C/C230C genotypes were significantly more frequent in the low HDL cholesterol (≤10 percentile of the Mexican population) than in the high HDL cholesterol group (≥90 percentile) (45 vs. 2.9%, P = 0.00006, P = 0.0005 after adjusting for admixture). Although the R230C variant has not been functionally tested, it is very likely that this change results in decreased activity of the transporter as supported by computer modeling. An additional finding was that the R230C variant appears to be specific for the Mexican Amerindian populations. The C230 allele had a frequency of 0.109 in mestizos; as expected, this was half the prevalence found in Mexican native groups (0.28 in Mayans, 0.214 in Purepechas, 0.203 in Yaquis and 0.179 among Teenek). In contrast, the C230 allele has not been found in African, European, Chinese, South Asian or Inuit populations. R230C seems to be exclusive for Amerindian and Amerindian-derived populations such as Mexican Mestizos. These results have been confirmed by Kooner et al. [49•]. The authors did a three-stage association study to identify genetic polymorphisms affiliated with metabolic syndrome traits. In stage 2, 900 SNPs were tested against HDL cholesterol in 4568 individuals from four cohorts: 859 European women, 1181 Indian Asian women, 1560 Mexican women and 968 Mexican men. For HDL cholesterol, nine SNPs were significantly associated with HDL cholesterol levels. Six of these were in or around the CETP gene, one was in the LPL gene, one was in the LIPC gene and one was a nsSNP in ABCA1 (rs9282541, Arg230Cys). This ABC-A1 variant was exclusively found in the Mexican cohort. Its presence has a significant negative effect on HDL cholesterol levels (−4.2%). We believe that this is a relevant finding that may be a result of a survival effect. This variant may be preserved in these populations because it provided some advantage in the past (i.e. allowing the cells to preserve cholesterol inside during times of famine). No similar phenomenon has been reported between an ethnic-specific variant and hypoalphalipoproteinemia.
Hypoalphalipoproteinemia is a common feature of Hispanic and Native American populations. The observations summarized here provide strong arguments for the inclusion of Hispanic and Native American individuals in future genome-wide scans. The assessment of the genetic and environmental determinants of hypoalphalipoproteinemia in populations with Native American origin provides an opportunity to assess the population-specific interactions between genes and the environment. This is a unique opportunity to do nutrigenomic studies, as these populations are undergoing an epidemiological transition. The high prevalence of the R230C allele of ABC-A1 in populations of Native American origin may be the result of a survival process (Fig. 1). However, after major changes in environmental factors, this variant may have become a susceptibility factor for hypoalphalipoproteinemia and possibly other metabolic traits and atherosclerosis.
The authors would like to express their gratitude to the collaborators that have participated in the ABC-A1 studies. Of special mention is the invariably stimulating collaboration with David Cox, PhD (Perlegen laboratories). We are also grateful to Ivan Dario Sierra MD and Nestor Caceres, MD for providing data (from Colombia and Salvador, respectively) for the preparation of this review.
Some of the research presented here was supported by grants from the Consejo Nacional de Ciencia y Tecnologıa (CONACyT) and by Dirección General de Asuntos del Personal Académico (DGAPA) of the Universidad Nacional Autónoma de México (UNAM).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 141–142).
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© 2009 Lippincott Williams & Wilkins, Inc.
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