Using genetic admixture analysis, we found that Hispanics in MESA are admixed with European, African and Native American ancestries and that the proportion of each ancestral group varies strikingly by country of origin, with Mexicans/Central Americans having the largest Native American component, Dominicans having the largest African component, and Puerto Ricans having the highest European component. Moreover, we found that cardiovascular and renal risk factor profiles differ by country of origin among Hispanic subgroups, with Mexicans/Central Americans having more truncal obesity, worse lipid profile, and the highest levels of albuminuria compared to Dominicans or Puerto Ricans, but lower prevalence of smoking. Differences observed among Hispanics subgroups greatly impact the association of Hispanic ethnicity and urinary albumin to creatinine ratio compared to whites, where Hispanic ethnicity was associated with significantly higher levels of albumin to creatinine ratio among Mexican/Central Americans and Dominican Hispanics but not Puerto Ricans. Most interestingly, we found that higher European ancestry may be associated with lower albuminuria, particularly among Puerto Ricans, and that Native American ancestry may, at least in part, be associated with higher levels of albuminuria among Hispanics.
Differences in the genetic ancestral component by country of origin have been documented in prior studies of Mexican-Americans and Puerto Ricans.13, 25, 31, 32
Our study extends these findings to other Hispanic subgroups in a large, community-based cohort in the United States. We found that the differences by country of origin are also apparent in risk factor profiles in MESA. Whether the differences in genetic ancestral component among Hispanic subgroups account for these observed differences is still unclear.30, 33
It is also possible that social, cultural and environmental factors may account for the differences observed in risk factor profile. Our findings have important implications for future epidemiological and genetic studies among Hispanics. Future analyses should take into account country of origin when studying Hispanic populations.
Our observation that Hispanics have higher levels of albuminuria than whites is consistent with prior reports.8, 9, 34
However, most national studies have focused on Mexican Americans.8, 9
Our study is the first to show that levels of albuminuria among Hispanics may vary by country of origin, and that these observed differences significantly impact the association of Hispanic ethnicity and albuminuria when compared to whites. Since albuminuria is a known important risk factor for adverse cardiovascular events and kidney disease progression,7
our findings highlight the importance of recognizing the heterogeneity of Hispanic subgroups. That is, future studies should be aimed at understanding whether different Hispanic subgroups have different risk of kidney disease onset, progression, and whether the mediators may vary by country of origin. Accurately describing Hispanic subgroups may aid in the understanding of the conundrum of lower CKD prevalence but higher ESRD incidence among Hispanics in the United States.
Our study is the first to report the association of genetic ancestry and albuminuria among Hispanics. The observation that European ancestry may be protective for albuminuria, particularly among Puerto Ricans, may suggest that alleles more commonly found in Europeans reduce risk of albuminuria. One study of Hispanics patients with systemic lupus erythematosus has suggested that differences in the frequency of lupus nephritis correlated with the relative proportion of non-European admixture.35
However, these findings may also be due to unmeasured environmental factors. For example, the fact that European ancestry was significantly associated with lower albumin to creatinine ratio among Puerto Ricans, but not among other groups, could be explained by differences in social or environmental factors unique to Puerto Ricans with higher European ancestry (i.e. diet, socioeconomic status, neighborhood, acculturation). Our findings that Native American ancestry may, at least in part, be associated with higher levels of albuminuria is also noteworthy. Native Americans in the United States have been reported to have over 20% prevalence of albuminuria.36
If higher Native American ancestry is associated with higher albuminuria among Hispanics, it is possible that genetic factors due to a common Native American ancestry may play some role in explaining this observation. The attenuation by measures of socioeconomics and comorbidities could suggest mediation of the pathway by these factors, confounding, or an important gene-environment interaction that was not elucidated in this study. The heritability of albuminuria among Mexican Americans with high degree of Native American ancestry has been shown in prior studies37
, and certain loci have been associated with albuminuria38
and other risk factors among Mexican Americans.39
These suggest that albuminuria may be a phenotype amenable to admixture mapping among Hispanics, a method that has proven fruitful among African Americans.21, 22, 40
However, these maps need to take into account the 3 ancestral populations among Hispanics.11, 41
The strengths of our study include a large, community-based, well characterized, multi-ethnic cohort. Participants were mostly healthy, had a wide age range, low rates of CKD, and had no known cardiovascular disease at study entry. Our study used 171 ancestry informative markers well selected for allele frequency differences between populations. Some error may still be present in the estimate, but prior studies have shown that accurate estimates may be obtained with 100 AIMS.42
However, our findings should be interpreted with caution given that we were likely limited by power in our subgroup analyses. In particular, Dominican and Puerto Rican subgroups were much smaller than Mexican/Central American, thus potentially biasing results toward the null. There may have also been some misclassification as we used self-reported country of origin for categorization into genetic groups. Although our study represents the major Hispanic subgroups in the United States (http://www.census.gov/population/www/socdemo/hispanic/reports.html
), most Hispanics were recruited from only three sites. Most Dominicans and Puerto Ricans were recruited from New York, while Mexicans and Central Americans were recruited in Los Angeles and Minnesota. Thus their characteristics may not be representative of the whole country. It is also possible that some Hispanics born in the U.S. may have parents from different countries of origin. However, the majority of MESA participants were born outside the U.S. or were generation one immigrants.”
In addition, we did not account for other possible factors that may differ across Hispanic groups like acculturation43
, access to health care, discrimination, and poverty.44
We used only one spot measure of albuminuria rather a 24 hour collection which may lead to some misclassification, but studies have shown that one spot ratio is highly associated with 24 hour excretion.7, 45
In summary, we found that Hispanic subgroups differ significantly in their genetic ancestral components, as well as in their risk factor profile by country of origin. We also found that levels of albuminuria vary significantly by country of origin among Hispanics and when compared to whites. Moreover, genetic ancestry may explain, at least in part, differences observed between Hispanics and whites in albuminuria. Our findings have important implications for future epidemiologic and genetic studies which should take into account Hispanic country of origin. In addition, albuminuria may be a phenotype amenable to admixture mapping among Hispanics. se in each ancestral component in nested models as above. We also conducted separate analyses with African ancestry because it is unknown, a priori, which ancestral component will be most associated with the outcome, and there is a potential for the associations to vary by Hispanic subgroup.
We investigated whether Hispanic subgroups (identified by country of origin) differ in both genetic component and risk for albumin in the urine, which is an important risk factor for cardiovascular events and kidney disease. We observed that Hispanics differ in their genetic ancestral component by country of origin. In addition, their risk of albuminuria differs by country of origin when compared with whites. Our findings suggest that country of origin should be included as a covariate when studying differences between Hispanics and non-Hispanic whites for select cardiovascular risk factors.