Biomedical subjects

Esteban J Parra

Publications and source records attributed to Esteban J Parra.

18 recordsLinked to original sources

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2006

Admixture in Mexico City: implications for admixture mapping of type 2 diabetes genetic risk factors.

Admixture mapping is a recently developed method for identifying genetic risk factors involved in complex traits or diseases showing prevalence differences between major continental groups. Type 2 diabetes (T2D) is at least twice as prevalent in Native American populations as in populations of European ancestry, so admixture mapping is well suited to study the genetic basis of this complex disease. We have characterized the admixture proportions in a sample of 286 unrelated T2D patients and 275 controls from Mexico City and we discuss the implications of the results for admixture mapping studies. Admixture proportions were estimated using 69 autosomal ancestry-informative markers (AIMs). Maternal and paternal contributions were estimated from geographically informative mtDNA and Y-specific polymorphisms. The average proportions of Native American, European and, West African admixture were estimated as 65, 30, and 5%, respectively. The contributions of Native American ancestors to maternal and paternal lineages were estimated as 90 and 40%, respectively. In a logistic model with higher educational status as dependent variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions was 9.4 (95%, credible interval 3.8-22.6). This association of socioeconomic status with individual admixture proportion shows that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The effective number of generations back to unadmixed ancestors was 6.7 (95% CI 5.7-8.0), from which we can estimate that genome-wide admixture mapping will require typing about 1,400 evenly distributed AIMs to localize genes underlying disease risk between populations of European and Native American ancestry. Sample sizes of about 2,000 cases will be required to detect any locus that contributes an ancestry risk ratio of at least 1.5.

Africa, Western↗

PubMed2006

What makes a champion? Explaining variation in human athletic performance.

Variation in human athletic performance is determined by a complex interaction of socio-cultural, psychological, and proximate physiological factors. Human physiological trait variance has both an environmental and genetic basis, although the classic gene-environment dichotomy is clearly too simplistic to understand the full range of variation for most proximate determinants of athletic performance, e.g., body composition. In other words, gene and environment interact, not just over the short term, but also over the lifetime of an individual with permanent effects on the adult phenotype. To further complicate matters, gene and environment may also be correlated. That is, genetically gifted individuals may be identified as children and begin training pulmonary, cardiovascular, and muscle systems at an early critical age. This review covers evidence in support of a genetic basis to human athletic performance, with some emphasis on the recent explosion of candidate gene studies. In addition, the review covers environmental influences on athletic performance with an emphasis on irreversible environmental effects, i.e., developmental effects that may accrue during critical periods of development either before conception (epigenetic effects), during fetal life (fetal programming), or during childhood and adolescence. Throughout, we emphasize the importance of gene-environment interaction (G x E) as a means of understanding variation in human physiological performance and we promote studies that integrate genomics with developmental biology.

Cardiovascular Physiological Phenomena↗

PubMed2006

Finding the genes underlying adaptation to hypoxia using genomic scans for genetic adaptation and admixture mapping.

The complete sequencing the human genome and recent analytical advances have provided the opportunity to perform genome-wide studies of human variation. There is substantial potential for such population-genomic approaches to assist efforts to uncover the historical and demographic histories of human populations. Additionally, these genome-wide datasets allow for investigations of variability among genomic regions. Although all genomic regions in a population have experienced the same demographic events, they have not been affected by these events in precisely the same way. Much of the variability among genomic regions is simply the result of genetic drift (i.e., gene frequency changes resulting from the effects of small breeding-population size), but some is also the result of genetic adaptation, which will only affect the gene under selection and nearby regions. We have used a new DNA typing assay that allows for the genotyping of thousands of SNPs on hundreds of samples to identify regions most likely to have been affected by genetic adaptation. Populations that have inhabited different niches (e.g., high-altitude regions) can be used to identify genes underlying the physiological differences. We have used two methods (admixture mapping and genome scans for genetic adaptation) founded on the population-genomic paradigms to search for genes underlying population differences in response to chronic hypoxia. There is great promise that together these methods will facilitate the discovery of genes influencing hypoxic response.

Alleles↗

PubMed2005

SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.

Black or African American↗

PubMed2005

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives.

Andean high-altitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O(2) saturation (Sa(O(2))). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10-12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia (r = -0.36, P = 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r = -0.50, P = 0.005) and ventilatory equivalent (VE/Vo(2), r = -0.51, P = 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the well-known blunted HVR (10, 35, 36, 57, 62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua.

Adult↗

PubMed2005

The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans.

Skin color, a predictor of social interactions and risk factor for several types of cancer, is due to two contrasting forms of melanin, the darker eumelanin and lighter phaeomelanin. The lighter pigment phaeomelanin is the product of the antagonistic function of the agouti signaling protein (ASIP) on the alpha-melanocyte stimulating hormone receptor (MC1R). Studies have shown that a single-nucleotide polymorphism (SNP) in the 3'UTR of the ASIP gene is associated with dark hair and eyes; however, little is known about its role in inter-individual variation in skin color. Here we examine the relationship between the ASIP g.8818A>G SNP and skin color (M index) as assessed by reflectometry in 234 African Americans. Analyses of variance (ANOVA) were performed to evaluate the effects of ASIP genotypes, age, individual ancestry, and sex on skin color variation. Significant effects on M index variation were observed for ASIP genotypes (F(2,236)=4.37, P=0.01), ancestry (F(1,243)=37.2, P<0.001), and sex (F(1,244)=4.08, P=0.05). Subsequent analyses revealed a strong effect on M index from ASIP genotypes in African American females (P<0.001). Our study suggests that the ASIP G>A polymorphism exhibits a dominant effect leading to lighter skin color and that variation in the ASIP gene may have been one of several factors contributing to reductions in pigmentation in some populations. Further study is needed to reveal how interactions between ASIP and several other genes, such as MC1R and P, predict human pigmentation.

Adult↗

PubMed2005

Admixture analysis of a rural population of the state of Guerrero, Mexico.

We studied 156 individuals of Native American descent from the city of Tlapa in the state of Guerrero in western Mexico. Most individuals' ethnicity was either Nahua, Mixtec, or Tlapanec, but self-identified Mestizos and individuals of mixed ethnicities were also included in the sample. We typed 24 autosomal, one Y-chromosome, and four mitochondrial ancestry-informative markers (AIMs) to estimate group and individual admixture proportions, and determine whether the admixture process involved directional gene flow between parental groups. When genetically defined (GD) Mestizos were excluded from the analysis, Native American ancestry represented approximately 98% of the population's gene pool, while European and West African ancestry represented approximately 1% each. Maternally inherited markers also showed an exceptionally high Native American contribution (98.5%), as did the paternally inherited marker, DYS199 (90.7%). We did not detect genetic structure in this population using these AIMs, which appears consistent with the homogeneity of the sample in terms of admixture proportions. The addition of GD Mestizos to the sample did not produce a considerable change in admixture estimates, but it had a major effect on population structure. These results show that the population of Tlapa in Guerrero, Mexico, has experienced little admixture with Europeans and/or West Africans. They also show that the impact of a small number of admixed individuals on an otherwise homogeneous population might have profound implications on subsequent ancestry/phenotype analysis and mapping strategies. We suggest that heterogeneity is a major characteristic of Mexican populations and, as a consequence, should not be disregarded when designing epidemiological studies of Mexican and Mexican American populations.

Black People↗

PubMed2005

Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation.

Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

Chromosomes, Human, X↗

PubMed2004

Ancestral proportions and their association with skin pigmentation and bone mineral density in Puerto Rican women from New York city.

Hispanic and African American populations exhibit an increased risk of obesity compared with populations of European origin, a feature that may be related to inherited risk alleles from Native American and West African parental populations. However, a relationship between West African ancestry and obesity-related traits, such as body mass index (BMI), fat mass (FM), and fat-free mass (FFM), and with bone mineral density (BMD) in African American women has only recently been reported. In order to evaluate further the influence of ancestry on body composition phenotypes, we studied a Hispanic population with substantial European, West African, and Native American admixture. We ascertained a sample of Puerto Rican women living in New York ( n=64), for whom we measured BMI and body composition variables, such as FM, FFM, percent body fat, and BMD. Additionally, skin pigmentation was measured as the melanin index by reflectance spectroscopy. We genotyped 35 autosomal ancestry informative markers and estimated population and individual ancestral proportions in terms of European, West African, and Native American contributions to this population. The ancestry proportions corresponding to the three parental populations are: 53.3+/-2.8% European, 29.1+/-2.3% West African, and 17.6+/-2.4% Native American. We detected significant genetic structure in this population with a number of different tests. A highly significant correlation was found between skin pigmentation and individual ancestry ( R(2)=0.597, P<0.001) that was not attributable to differences in socioeconomic status. A significant association was also found between BMD and European admixture ( R(2)=0.065, P=0.042), but no such correlation was evident with BMI or the remaining body composition measurements. We discuss the implications of our findings for the potential use of this Hispanic population for admixture mapping.

Aged↗

PubMed2004

The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs.

Understanding the nature of evolutionary relationships among persons and populations is important for the efficient application of genome science to biomedical research. We have analysed 8,525 autosomal single nucleotide polymorphisms (SNPs) in 84 individuals from four populations: African-American, European-American, Chinese and Japanese. Individual relationships were reconstructed using the allele sharing distance and the neighbour-joining tree making method. Trees show clear clustering according to population, with the root branching from the African-American clade. The African-American cluster is much less star-like than European-American and East Asian clusters, primarily because of admixture. Furthermore, on the East Asian branch, all ten Chinese individuals cluster together and all ten Japanese individuals cluster together. Using positional information, we demonstrate strong correlations between inter-marker distance and both locus-specific FST (the proportion of total variation due to differentiation) levels and branch lengths. Chromosomal maps of the distribution of locus-specific branch lengths were constructed by combining these data with other published SNP markers (total of 33,704 SNPs). These maps clearly illustrate a non-uniform distribution of human genetic substructure, an instructional and useful paradigm for education and research.

Genetics, Population↗

PubMed2004

Characterization of admixture in an urban sample from Buenos Aires, Argentina, using uniparentally and biparentally inherited genetic markers.

In this study we analyzed a sample of the urban population of La Plata, Argentina, using 17 mtDNA haplogroups, the DYS 199 Y-chromosome polymorphism, and 5 autosomal population-associated alleles (PAAs). The contribution of native American maternal lineages to the population of La Plata was estimated as 45.6%, whereas the paternal contribution was much lower (10.6%), clearly indicating directional mating. Regarding autosomal evidence of admixture, the relative European, native American, and West African genetic contributions to the gene pool of La Plata were estimated to be 67.55% (+/-2.7), 25.9% (+/-4.3), and 6.5% (+/-6.4), respectively. When admixture was calculated at the individual level, we found a low correlation between the ancestral contribution estimated with uniparental lineages and autosomal markers. Most of the individuals from La Plata with a native American mtDNA haplogroup or the DYS199*T native American allele show a genetic contribution at the autosomal level that can be traced primarily to Europe. The results of this study emphasize the need to use both uniparentally and biparentally inherited genetic markers to understand the history of admixed populations.

Argentina↗

PubMed2004

A simple and efficient method for extracting DNA from old and burned bone.

It has been a challenge to extract DNA from bones previously soaked in water, burned, or buried for a long time, due to the reduced quality and quantity of DNA in the bone samples. The dramatic degradation of the DNA and the presence of PCR inhibitors in the collagen significantly complicate the process of DNA identification in dated and charred bones. In this article, we present a novel strategy to obtain DNA from bones based on the use of cetyltrimethylammonium bromide (CTAB) lysis buffer and isoamyl alcohol-chloroform extraction with subsequent DNA purification using the DNA IQ System, or alternatively the QIAquick system. When applied to bones soaked, burned or buried for up to nine years, this method increases the purity and yield of DNA with respect to the traditional phenol-chloroform method and significantly improves multiplex STR genotyping using fluorescence-based methods. The results of this research will assist forensic scientists in the identification of DNA from victims whose bodies underwent significant trauma or burning, precluding the utilization of traditional forensic DNA identification techniques.

Bone and Bones↗

PubMed2003

Spanish genetic admixture is associated with larger V(O2) max decrement from sea level to 4338 m in Peruvian Quechua.

Quechua in the Andes may be genetically adapted to altitude and able to resist decrements in maximal O2 consumption in hypoxia (DeltaVo2 max). This hypothesis was tested via repeated measures of Vo2 max (sea level vs. 4338 m) in 30 men of mixed Spanish and Quechua origins. Individual genetic admixture level (%Spanish ancestry) was estimated by using ancestry-informative DNA markers. Genetic admixture explained a significant proportion of the variability in DeltaVo2 max after control for covariate effects, including sea level Vo2 max and the decrement in arterial O2 saturation measured at Vo2 max (DeltaSpO2 max) (R2 for admixture and covariate effects approximately 0.80). The genetic effect reflected a main effect of admixture on DeltaVo2 max (P = 0.041) and an interaction between admixture and DeltaSpO2 max (P = 0.018). Admixture predicted DeltaVo2 max only in subjects with a large DeltaSpO2 max (P = 0.031). In such subjects, DeltaVo2 max was 12-18% larger in a subgroup of subjects with high vs. low Spanish ancestry, with least squares mean values (+/-SE) of 739 +/- 71 vs. 606 +/- 68 ml/min, respectively. A trend for interaction (P = 0.095) was also noted between admixture and the decrease in ventilatory threshold at 4338 m. As previously, admixture predicted DeltaVo2 max only in subjects with a large decrease in ventilatory threshold. These findings suggest that the genetic effect on DeltaVo2 max depends on a subject's aerobic fitness. Genetic effects may be more important (or easier to detect) in athletic subjects who are more likely to show gas-exchange impairment during exercise. The results of this study are consistent with the evolutionary hypothesis and point to a better gas-exchange system in Quechua.

Adult↗

PubMed2003

Skin pigmentation, biogeographical ancestry and admixture mapping.

Ancestry informative markers (AIMs) are genetic loci showing alleles with large frequency differences between populations. AIMs can be used to estimate biogeographical ancestry at the level of the population, subgroup (e.g. cases and controls) and individual. Ancestry estimates at both the subgroup and individual level can be directly instructive regarding the genetics of the phenotypes that differ qualitatively or in frequency between populations. These estimates can provide a compelling foundation for the use of admixture mapping (AM) methods to identify the genes underlying these traits. We present details of a panel of 34 AIMs and demonstrate how such studies can proceed, by using skin pigmentation as a model phenotype. We have genotyped these markers in two population samples with primarily African ancestry, viz. African Americans from Washington D.C. and an African Caribbean sample from Britain, and in a sample of European Americans from Pennsylvania. In the two African population samples, we observed significant correlations between estimates of individual ancestry and skin pigmentation as measured by reflectometry (R(2)=0.21, P<0.0001 for the African-American sample and R(2)=0.16, P<0.0001 for the British African-Caribbean sample). These correlations confirm the validity of the ancestry estimates and also indicate the high level of population structure related to admixture, a level that characterizes these populations and that is detectable by using other tests to identify genetic structure. We have also applied two methods of admixture mapping to test for the effects of three candidate genes (TYR, OCA2, MC1R) on pigmentation. We show that TYR and OCA2 have measurable effects on skin pigmentation differences between the west African and west European parental populations. This work indicates that it is possible to estimate the individual ancestry of a person based on DNA analysis with a reasonable number of well-defined genetic markers. The implications and applications of ancestry estimates in biomedical research are discussed.

Africa↗

PubMed2002

Comparing quantitative measures of erythema, pigmentation and skin response using reflectometry.

We measured a number of pigmentation and skin response phenotypes in a sample of volunteers (n=397) living in State College, PA. The majority of this sample was composed of four groups based on stated ancestry: African-American, European-American, Hispanic and East Asian. Several measures of melanin concentration (L*, melanin index and adjusted melanin index) were estimated by diffuse reflectance spectroscopy and compared. The efficacy of these measures for assessing constitutive pigmentation and melanogenic dose-response was evaluated. Similarly, several measures of erythema (a*, erythema index and adjusted erythema index) were compared and evaluated in their efficacy in measuring erythema and erythemal dose-response. We show a high correspondence among all of the measures for the assessment of constitutive pigmentation and baseline erythema. However, our results demonstrate that evaluating melanogenic dose-response is highly dependent on the summary statistic used: while L* is a valid measure of constitutive pigmentation it is not an effective measure of melanogenic dose-response. Our results also confirm the use of a*, as it is shown to be highly correlated with the adjusted erythema index, a more advanced measure of erythema based on the apparent absorbance. Diffuse reflectance spectroscopy can be used to quantify the constitutive pigmentation, melanogenic dose-response at 7 d and erythemal dose-response at both 24 h and 7 d postexposure.

Adolescent↗

PubMed2002

Skin responses to ultraviolet radiation: effects of constitutive pigmentation, sex, and ancestry.

Constitutive skin pigmentation and skin responses to ultraviolet radiation were measured on a sample of volunteers (n=250) living in State College, PA, USA. The sample was composed of individuals of European American (n=190), Hispanic (n=45), and East Asian ancestry (n=15). Constitutive pigmentation was measured using the Adjusted Melanin Index (AMI), Erythemal Dose Response (EDR) was measured using the slope of a* at 24 h (Deltaa*), and Melanogenic Dose-Response (MDR) was measured using DeltaAM, the slope of AMI at 7 d. The relationships between constitutive skin pigmentation, EDR, MDR, sex, age, and ancestry were investigated. European Americans showed a lower constitutive pigmentation, had a significantly higher burn response (EDR), and had a significantly lower tanning response (MDR) than Hispanics and East Asians. No significant difference is seen between Hispanics and East Asians for either constitutive pigmentation or EDR. Constitutive pigmentation in females was slightly lower than in males in all three samples, but the difference was not significant. While no differences were observed in MDR between sexes, males had a stronger EDR than females regardless of population or constitutive pigmentation level, and this difference was significant in European Americans and Hispanics. We observed no age-related differences in any of the populations or measures investigated. We evaluated the relationship between constitutive pigmentation, EDR and MDR. There was a strong inverse correlation between constitutive pigmentation and EDR in the three samples (European Americans, R2=0.176, P < 0.001; Hispanics, R2=0.204, P=0.009; East Asians, R2=0.223, P=0.098) and a strong direct correlation between constitutive pigmentation and MDR in European Americans and Hispanics (European Americans, R2=0.094, P < 0.001; Hispanics, R2=0.164, P=0.012). In other words, persons with lower constitutive pigmentation both burn more and tan less than persons with higher pigmentation. However, after controlling for constitutive pigmentation, EDR and MDR were significantly correlated in European Americans (R2=0.041 P=0.006). Thus, the general observation that persons who burn more tan less is probable because of the common link that these two phenotypes have with constitutive skin pigmentation and, in fact, once pigmentation has been adjusted for, there is a positive correlation between tanning response and burning response in European Americans.

Adolescent↗

PubMed2002

Melting curve SNP (McSNP) genotyping: a useful approach for diallelic genotyping in forensic science.

The increasing availability of Single Nucleotide Polymorphisms (SNPs) and Deletion/Insertion Polymorphisms (DIPs), as well as the outstanding progress in SNP genotyping technologies, will impact forensics profoundly. We have developed a new method for genotyping SNPs and DIPs, which is based on the determination of melting curve profiles of amplified DNA in solution. We have termed this method Melting curve SNP (McSNP) genotyping. Melting curve profiles are composites of the particular melting temperatures (Tm) of the individual fragments that comprise the DNA sample. Simple mixtures of DNA can be resolved in a very robust and efficient fashion, since the samples can be scored in the plates in which they were amplified with no or very few post-PCR manipulations. As such, McSNP is one of the least expensive genotyping methods available and can and should be useful in forensic science.

Alleles↗