Publications by authors named "Humberto Garcia-Ortiz"

21 Publications

  • Page 1 of 1

Metabolic syndrome in indigenous communities in Mexico: a descriptive and cross-sectional study.

BMC Public Health 2020 Mar 17;20(1):339. Epub 2020 Mar 17.

Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, Periférico Sur 4809, Colonia Arenal Tepepan, Delegación Tlalpan, C.P. 14610, Ciudad de México, Mexico.

Background: An Amerindian genetic background could play an important role in susceptibility to metabolic diseases, which have alarmingly increased in recent decades. Mexico has one of the highest prevalences of metabolic disease worldwide. The purpose of this study was to determine the prevalence of metabolic syndrome and its components in a population with high Amerindian ancestry.

Methods: We performed a descriptive, quantitative, and analytical cross-sectional study of 2596 adult indigenous volunteers from 60 different ethnic groups. Metabolic syndrome and its components were evaluated using the American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement criteria.

Results: The overall prevalence of metabolic syndrome in the indigenous Mexican population was 50.3%. Although females had a higher prevalence than males (55.6% vs. 38.2%), the males presented with combinations of metabolic syndrome components that confer a higher risk of cardiovascular disease. The most frequent metabolic syndrome component in both genders was low HDL-cholesterol levels (75.8%). Central obesity was the second most frequent component in females (61%), though it had a low prevalence in males (16.5%). The overall prevalence of elevated blood pressure was 42.7% and was higher in males than females (48.8 vs. 40%). We found no gender differences in the overall prevalence of elevated triglycerides (56.7%) or fasting glucose (27.9%).

Conclusions: We documented that individuals with Amerindian ancestry have a high prevalence of metabolic syndrome. Health policies are needed to control the development of metabolic disorders in a population with high genetic risk.
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http://dx.doi.org/10.1186/s12889-020-8378-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076922PMC
March 2020

Genetic variability of five ADRB2 polymorphisms among Mexican Amerindian ethnicities and the Mestizo population.

PLoS One 2019 2;14(12):e0225030. Epub 2019 Dec 2.

Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Mexico City, Mexico.

The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225030PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886845PMC
April 2020

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico.

Front Pharmacol 2019 10;10:1169. Epub 2019 Oct 10.

Pharmacogenomics Laboratory, INMEGEN, CDMX, Mexico City, Mexico.

The identification and characterization of pharmacogenetic variants in Latin American populations is still an ongoing endeavor. Here, we investigated SNVs on genes listed by the Pharmacogenomics Knowledge Base in 1284 Mestizos and 94 Natives from Mexico. Five institutional cohorts with NGS data were retrieved from different research projects at INMEGEN, sequencing files were filtered for 55 pharmacogenes present in all cohorts to identify novel and known variation. Bioinformatic tools VEP, PROVEAN, and FATHMM were used to assess, , the functional impact of this variation. Next, we focused on 17 genes with actionable variants that have been clinically implemented. Allele frequencies were compared with major continental groups and differences discussed in the scope of a pharmacogenomic impact. We observed a wide genetic variability for known and novel SNVs, the largest variation was on and the lowest on and . Although with allele frequencies around 1%, novel variation was observed in 16 of 17 PGKB genes. In Natives we identified 59 variants and 58 in Mestizos. Several genes did not show novel variation, on , , and in Natives; and , , and in Mestizos. Similarities in allele frequency, comparing major continental groups for VIP pharmacogenes, hint towards a comparable PGx for drugs metabolized by , , , , , and ; in contrast to variants on and for which significant MAF differences were identified. Our observations offer some discernment into the extent of pharmacogenetic variation registered up-to-date in Mexicans and contribute to quantitatively dissect actionable pharmacogenetic variants in Natives and Mestizos.
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http://dx.doi.org/10.3389/fphar.2019.01169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796793PMC
October 2019

Association between APOE polymorphisms and lipid profile in Mexican Amerindian population.

Mol Genet Genomic Med 2019 11 26;7(11):e958. Epub 2019 Sep 26.

National Institute of Genomic Medicine (Instituto Nacional de Medicina Genómica INMEGEN), Laboratory of Genomics of Psychiatric Diseases, Neurodegenerative and Addictions, Ministry of Health, Mexico City, Mexico.

Background: Apolipoprotein E (ApoE) is a glycoprotein that plays an important role in lipid homeostasis at both cerebral and systemic levels. Moreover, the differential distribution of APOE gene alleles among different populations, means that ApoE isoforms could have different effects on lipids metabolism. The present study aims to evaluate the relationship between APOE gene alleles and the lipid profile in a Mexican Amerindian (MA) population.

Methods: This study included 1997 MA individuals of different ethnicities distributed throughout different states of Mexico. All individuals underwent anthropometric measurements as well as laboratory tests including fasting glucose (FG), total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). TaqMan probe genotyping assays were used to genotype APOE. The Kruskal-Wallis test was performed to determine the correlation between APOE gene alleles and genotypes and the biochemical variables measured.

Results: Among the biochemical variables analyzed, only the HDL-C and LDL-C levels showed statistical differences (p-value < .05) between individuals carrying different APOE alleles. For HDL-C, individuals carrying the E2 allele had higher HDL-C levels, followed by individuals carrying the E3 allele and carriers of the E4 allele presented the lowest levels of HDL-C (E2 > E3 > E4). This relationship was inversed for LDL-C levels (E2 < E3 < E4). Nevertheless, the difference of HDL-C levels between APOE-E3 and APOE-E4 carriers remained only in obese individuals.

Conclusions: Our results suggest that APOE gene genotypes play an important role in the differential modulation of lipid profiles in the MA population with obesity.
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http://dx.doi.org/10.1002/mgg3.958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825948PMC
November 2019

Catalytically Impaired TYK2 Variants are Protective Against Childhood- and Adult-Onset Systemic Lupus Erythematosus in Mexicans.

Sci Rep 2019 08 21;9(1):12165. Epub 2019 Aug 21.

Immunogenomics and Metabolic Diseases Laboratory, National Institute of Genomic Medicine, SS, Mexico City, Mexico.

Type I interferon (IFN-I) pathway plays a central role in the systemic lupus erythematosus (SLE) pathogenesis. Recent data suggest that SLE is associated with variants in IFN-I genes, such as tyrosine kinase 2 (TYK2), which is crucial in anti-viral immunity. Here, five TYK2 single nucleotide polymorphisms (SNPs) were genotyped in 368 childhood-onset SLE Mexican patients and 516 sex-matched healthy controls. Allele frequencies were also estimated in four indigenous groups. SLE protection was associated with TYK2 risk infection variants affecting residually its catalytic domain, rs12720356 (OR = 0.308; p = 0.041) and rs34536443 (OR = 0.370; p = 0.034), but not with rs2304256, rs12720270, and rs280500. This association was replicated in a 506 adult-onset SLE patients sample (OR = 0.250; p = 0.005, and OR = 0.277; p = 0.008, respectively). The minor alleles of both associated SNPs had a lower frequency in Mestizos than in Spaniards and were absent or rare in indigenous, suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards. For the first time, we report genetic variants with a protective effect in childhood- and adult-onset SLE Mexican population. Our results suggest that the frequency of IFN-I alleles associated with SLE, may have been shaped in populations exposed to infectious diseases for long periods, and this could be an explanation why Native American ancestry is associated with a higher SLE prevalence and an earlier onset.
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http://dx.doi.org/10.1038/s41598-019-48451-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704113PMC
August 2019

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Authors:
Jason Flannick Josep M Mercader Christian Fuchsberger Miriam S Udler Anubha Mahajan Jennifer Wessel Tanya M Teslovich Lizz Caulkins Ryan Koesterer Francisco Barajas-Olmos Thomas W Blackwell Eric Boerwinkle Jennifer A Brody Federico Centeno-Cruz Ling Chen Siying Chen Cecilia Contreras-Cubas Emilio Córdova Adolfo Correa Maria Cortes Ralph A DeFronzo Lawrence Dolan Kimberly L Drews Amanda Elliott James S Floyd Stacey Gabriel Maria Eugenia Garay-Sevilla Humberto García-Ortiz Myron Gross Sohee Han Nancy L Heard-Costa Anne U Jackson Marit E Jørgensen Hyun Min Kang Megan Kelsey Bong-Jo Kim Heikki A Koistinen Johanna Kuusisto Joseph B Leader Allan Linneberg Ching-Ti Liu Jianjun Liu Valeriya Lyssenko Alisa K Manning Anthony Marcketta Juan Manuel Malacara-Hernandez Angélica Martínez-Hernández Karen Matsuo Elizabeth Mayer-Davis Elvia Mendoza-Caamal Karen L Mohlke Alanna C Morrison Anne Ndungu Maggie C Y Ng Colm O'Dushlaine Anthony J Payne Catherine Pihoker Wendy S Post Michael Preuss Bruce M Psaty Ramachandran S Vasan N William Rayner Alexander P Reiner Cristina Revilla-Monsalve Neil R Robertson Nicola Santoro Claudia Schurmann Wing Yee So Xavier Soberón Heather M Stringham Tim M Strom Claudia H T Tam Farook Thameem Brian Tomlinson Jason M Torres Russell P Tracy Rob M van Dam Marijana Vujkovic Shuai Wang Ryan P Welch Daniel R Witte Tien-Yin Wong Gil Atzmon Nir Barzilai John Blangero Lori L Bonnycastle Donald W Bowden John C Chambers Edmund Chan Ching-Yu Cheng Yoon Shin Cho Francis S Collins Paul S de Vries Ravindranath Duggirala Benjamin Glaser Clicerio Gonzalez Ma Elena Gonzalez Leif Groop Jaspal Singh Kooner Soo Heon Kwak Markku Laakso Donna M Lehman Peter Nilsson Timothy D Spector E Shyong Tai Tiinamaija Tuomi Jaakko Tuomilehto James G Wilson Carlos A Aguilar-Salinas Erwin Bottinger Brian Burke David J Carey Juliana C N Chan Josée Dupuis Philippe Frossard Susan R Heckbert Mi Yeong Hwang Young Jin Kim H Lester Kirchner Jong-Young Lee Juyoung Lee Ruth J F Loos Ronald C W Ma Andrew D Morris Christopher J O'Donnell Colin N A Palmer James Pankow Kyong Soo Park Asif Rasheed Danish Saleheen Xueling Sim Kerrin S Small Yik Ying Teo Christopher Haiman Craig L Hanis Brian E Henderson Lorena Orozco Teresa Tusié-Luna Frederick E Dewey Aris Baras Christian Gieger Thomas Meitinger Konstantin Strauch Leslie Lange Niels Grarup Torben Hansen Oluf Pedersen Philip Zeitler Dana Dabelea Goncalo Abecasis Graeme I Bell Nancy J Cox Mark Seielstad Rob Sladek James B Meigs Steve S Rich Jerome I Rotter David Altshuler Noël P Burtt Laura J Scott Andrew P Morris Jose C Florez Mark I McCarthy Michael Boehnke

Nature 2019 06 22;570(7759):71-76. Epub 2019 May 22.

Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
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http://dx.doi.org/10.1038/s41586-019-1231-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699738PMC
June 2019

Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report.

BMC Med Genomics 2019 05 22;12(1):68. Epub 2019 May 22.

Laboratorio de Inmunogenómica y enfermedades metabólicas, Instituto Nacional de Medicina Genómica,SS, Periférico Sur No. 4809, Arenal Tepepan,Tlalpan, 14610. CDMX, Mexico City, Mexico.

Background: Mexico is among the countries showing the highest heterogeneity of CFTR variants. However, no de novo variants have previously been reported in Mexican patients with cystic fibrosis (CF).

Case Presentation: Here, we report the first case of a novel/de novo variant in a Mexican patient with CF. Our patient was an 8-year-old male who had exhibited the clinical onset of CF at one month of age, with steatorrhea, malabsorption, poor weight gain, anemia, and recurrent respiratory tract infections. Complete sequencing of the CFTR gene by next generation sequencing (NGS) revealed two different variants in trans, including the previously reported CF-causing variant c.3266G > A (p.Trp1089*, W1089*), that was inherited from the mother, and the novel/de novo CFTR variant c.1762G > T (p.Glu588*).

Conclusion: Our results demonstrate the efficiency of targeted NGS for making a rapid and precise diagnosis in patients with clinically suspected CF. This method can enable the provision of accurate genetic counselling, and improve our understanding of the molecular basis of genetic diseases.
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http://dx.doi.org/10.1186/s12920-019-0528-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532186PMC
May 2019

Comparing signals of natural selection between three Indigenous North American populations.

Proc Natl Acad Sci U S A 2019 05 15;116(19):9312-9317. Epub 2019 Apr 15.

Department of Anthropology, University of Connecticut, Storrs, CT 06269-1176.

While many studies have highlighted human adaptations to diverse environments worldwide, genomic studies of natural selection in Indigenous populations in the Americas have been absent from this literature until very recently. Since humans first entered the Americas some 20,000 years ago, they have settled in many new environments across the continent. This diversity of environments has placed variable selective pressures on the populations living in each region, but the effects of these pressures have not been extensively studied to date. To help fill this gap, we collected genome-wide data from three Indigenous North American populations from different geographic regions of the continent (Alaska, southeastern United States, and central Mexico). We identified signals of natural selection in each population and compared signals across populations to explore the differences in selective pressures among the three regions sampled. We find evidence of adaptation to cold and high-latitude environments in Alaska, while in the southeastern United States and central Mexico, pathogenic environments seem to have created important selective pressures. This study lays the foundation for additional functional and phenotypic work on possible adaptations to varied environments during the history of population diversification in the Americas.
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http://dx.doi.org/10.1073/pnas.1819467116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511053PMC
May 2019

Influence of obesity, parental history of diabetes, and genes in type 2 diabetes: A case-control study.

Sci Rep 2019 02 26;9(1):2748. Epub 2019 Feb 26.

Fundación Carlos Slim, México City, Mexico.

Obesity, parental history (PH) of type 2 diabetes (T2D), and genes play an important role in T2D development. However, the influence of each factor on T2D variability is unclear. This study aimed to investigate the influence of obesity (body mass index [BMI], waist/hip ratio), PH, and 16 single-nucleotide polymorphisms (SNPs) associated with T2D on T2D variability in Mexico, comparing 1234 non-diabetic controls and 1219 diabetic patients. To replicate the data, a case-control (n = 2904) and a cross-sectional (n = 1901) study were also included. In a multivariate logistic regression model, all factors accounted for only 27.3% of T2D variability: SNPs (8.4%); PH (11.8%) and obesity (7.1%). These factors contributed more in men (33.2%) than in women (25%), specifically when the disease was diagnosed before the age of 46 (46.7% vs. 30%). Genes played a substantially more important role in men than in women (14.9% vs. 5.5%), while obesity and PH played a similar role in both genders. Genes and PH appeared to play a greater role than obesity in T2D. However, obesity contribution was calculated at the time of recruitment and may be underestimated in patients because the BMI decreased linearly with the number of years with the disease. The data suggest that sexual hormones may play important roles in genes that are associated with T2D.
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http://dx.doi.org/10.1038/s41598-019-39145-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391418PMC
February 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos.

Gene 2018 Dec 31;679:160-171. Epub 2018 Aug 31.

Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico. Electronic address:

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date. We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.
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http://dx.doi.org/10.1016/j.gene.2018.08.076DOI Listing
December 2018

Demographic history and biologically relevant genetic variation of Native Mexicans inferred from whole-genome sequencing.

Nat Commun 2017 10 18;8(1):1005. Epub 2017 Oct 18.

Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico.

Understanding the genetic structure of Native American populations is important to clarify their diversity, demographic history, and to identify genetic factors relevant for biomedical traits. Here, we show a demographic history reconstruction from 12 Native American whole genomes belonging to six distinct ethnic groups representing the three main described genetic clusters of Mexico (Northern, Southern, and Maya). Effective population size estimates of all Native American groups remained below 2,000 individuals for up to 10,000 years ago. The proportion of missense variants predicted as damaging is higher for undescribed (~ 30%) than for previously reported variants (~ 15%). Several variants previously associated with biological traits are highly frequent in the Native American genomes. These findings suggest that the demographic and adaptive processes that occurred in these groups shaped their genetic architecture and could have implications in biological processes of the Native Americans and Mestizos of today.
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http://dx.doi.org/10.1038/s41467-017-01194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647344PMC
October 2017

A Loss-of-Function Splice Acceptor Variant in Is Protective for Type 2 Diabetes.

Diabetes 2017 11 24;66(11):2903-2914. Epub 2017 Aug 24.

Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of isoform 2. In individuals who do not carry the protective allele, expression of isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
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http://dx.doi.org/10.2337/db17-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652606PMC
November 2017

Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico.

PLoS One 2016 20;11(9):e0163248. Epub 2016 Sep 20.

Inmunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, Mexico City, Mexico.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029802PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163248PLOS
August 2017

Gender-Dependent Association of FTO Polymorphisms with Body Mass Index in Mexicans.

PLoS One 2016 4;11(1):e0145984. Epub 2016 Jan 4.

Laboratorio de Immunogenómica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Mexico City, Mexico.

To evaluate the associations between six single-nucleotide polymorphisms (SNPs) in intron 1 of FTO and body mass index (BMI), a case-control association study of 2314 unrelated Mexican-Mestizo adult subjects was performed. The association between each SNP and BMI was tested using logistic and linear regression adjusted for age, gender, and ancestry and assuming additive, recessive, and dominant effects of the minor allele. Association analysis after BMI stratification showed that all five FTO SNPs (rs1121980, rs17817449, rs3751812, rs9930506, and rs17817449), were significantly associated with obesity class II/III under an additive model (P<0.05). Interestingly, we also documented a genetic model-dependent influence of gender on the effect of FTO variants on increased BMI. Two SNPs were specifically associated in males under a dominant model, while the remainder were associated with females under additive and recessive models (P<0.05). The SNP rs9930506 showed the highest increased in obesity risk in females (odds ratio = 4.4). Linear regression using BMI as a continuous trait also revealed differential FTO SNP contributions. Homozygous individuals for the risk alleles of rs17817449, rs3751812, and rs9930506 were on average 2.18 kg/m(2) heavier than homozygous for the wild-type alleles; rs1121980 and rs8044769 showed significant but less-strong effects on BMI (1.54 kg/m(2) and 0.9 kg/m(2), respectively). Remarkably, rs9930506 also exhibited positive interactions with age and BMI in a gender-dependent manner. Women carrying the minor allele of this variant have a significant increase in BMI by year (0.42 kg/m(2), P = 1.17 x 10(-10)). Linear regression haplotype analysis under an additive model, confirmed that the TGTGC haplotype harboring all five minor alleles, increased the BMI of carriers by 2.36 kg/m(2) (P = 1.15 x 10(-5)). Our data suggest that FTO SNPs make differential contributions to obesity risk and support the hypothesis that gender differences in the mechanisms involving these variants may contribute to disease development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145984PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703196PMC
July 2016

Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components.

PLoS One 2015 1;10(5):e0123313. Epub 2015 May 1.

Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, Mexico City, Mexico.

Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123313PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416764PMC
January 2016

Genomewide admixture study in Mexican Mestizos with multiple sclerosis.

Clin Neurol Neurosurg 2015 Mar 24;130:55-60. Epub 2014 Dec 24.

National Institute of Neurology and Neurosurgery of Mexico, Insurgentes Sur #3877, Mexico City 14269, Mexico. Electronic address:

Background: Multiple sclerosis (MS) is a complex immune-mediated disease. It has been suggested that genetic factors could explain differences in the prevalence among ethnic groups. To know whether genetic ancestry is a potential risk factor for MS in Mexican patients and to identify candidate genes for the susceptibility to the disease we conducted an initial trial of genome-wide analysis.

Methods: 29 patients with diagnosis of definitive MS and 132 unrelated healthy controls were genotyped using the Affymetrix human 6.0 array. After QC procedures, ancestry determination and a preliminary case-control association study were performed.

Results: We identified significant differences in the European ancestry proportion between MS cases and controls (33.1 vs. 25.56, respectively; p=0.0045). Imputation analysis in the MHC region on chromosome 6 showed a signal with a significant level (p<0.00005) on the HLA-DRB region. Additionally, a preliminary association analysis highlighted the ASF1B as novel candidate gene participating in MS.

Conclusion: Our data suggest that European ancestry is a risk factor to develop MS in Mexican Mestizo population. Conversely, indigenous ancestry of Asian origin seems to confer protection. Further studies with more MS cases are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.clineuro.2014.11.026DOI Listing
March 2015

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

JAMA 2014 Jun;311(22):2305-14

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts3Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Importance: Latino populations have one of the highest prevalences of type 2 diabetes worldwide.

Objectives: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships.

Design, Setting, And Participants: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays.

Main Outcome And Measures: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.

Results: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19).

Conclusions And Relevance: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
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http://dx.doi.org/10.1001/jama.2014.6511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425850PMC
June 2014

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening.

Age (Dordr) 2014 Jun 3;36(3):9635. Epub 2014 Mar 3.

Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, México, D.F., C.P. 14610, México,

Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward's triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.
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http://dx.doi.org/10.1007/s11357-014-9635-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082595PMC
June 2014

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Nature 2014 Feb 25;506(7486):97-101. Epub 2013 Dec 25.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
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http://dx.doi.org/10.1038/nature12828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127086PMC
February 2014

Association of TLR7 copy number variation with susceptibility to childhood-onset systemic lupus erythematosus in Mexican population.

Ann Rheum Dis 2010 Oct 4;69(10):1861-5. Epub 2010 Jun 4.

Genomic of Complex Diseases Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.

Objective: Variations in gene copy number (CNV) have been recognised as a hereditable source of susceptibility in human complex diseases. Recent studies have shown that Tlr7 gene dosage has a significant contribution in the autoimmune-enhancing effect in mouse models of systemic lupus erythematosus (SLE). A study was therefore performed to investigate whether CNVs in TLR7 contribute to the genetic component of childhood-onset SLE.

Methods: A case-control association study was performed in 328 Mexican children with SLE and 403 healthy controls. Determination of CNVs of TLR7 was achieved by real-time PCR using the ΔΔCt method. Expression levels of TLR7 and interferon α (IFNα) were determined in 23 patients. In addition, a stratification analysis was performed to investigate the association of TLR7 gene copy number (CN) with lupus nephritis.

Results: A significant increase was found in the relative TLR7 gene CN in females patients with SLE compared with female controls (p<0.0001). However, logistic regression analysis by gender showed a higher OR (OR 6.61, p=0.005) in male patients with >1 copy of TLR7 than in female patients with >2 copies (OR 3.07, p<0.0001). This association was not observed with lupus nephritis. TLR7 mRNA levels correlated significantly with TLR7 CN and with IFNα mRNA levels.

Conclusion: These results show that an increase in TLR7 CN is a risk factor for childhood-onset SLE and provide new evidence for a role for X-linked gene dosage in SLE susceptibility. There is also evidence to suggest that TLR7 may be involved in the pathogenesis of SLE through the induction of IFNα.
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http://dx.doi.org/10.1136/ard.2009.124313DOI Listing
October 2010