Amerindian Ancestry Research Articles

Genomic ancestry and metabolic syndrome in individuals with type 1 diabetes from an admixed population: a multicentre, cross-sectional study in Brazil.

To evaluate the relationship between self-reported colour-race, genomic ancestry, and metabolic syndrome in an admixed Brazilian population with type 1 diabetes. We included 1640 participants with type 1 diabetes. The proportions of European, African and Amerindian genomic ancestries were determined by 46 ancestry informative markers of insertion deletion. Two different sets of analyses were performed to determine whether self-reported colour-race and genomic ancestry were predictors of metabolic syndrome. Metabolic syndrome was identified in 29.8% of participants. In the first model, the factors associated with metabolic syndrome were: female gender (odds ratio 1.95, P < 0.001); diabetes duration (odds ratio 1.04, P < 0.001); family history of type 2 diabetes (odds ratio 1.36, P = 0.019); and acanthosis nigricans (odds ratio 5.93, P < 0.001). Colour-race was not a predictive factor for metabolic syndrome. In the second model, colour-race was replaced by European genomic ancestry. The associated factors were: female gender (odds ratio 1.95, P < 0.001); diabetes duration (odds ratio 1.04, P < 0.001); family history of type 2 diabetes (odds ratio 1.39, P = 0.011); and acanthosis nigricans (odds ratio 6.12, P < 0.001). Physical exercise (≥3 times a week) was a protective factor (odds ratio 0.77, P = 0.041), and European genomic ancestry was not associated with metabolic syndrome but showed an odds ratio of 1.77 (P = 0.05). Although a higher level of European genomic ancestrywas observed among participants with metabolic syndrome in the univariate analysis, this association did not persist after multivariable adjustments. Further prospective studies in other highly admixed populations remain necessaryto better evaluate whether the European ancestral component modulates the development of metabolic syndrome in type 1 diabetes.

Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region.

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

Abstract P127: Sex-differences In The Association Of TMEM27 Variants With Hypertension Traits

Introduction: The global deletion of collectrin encoded by the TMEM27 gene leads to endothelial dysfunction, salt sensitivity and hypertension. To translate experimental findings to population studies, we studied the association of single nucleotide polymorphisms (SNPs) with blood pressure (BP) traits. Methods: We examined the SNP associations within TMEM27 with BP traits in 11,926 Hispanics/Latinos. BP was measured during a clinic visit and two measures were averaged. Genotypes were imputed from 1000 Genomes Project (1000G). Analyses were stratified by sex, given TMEM27 is located on the chromosome X. We used linear or logistic mixed models for association analyses with systolic and diastolic BP, or hypertension, respectively, in models adjusted for age, body mass index, relatedness and population stratification. Results: The mean age was 46 years-old (standard deviation 14), 41% were men, 28% had hypertension (BP&gt; 140/90 mm Hg). Two intronic SNPs were associated with BP traits in men but not women, when adjusting for multiple testing (Table). SNP rs5936004 associated with lower diastolic BP is more common in Admixed Americans in the 1000G samples (minor allele frequency [MAF] 0.15), and low frequency in European and African ancestry (0.02 and 0.04). SNP rs183583165 is more common in 1000G African sample (MAF 0.03) but rare in other populations. These SNPs were not in linkage disequilibrium with SNPs in the nearby ACE2 gene, which has a role in BP control. Conclusion: This study identified associations of TMEM27 SNPs with BP traits in Hispanic/Latino men but not women, for variants present in higher frequency in Amerindian and African ancestries.

Amerindian Ancestry Influences Genetic Susceptibility to Chronic Obstructive Pulmonary Disease

The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5 × 10−4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10−3 to 3.77 × 10−8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.

Amerindian genetic ancestry as a risk factor for tuberculosis in an amazonian population.

In recent years, the incidence of tuberculosis (TB) has declined worldwide, although this disease still occurs at relatively high rates in Amerindian populations. This suggests that the genetic ancestry of Amerindians may be an important factor in the development of infections, and may account for at least some of the variation in infection rates in the different populations. The present study investigated the potential influence of Amerindian genetic ancestry on susceptibility to tuberculosis in an Amazon population. The study included 280 patients diagnosed with tuberculosis and 138 asymptomatic hospital employees with no history of TB, but who were in contact with bacterially active TB patients. Ancestry analysis was run on a set of 61 Ancestry-Informative Markers to estimate European, African, and Amerindian genetic ancestry using STRUCTURE v2.2. The TB group had significantly higher Amerindian ancestry in comparison with the control group, and significantly lower European ancestry. Amerindian ancestry in the 20–60% range was found to be the principal risk factor for increased susceptibility to TB. The results of the study indicate that Amerindian ancestry is an important risk factor for susceptibility to TB in the admixed population of the Brazilian Amazon region.

Prevalence and Correlates of Intracranial Atherosclerotic Disease Among Community-Dwelling Older Adults of Amerindian Ancestry. The Three Villages Study

BackgroundKnowledge on the prevalence and correlates of intracranial atherosclerotic disease (ICAD) is limited. We aimed to assess prevalence, clinical and neuroimaging correlates of ICAD in a cohort of older adults of Amerindian ancestry. MethodsThe study included 581 community-dwellers aged ≥60 years (mean age 71 ± 8.4 years; 57% women) living in rural Ecuadorian villages. ICAD was identified by means of CT determinations of carotid siphon calcifications (CSC) or MRA findings of significant stenosis of intracranial arteries. Fully-adjusted logistic regression models were fitted with biomarkers of ICAD as the dependent variables. ResultsA total of 205 (35%) of 581 participants had ICAD, including 185 with high calcium content in the carotid siphons and 40 with significant stenosis of at least one intracranial artery (20 subjects had both biomarkers). Increasing age, high fasting blood glucose, >10 enlarged basal ganglia-perivascular spaces and non-lacunar strokes were associated with high calcium content in the carotid siphons. In contrast, male gender, moderate-to-severe white matter hyperintensities, lacunar and non-lacunar strokes were associated with significant stenosis of intracranial arteries. Stroke was more common among subjects with any biomarker of ICAD than in those with no biomarkers (29% versus 9%, p < 0.001). Significant stenosis of intracranial arteries was more often associated with stroke than high calcium content in the carotid siphons, suggesting that CSC are more likely an ICAD biomarker than causally related to stroke. ConclusionsICAD prevalence in Amerindians is high, and is significantly associated with stroke. CSC and significant stenosis of intracranial arteries may represent different phenotypes of ICAD.

Abstract B057: Racial disparity research in ovarian cancer: Evaluating race definition in differential gene expression

Abstract Objective: Several studies have reported worse prognosis for Black ovarian cancer patients in comparison to non-Hispanic White patients, even after adjusting for clinical parameters, treatment and environmental factors. Self-reported race has been widely recognized as one of the biggest limitations to racial disparities research. Here we evaluated the effect of race definition in the survival outcome and differential gene expression profiling of 72 high-grade serous ovarian carcinoma patients. Methods: We isolated total RNA and genomic DNA from tumor tissue cores of 72 self-reported (SR) Black and non-Hispanic White patients with high-grade serous ovarian carcinoma. Racial genetic admixture (RGA) was performed using a custom panel of previously validated SNPs for estimation of ancestry from African, European, and Amerindian ancestry. Full-genome RNAseq library was constructed and sequenced on Illumina HiSeq instrument. Differentially expressed genes were inferred using DESeq2 software. Candidate gene sets of significantly regulated genes were used for functional and pathway enrichment analyses. Results: 72 patients were included with SR 58% (n=42) Non-Hispanic White and 42% (n=30) Black. SR black patients had mean RGA of African descent of 89.6% (range 48.3-100%), while SR white patients had mean European descent of 88.6% (range 27.5-99.7%). Survivals were similar between SR groups. However, survival differences were seen when compared by proportion of African racial genetic admixture (RGA). Regardless of SR, patients with the highest tertile of African ancestry (AA) had lower median progression-free survival than patients in the lowest AA tertile (8 vs. 23mos; p=0.003). An OS difference of 27 vs. 54mos was seen for the highest and lowest AA tertiles, respectively (p=0.02). Genetic analyses were grouped based on (a) SR vs. (b) Tertiles for African RGA vs. (c) Continuous African RGA. A total of 1,954 genes demonstrated significant up/down expression across all racial cohorts. The “Top 40” genes with the greatest 20 upregulated and 20 downregulated log-fold expression for each genetic cohort demonstrated low concordance among the 3 genetic cohorts, with sentinel genes specific to each racial cohort. Subsequent pathway analyses based on gene expression demonstrated low concordance rates among racial cohorts as well. Conclusions: Racial genetic admixture for African ancestry was more predictive of disparate progression-free survival in high-grade serous ovarian carcinoma than self-designated race. Additionally, how race was defined had significant differences in global gene expression levels and subsequent molecular pathway analyses. Collectively, these data support the incorporation of racial genetic admixture when evaluating biologic etiologies of racial disparities in cancer. Citation Format: Luciana Madeira da Silva, Dmytro Starenki, Megan Missanelli, Jennifer Young-Pierce, Jerlinda Ross, Jaroslav Slamecka, Nathaniel Jones, Jennifer Scalici, Rodney P. Rocconi. Racial disparity research in ovarian cancer: Evaluating race definition in differential gene expression [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B057.

Association analysis in a Latin American population revealed ethnic differences in rheumatoid arthritis-associated SNPs in Caucasian and Asian populations

Large genome-wide association studies (GWAS) have increased our knowledge of the genetic risk factors of rheumatoid arthritis (RA). However, little is known about genetic susceptibility in populations with a large admixture of Amerindian ancestry. The aim of the present study was to test the generalizability of previously reported RA loci in a Latin American (LA) population with admixed ancestry. We selected 128 single nucleotide polymorphisms (SNPs) in linkage equilibrium, with high association to RA in multiple populations of non-Amerindian origin. Genotyping of 118 SNPs was performed in 313 RA patients/487 healthy control subjects by mid-density arrays of polymerase chain reaction (PCR). Some of the identified associations were validated in an additional cohort (250 cases/290 controls). One marker, the SNP rs2451258, located upstream of T Cell Activation RhoGTPase Activating Protein (TAGAP) gene, showed significant association with RA (p = 5 × 10−3), whereas 18 markers exhibited suggestive associations (p < 0.05). Haplotype testing showed association of some groups of adjacent SNPs around the signal transducer and activator of transcription 4 (STAT4) gene (p = 9.82 × 10−3 to 2.04 × 10−3) with RA. Our major finding was little replication of previously reported genetic associations with RA. These results suggest that performing GWAS and admixture mapping in LA populations has the potential to reveal novel loci associated with RA. This in turn might help to gain insight into the ‘pathogenomics’ of this disease and to explore trans-population differences for RA in general.

Influence of Genetic Admixture Components on CYP3A5*3 Allele-Associated Hypertension in Amerindian Populations From Northwest Mexico.

CYP3A5 metabolizes endogenous substrates and ~30% of prescription drugs. The CYP3A5 gene contains an active CYP3A5*1 allele, and a non-functional version, the CYP3A5*3 (rs776746), with consequences for drug therapeutic responses and side effects. Both CYP3A5*1 and *3 have been associated with hypertension. The frequency of CYP3A5*3 varies between populations of different ancestries, with Europeans having the highest allele frequency (> 90%). Given the importance of CYP3A5*3 in drug response and hypertension development, the aim of the present study was to evaluate the frequency of this polymorphism and its association with hypertension in vulnerable indigenous populations in Mexico. A total of 372 subjects were recruited from eight ethnic groups in Northwest Mexico. Systolic (SBP), diastolic (DBP), and median (MBP) blood pressures as well as body mass index (BMI) were measured. Ancestry was evaluated through STR analysis, and the CYP3A5*1/*3 polymorphisms were identified using real-time PCR with TaqMan® probes. Higher frequencies of CYP3A5*1 and *3 were observed in groups with higher (>90%) and lower (<90%) Amerindian ancestry, respectively. The CYP3A5*3/*3 genotype was more frequent in indigenous women with higher SBP and DBP values. On the other hand, the *1 allele showed a protective effect against both high SBP (OR, 0.38; 95% CI, 0.17–0.83, p = 0.001) and DBP (OR 0.38, 95% CI 0.18–0.81, p = 0.007) in women. This association remained significant after adjusting for BMI and age for diastolic (OR, 0.38; 95% CI, 0.17–0.84, p = 0.011) and systolic BP (OR, 0.33; 95% CI, 0.15–0.76, p = 0.005) BP levels in women. Thus, the frequency of CYP3A5*3 varies between groups and seems to depend on ancestry, and CYP3A5*1 decreases the risk of hypertension in Mexican indigenous women. This population analysis of CYP3A5*1/*3 has profound implications not only for the susceptibility to diseases, such as hypertension, but also for safer drug administration regimens, assuring better therapeutic responses and fewer side effects.

Role of HLA-DRB1*04 in the susceptibility and HLA-DRB1*08 in the protection for development of rheumatoid arthritis in a population of Southern Mexico: brief report.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with an increased prevalence in Mexico. Although its etiology is unknown, its development can be influenced by environmental factors such as smoking and viral infections. But among the factors influencing susceptibility, it is the genetic factors that predominate, mainly the HLA-DRB1 genes, and specifically the alleles that have the shared epitope (SE). A transversal study was performed, in which 31 patients (28 women and 3 men) with RA, treated at the autoimmunity clinic of the High Specialty Hospital Ciudad Salud in Tapachula, Chiapas, southern México, were enrolled. Clinical, biochemical, and demographic data were analyzed; ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RF (rheumatoid factor), and ACPA (anticitrullinated peptide antibody) were recorded. All patients had at least one positive RA biological marker. For HLA alleles frequencies comparison, we enrolled ethnically matched healthy controls in a ratio of 3:1 for 25 cases and 4:1 for 6 cases in order to guarantee the balance between groups regarding the mean of age and proportion of gender (males vs females). HLA-DRB1*04 was found to be significantly increased in patients compared with ethnically matched healthy controls (p 0.0007, OR: 2.8, 95% CI 1.5-5.1); contrarily, DRB1*08 showed a protective effect (p 0.005, OR 0.1). This paper confirmed the involvement of HLA genes on risk determination for RA in a population of Mexican Mestizos from Tapachula, Chiapas. Key Points • HLA-DRB1*04 confirms the increased risk of rheumatoid arthritis. • HLA-DRB1*08 showed a more definite protective effect in southern Mexicans mestizos, a population with more Amerindian ancestry.

The association between aortic arterial stiffness, carotid intima-media thickness and carotid plaques in community-dwelling older adults: A population-based study.

Information on the associations among arterial stiffness, carotid intima-media thickness (cIMT) and carotid plaques as biomarkers of atherosclerosis is limited in diverse populations. We aimed to assess whether aortic pulse wave velocity (aPWV) - as a surrogate of arterial stiffness - is associated with increased cIMT and the presence of carotid plaques in a cohort of older adults of Amerindian ancestry. Atahualpa residents aged ≥60 years (n = 320) underwent aPWV determinations, and carotid ultrasounds for cIMT and plaque assessment. Multivariate models were fitted to assess the independent association between the aPWV, and cIMT and carotid plaques, after adjusting for relevant confounders. Differences in risk factors across these biomarkers were investigated. Mean values of aPWV were 10.3 ± 1.8 m/s, and those of cIMT were 0.91 ± 0.21 mm (24% had a cIMT >1 mm). Carotid plaques were observed in 118 (37%) subjects. In univariate analyses, risk factors associated with an increased aPWV included age, female gender, poor physical activity and high blood pressure. An increased cIMT was associated with age, male gender, a poor diet, high blood pressure and severe tooth loss. The presence of carotid plaques was associated with increasing age, poor physical activity and high blood pressure. Multivariate models showed a significant association between aPWV and cIMT (β: 0.028; 95% C.I.: 0.001-0.056; p = 0.047) but not between aPWV and carotid plaques (OR: 1.14; 95% C.I.: 0.83-1.56; p = 0.423). This study shows an independent association between aPWV and cIMT but not with carotid plaques. These biomarkers may indicate distinct phenotypes for atherosclerosis.

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

BackgroundAn 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.MethodsWe 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.ResultsThe 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%).ConclusionsWe 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.

Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics

BackgroundQuantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population.ResultsWe used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP.ConclusionThis work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.

Abstract WP241: Prevalence of Subclinical Extracranial Carotid Atherosclerosis Detected by Ultrasound Among Amerindians: A Population Study in Rural Ecuador

Background: Epidemiological information on extracranial carotid atherosclerosis (ECA) among Amerindians is limited. We aim to determine the prevalence of subclinical ECA and its correlation with cardiovascular risk factors in community-dwelling adults of Amerindian ancestry living in a rural Ecuadorian village. Methods: Utilizing a population-based design, stroke-free individuals aged ≥40 years were invited to undergo carotid ultrasound. Subclinical ECA was defined as an intima-media thickness (cIMT) &gt;1mm and/or the presence of carotid plaques (focal intima thickening &gt;1.5mm that protrudes into the lumen). Degree of luminal stenosis was calculated and considered significant if &gt;50%. We investigated the association between these biomarkers and cardiovascular risk factors. Results: Of 728 candidates, 559 (77%) stroke-free individuals underwent carotid sonographic evaluation and were included. The mean age was 62.3 ±12.5 and 238 (43%) were men. The mean value of the cIMT was 0.85 ± 0.17mm (median cIMT: 0.83mm; IQ range: 0.74-0.92 mm). The prevalence of increased cIMT, carotid plaques, and increased cIMT and/or carotid plaques were 14%, 23.8%, and 26.1%, respectively. Table depicts the association of these biomarkers with cardiovascular risk factors. A multinomial logistic regression model, using individuals with normal carotids as the referent category, showed significant associations of ECA with increasing age, male gender, smoking and high blood pressure. Significant carotid stenosis was found in 19 subjects (3.4%). Conclusions: About one-fourth of Amerindians living in a rural setting have subclinical ECA. Increasing age, male gender, smoking and high blood pressure were independent determinants of the burden of ECA, while elevated glucose and total cholesterol showed no significant association. Obesity was inversely associated with ECA in univariate analysis, but such association disappeared in the multivariate model.

Abstract WP173: The Association Between Aortic Arterial Stiffness, Carotid Intima-Media Thickness and Carotid Plaques in Community-Dwelling Older Adults. A Population-Based Study (the Atahualpa Project)

Background: Information on the associations among arterial stiffness, carotid intima-media thickness (cIMT) and carotid plaques as biomarkers of atherosclerosis is limited. We aimed to assess whether aortic pulse wave velocity (PWV) - as a surrogate of arterial stiffness - is associated with increased cIMT and the presence of carotid plaques in a cohort of older adults of Amerindian ancestry. Methods: Atahualpa residents aged ≥60 years (n=320) underwent aortic PWV determinations, and carotid ultrasound for cIMT and plaque assessment. Multivariate models were fitted to assess the independent association between the aortic PWV, and cIMT and carotid plaques (as dependent variables), after adjusting for relevant confounders. Differences in risk factors across these biomarkers were investigated. Results: Mean values of aortic PWV were 10.3±1.8 m/s, and those of cIMT were 0.91±0.21 mm (24% had a cIMT &gt;1 mm). Carotid plaques were observed in 118 (37%) subjects. In univariate analyses, risk factors associated with an increased aortic PWV included age, female gender, poor physical activity and high blood pressure. An increased cIMT was associated with age, male gender, poor diet, high blood pressure and severe edentulism. The presence of carotid plaques was associated with increasing age, poor physical activity and high blood pressure. A fully-adjusted generalized linear model showed a significant association between aortic PWV and cIMT (β: 0.028; 95% C.I.: 0.001 - 0.056; p =0.047). In contrast, a logistic regression model showed no association between aortic PWV and carotid plaques (OR: 1.14; 95% C.I.: 0.83 - 1.56; p =0.423), after adjusting for relevant confounders. Conclusions: This study shows an independent association between aortic PWV and cIMT but not with carotid plaques. These biomarkers may indicate distinct phenotypes for atherosclerosis.

Effect of 15 BMI-Associated Polymorphisms, Reported for Europeans, across Ethnicities and Degrees of Amerindian Ancestry in Mexican Children.

In Mexico, the genetic mechanisms underlying childhood obesity are poorly known. We evaluated the effect of loci, known to be associated with childhood body mass index (BMI) in Europeans, in Mexican children from different ethnic groups. We performed linear and logistic analyses of BMI and obesity, respectively, in Mestizos and Amerindians (Seris, Yaquis and Nahuatl speakers) from Northern (n = 369) and Central Mexico (n = 8545). We used linear models to understand the effect of degree of Amerindian ancestry (AMA) and genetic risk score (GRS) on BMI z-score. Northern Mexican Mestizos showed the highest overweight-obesity prevalence (47.4%), followed by Seri (36.2%) and Central Mexican (31.5%) children. Eleven loci (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2/rs13130484, FAIM2/rs7132908, FAM120AOS/rs944990, LMX1B/rs3829849, ADAM23/rs13387838, HOXB5/rs9299) were associated with BMI and seven (SEC16B/rs543874, OLFM4/rs12429545/rs9568856, FTO/rs9939609, MC4R/rs6567160, GNPDA2 rs13130484, LMX1B/rs3829849) were associated with obesity in Central Mexican children. One SNP was associated with obesity in Northern Mexicans and Yaquis (SEC16B/rs543874). We found higher BMI z-score at higher GRS (β = 0.11, p = 0.2 × 10−16) and at lower AMA (β = −0.05, p = 6.8 × 10−7). The GRS interacts with AMA to increase BMI (β = 0.03, p = 6.08 × 10−3). High genetic BMI susceptibility increase the risk of higher BMI, including in Amerindian children.

Assessment of Neck Grasp as a Screening Tool for Identifying Obstructive Sleep Apnea in Community-Dwelling Older Adults.

BackgroundInability to encircle the neck by hands (neck grasp) has been proposed as an indicator of obstructive sleep apnea (OSA) that would be useful for recognition of candidates for polysomnography (PSG). We assessed the value of neck grasp for predicting OSA in community-dwelling older adults of Amerindian ancestry.MethodsNeck grasp was evaluated in individuals aged ≥60 years undergoing PSG. The association between neck grasp and OSA was assessed by logistic regression models adjusted for relevant covariates. Mediation analysis was used to establish the proportion of the effect of the association between neck grasp and OSA, which is mediated by the neck circumference (a well-known OSA biomarker). Receiver operator characteristics curve analysis was used to estimate diagnostic accuracy of neck grasp for predicting OSA.ResultsOf 201 individuals undergoing PSG, 167 (83%) had the neck grasp test. The remaining 34 could not perform the test because of different factors. Neck grasp was positive in 127 (76%) cases, and 114 (68%) individuals had OSA (apnea-hypopnea index ≥5). Multivariate logistic regression models disclosed a significant association between neck grasp and OSA. The neck circumference was the single covariate remaining independently significant in these models. Neck grasp was not efficient at predicting OSA (sensitivity: 83.3%, specificity: 39.6%, positive predictive value: 0.75 and negative predictive value: 0.53). The area under the curve disclosed only a moderate predictive capability (61.5%) of neck grasp.ConclusionResults do not support the use of neck grasp as an independent predictor of OSA in the study population.

ITGAM is a risk factor to systemic lupus erythematosus and possibly a protection factor to rheumatoid arthritis in patients from Mexico.

ITGAM has consistently been associated with susceptibility to systemic lupus erythematosus (SLE) in many ethnically diverse populations. However, in populations with higher Amerindian ancestry (like Yucatan) or highly admixed population (like Mexican), ITGAM has seldom been evaluated (except few studies where patients with childhood-onset SLE were included). In addition, ITGAM has seldom been evaluated in patients with rheumatoid arthritis (RA). Here, we evaluated whether four single nucleotide polymorphisms (SNPs), located within ITGAM, were associated with SLE and RA susceptibility in patients from Mexico. Our study consisted of 1,462 individuals, which included 363 patients with SLE (292 from Central Mexico and 71 from Yucatan), and 621 healthy controls (504 from Central Mexico and 117 from Yucatan). Our study also included 478 patients with RA from Central Mexico. TaqMan assays were used to obtain the genotypes of the four SNPs: rs34572943 (G/A), rs1143679 (G/A), rs9888739 (C/T), and rs1143683 (C/T). We also verified the genotypes by Sanger sequencing. Fisher's exact test and permutation test were employed to evaluate the distribution of genotype, allele, and haplotype between patients and controls. Our data show that all four ITGAM SNPs are significantly associated with susceptibility to SLE using both genotypic and allelic association tests (corrected for multiple testing, but not for population stratification). A second study carried out in patients from Yucatan, a southeastern part of Mexico (with a high Amerindian ancestry), also replicated SLE association with all four SNPs, including the functional SNP, rs1143679 (OR = 24.6 and p = 9.3X10-6). On the other hand, none of the four SNPs are significant in RA after multiple testing. Interestingly, the GACC haplotype, which carries the ITGAM rs1143679 (A) minor allele, showed an association with protection against RA (OR = 0.14 and p = 3.0x10-4). Our data displayed that ITGAM is a risk factor to SLE in individuals of Mexican population. Concurrently, a risk haplotype in ITGAM confers protection against RA.

Genome-Wide Association Study of Body Mass Index and Body Fat in Mexican-Mestizo Children.

Background: Childhood obesity is a major health problem in Mexico. Obesity prevalence estimated by body mass index (BMI) is almost half than that estimated by percent body fat (%BF) in the Childhood Obesity pediatric cohort (COIPIS). Objective. We performed a genome-wide association study (GWAS) of BMI and %BF in 828 children from the COIPIS to identify markers of predisposition to high values for both phenotypes used for obesity classification. Methods: For the GWAS we used the LAT Axiom 1, Affymetrix and 2.5 million single loci from the 1000 Genomes Phase 3 imputation panel. We used a linear model, adjusted by age, sex, and Amerindian ancestry assuming an additive inheritance model. Results. Genome-wide significance (p ≤ 5.0 × 10−8) and 80% of statistical power was reached for associations of two loci in two genes (CERS3 and CYP2E1) to BMI. Also, 11 loci in six genes (ANKS1B, ARNTL2, KCNS3, LMNB1, SRGAP3, TRPC7) reached genome-wide significance for associations to %BF, though not 80% of statistical power. Discussion: None of the SNPs were previously reported as being associated to BMI or %BF. In addition, different loci were found for BMI and %BF. These results highlight the importance of gaining deeper understanding of genetic markers of predisposition to high values for the phenotypes used for obesity diagnosis.

Copy number variants in lipid metabolism genes are associated with gallstones disease in men

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10–20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10–4; OR = 2.76; CI 95% = 1.53–4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.