Amerindian Ancestry Research Articles

Influence of genomic ancestry and self-reported color-race in CKD in a nationwide admixed sample of Brazilian patients with type 1 diabetes.

AimsPatients with diabetes that are African-Americans or Asians have a higher chance of developing diabetic nephropathy than Caucasian. Our objective was to evaluate the association between self-reported color-race, genomic ancestry, and the presence of chronic kidney disease (CKD), assessed by glomerular filtration rate and albuminuria in patients with type 1 diabetes.MethodsThis is a multicenter, observational, cross-sectional study with 1564 patients, conducted between August 2011 and August 2014 in 14 public clinics from 10 Brazilian cities. The ethnic aspects of the patients were evaluated using self-reported color-race and genomic ancestry (divided in European, African, and Amerindian). We divided the patients into groups: normal renal function and CKD.ResultsMore patients self-declared themselves as black and brown in the group with CKD. The multivariate logistic analysis revealed that self-reported color-race was not associated with CKD and that a higher African ancestry was also not associated with CKD (p=0.06). Patients with an African ancestry of 50% or higher had an association with CKD that did not persist after the multivariate analysis.ConclusionIn our patients, from an admixed, multi-ethnic population, we did not find an association between self-reported color-race, genomic ancestry and CKD. It is important to note that despite the fact that we did not find a significant p-value in the multivariate analysis concerning African ancestry and CKD, we found a narrow confidence interval (0.961–3.98) with an OR of 1.956. Further studies should be conducted to confirm the lack of association between African ancestry and CKD, especially from populations with higher African or Amerindian ancestries to better understand the association between self-reported color-race and genomic ancestry with CKD.

A systematic literature review on the European, African and Amerindian genetic ancestry components on Brazilian health outcomes

The variables such as race, skin colour and ethnicity have become intensely discussed in medicine research, as a response to the rising debate over the importance of the ethnic-racial dimension in the scope of health-disease processes. The aim of this study was to identify the European (EUR), African (AFR) and Amerindian (AMR) ancestries on Brazilian health outcomes through a systematic literature review. This study was carried out by searching in three electronic databases, for studies published between 2005 and 2017. A total of 13 papers were eligible. The search identified the following health outcomes: visceral leishmaniosis, malaria, Alzheimer’s disease, neuromyelitis optica, multiple sclerosis, prostate cancer, non-syndromic cleft lip/palate, chronic heart failure, sickle cell disease, primary congenital glaucoma, preterm labour, preterm premature rupture of membranes, systemic lupus erythematosus and type 1 diabetes mellitus. Research paper assessments were guided by the STROBE instrument, and agreements between results were determined by comparing the points attributed by two authors. Increased EUR ancestry was identified from preterm labour (PTL), type 1 diabetes (T1D) and non-syndromic cleft lip with or without cleft palate (NSCL), as well as in patients presenting aggressive prostate cancer prognoses. On the other hand, the highest AFR ancestral component was verified from systemic lupus erythematosus (SLE) and primary congenital glaucoma (PCG) cases, presenting worse prognoses. AMR ancestry may be a protective factor in the development of Alzheimer’s disease (AD). The worst hemodynamic parameters in cases of heart failure (HF) were identified among individuals with greater AMR and AFR ancestry indices.

A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos.

We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries. We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies. Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

Epidemiological, clinical, and severity characterization of sickle cell disease in a population from the Brazilian Amazon

Objective/backgroundSickle cell disease (SCD) is a chronic inflammatory condition caused by a point mutation in the HBB gene. Here we characterized the clinical presentation of SCD in a population from Amazonas State in northern Brazil, in order to evaluate whether the higher Amerindian ancestry observed in this relatively isolated geographic region would influence the clinical presentation of SCD. MethodsThis was a cross-sectional study characterizing the clinical presentation of SCD patients registered at HEMOAM, Amazon, Brazil. Data were obtained using a structured questionnaire, and by a review of the medical records. ResultsOf the 236 SCD patients listed in the historical records, 122 were included in this study. The median age was 15 years, with a male to female ratio of 52:70. The population was characterized by a high level of socioeconomic vulnerability, with only 2.1% presenting a family income above five minimum wages. Homozygous HbS (SS) was the most prevalent form of SCD (89.7%), and the diagnosis of SCD was performed in the context of complications in 92.3% of patients. The median frequency of vaso-occlusive crisis in the past 12 months was 2 (0–10). Using a validated clinical severity score based on clinical and laboratory data, no significant difference could be observed when compared to other populations. ConclusionOur results represent the first comprehensive characterization of epidemiological, laboratorial, and clinical data of SCD in the region of the Brazilian Amazon. Despite the higher contribution of Amerindian ancestry previously demonstrated in this region, the main clinical characteristics of SCD seem similar to those reported in other populations.

Evaluation of variants in IL6R, TLR3, and DC-SIGN genes associated with dengue in sampled Colombian population

Host genetics is recognized as an influential factor for the development of dengue disease. This study evaluated the association of dengue with the polymorphisms rs8192284 for gene IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN. Of the 292 surveyed subjects, 191 were confirmed for dengue fever and the remaining 101 were included as controls. The genotypes were resolved using polymerase chain reaction and restriction fragment length polymorphism (PCRRFLP). In an attempt to determine the risk (Odds Ratio) of suffering dengue fever, data were analyzed using chi-square for alleles and logistic regression for both genotypes and allelic combinations. Confidence intervals were set to 95% for all tests regardless of the adjustment by either self-identification or ancestry. For Afro-Colombians, the allele rs8192284 C offered protection against dengue [OR=0.425,(0.204-0.887), p=0.020]. The alleles rs7248637 A and rs3775290 A posed, respectively, an increased risk of dengue for Afro-Colombians [OR=2.389, (1.170-4.879), p=0.015] and Mestizos [OR=2.329, (1.283-4.226), p=0.005]. The reproducibility for rs8192284 C/C [OR=2.45, (1.05-5.76), p=0.013] remained after adjustment by Amerindian ancestry [OR=2.52, (1.04-6.09), p=0.013]. The reproducibility for rs3775290 A/A [OR=2.48, (1.09-5.65), p=0.033] remained after adjustment by European [OR=2.34, (1.02-5.35), p=0.048], Amerindian [OR=2.49, (1.09-5.66), p=0.035], and African ancestry [OR=2.37, (1.04-5.41), p=0.046]. Finally, the association of dengue fever with the allelic combination CAG [OR=2.07, (1.06-4.05), p=0.033] remained after adjustment by Amerindian ancestry [OR=2.16, (1.09-4.28), p=0.028]. Polymorphisms rs8192284 for IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN were associated with the susceptibility to suffer dengue fever in the sampled Colombian population.

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen

Background/PurposeHigh serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE. MethodsWe previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture. ResultsWe find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10−6). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription. ConclusionThis study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2<90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P<5.7×10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2<90% (P<10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2<90% after adjusting for multiple tests (P<8×10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

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

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.

Association between Vitamin D Deficiency and Single Nucleotide Polymorphisms in the Vitamin D Receptor and GC Genes and Analysis of Their Distribution in Mexican Postmenopausal Women.

Genome-wide association studies in people with European ancestry suggest that polymorphisms in genes involved in vitamin D (VD) metabolism have an effect on serum concentrations of 25-hydroxyvitamin D. However, nothing is known about these polymorphisms in populations with Amerindian ancestry. Our aim was to evaluate the association between genetic variants on the vitamin D receptor (VDR) and the vitamin D binding protein (GC) genes, involved in the VD pathway, and VD deficiency in 689 unrelated Mexican postmenopausal women. We also described the frequencies of these variants in 355 postmenopausal women from different ethnic groups. Based on our preliminary results of 400 unrelated Mexican postmenopausal women, three single nucleotide polymorphisms (SNPs) were selected for genotyping. The SNPs rs4516035 in VDR and rs2282679 in GC were associated with VD deficiency. Additionally, women who carried three risk alleles had a 3.67 times higher risk of suffering VD deficiency, compared to women with no risk alleles (p = 0.002). The rs4516035-C allele frequency in the Amerindian population was enriched in the South East region of Mexico. In contrast, the highest frequency of the rs2298850-C allele, a proxy for the tag SNP rs2282679, was observed in the South region. Our results indicate that genetic variants in VDR and GC genes are associated with VD deficiency in Mexican postmenopausal women. Moreover, an association was observed for the variants rs3794060 and rs4944957 of the DHCR7/NADSYN1 gene with osteopenia/osteoporosis.

Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil.

BackgroundPhenylketonuria (PKU) is an autosomal recessive disease resulting from mutations in the PAH gene. Most of the patients are compound heterozygotes, and genotype is a major factor in determining the phenotypic variability of PKU. More than 1,000 variants have been described in the PAH gene. Rio de Janeiro's population has a predominance of Iberian, followed by African and Amerindian ancestries. It is expected that most PKU variants in this Brazilian state have originated in the Iberian Peninsula. However, rare European, African or pathogenic variants that are characteristic of the admixed population of the state might also be found.MethodsA total of 102 patients were included in this study. Genomic DNA was isolated from dried blood spots. Sanger sequencing was used for PAH gene variant identification. Deletions and duplications were also screened using MLPA analysis. Haplotypes were also determined.ResultsNine (8.8%) homozygous and 93 (91.2%) compound heterozygous patients were found. The spectrum included 37 causative mutations. Missense, nonsense, and splicing pathogenic variants corresponded to 63.7%, 2.9%, and 22.6% of the mutant alleles, respectively. Large (1.5%), and small deletions, inframe (5.4%) and with frameshift (3.9%), comprised the remainder. The most frequent pathogenic variants were: p.V388M (12.7%), p.R261Q (11.8%), IVS10‐11G>A (10.3%), IVS2+5G>C (6.4%), p.S349P (6.4%), p.R252W (5.4%), p.I65T (4.4%), p.T323del (4.4%), and p.P281L (3.4%). One novel variant was detected: c.934G>T (p.G312C) [rs763115697].ConclusionThe three most frequent pathogenic variants in our study (34.8% of the alleles) were also the most common in other Brazilian states, Portugal, and Spain (p.V388M, p.R261Q, IVS10‐11G>A), corroborating that the Iberian Peninsula is the major source of PAH mutations in Rio de Janeiro. Pathogenic variants that have other geographical origins, such IVS2+5G>C, p.G352Vfs*48, and IVS12+1G>A were also detected. Genetic drift and founder effect may have also played a role in the mutation spectrum we observed.

The potential European genetic predisposition for non-contact anterior cruciate ligament injury

Previous research has provided evidence of a hereditary predisposition for anterior cruciate ligament (ACL) injury. The purpose of this study was to evaluate the association between ancestral population genetics and risk of non-contact ACL injuries. Blood samples were collected from 177 individuals with a history of non-contact ACL injury and 556 non-injured control individuals for analysis of the genetic material through the use of a panel of 48 INDELs ancestry genetic markers from three ancestral origins. Among patients with non-contact ACL injury, 82% were male and 18% were female. In the control group, 78% were male, and 22% were female. The mean age of the non-contact ACL injury group was 31.7years (± 10.2), and the control group was 33.8years (± 13.2). The individual genetic contribution from INDELs of each ancestral origin varied considerably: ranging between 1.5-94.8% contribution for INDELs of African origin (mean of 21.4% of INDELs); between 2 and 96.1% contribution for INDELs of European origin (mean of 66.7% of INDELs); and between 1.3-96.4% contribution for INDELs of Amerindian origin (mean of 11.7% of INDELs). When comparing paired subjects from the non-contact ACL and control groups, the genetic analysis showed that the European ancestry score was higher in the non-contact ACL group than control group (0.70 ± 0.21 vs 0.63 ± 0.22 respectively, p < 0.001), whereas African ancestry scores (ACL group 0.18 ± 0.18 vs control group 0.24 ± 0.21, p < 0.001) and Amerindian ancestry scores (ACL group 0.11 ± 0.09 vs control group 0.12 ± 0.10, n.s.) were lower among the non-contact ACL group than in controls. European INDELs markers were found to represent a potential genetic predisposition for non-contact ACL injuries when compared to African and Amerindian INDELs. This study has the potential to correlate a measurable and distinct genetic marker with risk of a non-contact ACL injury. Thus, it increases knowledge base and volume of molecular and genetical factors associated with this pathology. Furthermore, this study provides guidance and evidence for the development of genetic risk-screening panels for non-contact ACL injury. Level III Diagnostic Study.

2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population.

The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here, we investigated 5 reported genome-wide loci for NSCL±P in an ancestry-structured case-control study containing 1697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single-markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL±P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31-2.24, P = 9 × 10-6 ) in the homozygous state. Several SNP-SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3-loci among rs7552, rs9891446 and rs73039426 (P = 6.1 × 10-9 and p1000 permutation = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL±P in the highly admixed Brazilian population.

Influence of pharmacogenetic polymorphisms and demographic variables on metformin pharmacokinetics in an admixed Brazilian cohort.

To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration-time curve, between 0 and 48h (AUC0-48h ), after single oral doses of metformin (500 or 1000mg). The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC0-48h 's (nghml-1 mg-1 ) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95% confidence interval; P=6.10-26 , t test). Multivariate modelling revealed that metformin AUC0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0-48h .

Genetic ancestry of patients with porphyria cutanea tarda in a country with mixed races: a cross-sectional study (Rio de Janeiro - Brazil)

Porphyria cutanea tarda has a complex etiology with genetic factors not completely elucidated. The miscegenation of the Brazilian population has important implications in the predisposition to diseases. There are no studies concerning the genetic ancestry of patients with porphyria cutanea tarda from a mixed population. Thirty patients living in Rio de Janeiro with sporadic porphyria cutanea tarda were studied for the genetic ancestry through informative markers - INDELS. There was a significant predominance of European ancestry across the sample of patients with porphyria cutanea tarda (70.2%), and a small contribution of African and Amerindian ancestry, 20.1% and 10.9%, respectively.

A Locus on Chromosome 5 Is Associated with Red Cell Allo-Immunization in Adults with Sickle Cell Disease

Background: Transfusion is a standard treatment for acute and chronic complications of sickle cell disease (SCD). This therapy is limited by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patient populations. Reasons for this increased prevalence have not been elucidated. One model based study suggested a genetic predisposition in all patient populations. Other studies have provided evidence that antigen mismatches occur commonly between blood donors of European ancestry and SCD patients and that this is a primary cause for alloimmunization. Accordingly, limited phenotypic antigen matching is a standard practice used to minimize alloimmunization risk. We hypothesized that if these population differences are the biologic basis for this phenomenon that admixture mapping could identify significant susceptibility loci.Methods: A cohort study consisting of adults evaluated at NIH and Howard University between 2001-2015 (n=721) had allo-antibody status confirmed with the blood bank at the hospital where the most recent transfusion was performed. Genomic DNA was genotyped for a panel of 1622 ancestry informative SNPs in 359 patients. Genotypes were used to infer ancestry proportions using Structure software assuming a 3 population model. Ancestry was analyzed by regression along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where ancestry differences between cases and controls suggested an association. We used AncestryMap for a log-additive case control study assuming various risk models.Results: Five hundred fifty four subjects (77% of cohort) had a transfusion history with 153 (27.6 %) with allo-antibodies and 65 (11.7 %) with no prior transfusions. Antibodies directed against RH, Kell, MNS and Duffy antigens were the most prevalent. Clinical factors associated with alloimmunization in regression models were only significant for lifetime transfusion history by both logistic (antibody status, β=0.56, P=6.31 x 10-6) and linear (number of antibodies, β=0.35, P=0.0004) regressions. When considering genotype data, Amerindian ancestry was associated with antibody status (logistic, β=4.60, P=0.03) and number of antibodies (linear, β=4.92, P=0.006), while African and European ancestry were not. The association between ancestry and alloimmunization risk remained unchanged when the number of prior transfusions was also included in both multivariable models for alloimmunization status and number of antibodies, P=0.09 and P=0.06, respectively. Genome wide mapping by admixture linkage disequilibrium compared 91 allo-Ab cases to 210 controls with prior transfusions under 10 different risk models (range 0.25-9.0). The most significant result was the 0.25 risk model which was highly suggestive for association (genome log factor 10.96, P<0.001; Figure 1A). This scan identified region of chromosome 5 (5q21.3-5q31.1) defined by 14 snps spanning 21.685 Mb and a highly significant peak LOD score of 13.5 (Figure 1B). While this region contains >540 genes, the linkage region is noteworthy for a cytokine gene cluster implicated in hematopoiesis and immune responses.Conclusions: In a large cohort of adults with SCD, the prevalence of red cell alloimmunization is 27.6%. Amerindian ancestry is a risk factor and suggests a genetic component to this phenotype. The number of prior transfusions is also a significant risk factor. Genome wide admixture mapping identified a strong association at chromosome 5q21.3-5q31.1 using a 0.25 risk model. This chromosome 5 association is particularly interesting given the presence a cytokine gene cluster within a portion of the associated region. Analysis of larger, admixed populations will help to fine map allo-immunization susceptibility variants within specific genes that underlie these loci. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

In vitro determination of Mexican Mestizo hair shaft diameter using optical coherence tomography.

Mexican mestizo population has a pluriethnic mixture of Amerindian, European and African ancestry, predominant in most Latin American countries. Until now, there are no reports about hair characteristics in this population, necessary to define normal values, for hair diseases evaluation and comparison among other ethnic groups. The VivoSight® swept-source multibeam optical coherence tomography system was used to evaluate hair diameter and shape in 30 females. Three hair samples from each volunteer were measured transversely along three distances, generating nine cross-sectional images, two measurements per image and 18 measurements per patient for a total of 540 diameter measurements. Minimum hair diameter (n=540) was 0.06mm while maximum was 0.14mm. Mean diameter was 0.10±0.01mm as compared with Asian hair, which ranges from 0.08mm to 0.12mm. On morphological analysis, Mexican Mestizo hair tends to have a round shape with homogenous diameters, resembling Caucasian and Asian hair. Mexican hair is similar to Asian hair in diameter and shape and can be classified as 'thick' hair, which make it more resistant and with more volume. Cosmetic products intended to improve hair care in this population must to consider this characteristic.

Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits.

Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), and pulse pressure (PP), in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian), for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP) and 0.04 (SBP) in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001) in a targeted association study of Blood Pressure (BP) traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations.

Effects of Amerindian Genetic Ancestry on Clinical Variables and Therapy in Patients with Rheumatoid Arthritis.

To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America. Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history. Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p < 0.0001, OR 0.05), rheumatoid factor (RF; p < 0.0001, OR 0.22), radiographic changes (p < 0.0001, OR 0.05), and higher number of criteria were associated with lower Amerindian ancestry after Bonferroni correction. Higher Amerindian ancestry correlated only with weight loss (pBonferroni < 0.0001, OR 2.85). Increased Amerindian ancestry correlated with higher doses of azathioprine (p < 0.0001, OR 163.6) and sulfasalazine (p < 0.0001, OR 48.6), and inversely with methotrexate (p = 0.001, OR 0.35), leflunomide (p = 0.001, OR 0.16), and nonsteroidal antiinflammatory drugs (pBonferroni = 0.001, OR 0.37). Only the presence of RF and weight loss were modified after confounders adjustment. Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles.

Origin of the myotonic dystrophy type 1 mutation in Mexican population and influence of Amerindian ancestry on CTG repeat allelic distribution

Myotonic dystrophy type 1 is caused by expansion of a CTG trinucleotide repeat situated in the DMPK gene. Worldwide genetic studies suggest a single or limited number of mutational events cause the disease. However, distribution of CTG alleles and disease incidence varies among ethnicities. Due to the great ethnic diversity of the Mexican population, the present study was aimed at analyzing the impact of different lineages in shaping the CTG-repeat allelic distribution in the contemporary Mexican-Mestizo population as well as to shed light on the DM1 ancestral origin. Distribution of CTG-repeat alleles was similar among Mestizo and Amerindian subpopulations with (CTG)11–13 being the most frequent alleles in both groups, which implies that Mexican-Mestizo allelic distribution has been modeled by Amerindian ancestry. We diagnosed a relatively high number of cases, consistent with the high frequency of large-normal alleles found in Mexican subpopulations. Haplotype analysis using various polymorphic-markers in proximity to DMPK gene indicates that a single founder mutation originates myotonic dystrophy type 1 in Mexico; however, Y-STR haplogroups data and the presence of pre-mutated and large normal alleles in Amerindians support the hypothesis that both European and Amerindian ancestral chromosomes might have introduced the disease to the Mexican population, which was further disseminated through mestizaje.