Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population.

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic white populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ~80 of Amerindian (AI) ancestry provides a unique opportunity to assess the role of AI ancestry in AD. In this study, we assess the effect of the ApoE ε4 allele on AD in the Peruvian population. A total of 79 AD cases and 128 unrelated cognitive healthy controls from Peruvian population were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array v2.0. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on AD was tested using a logistic regression model by adjusting for age, gender, and population substructure (first 3 principal components). Results showed that the genetic ancestry surrounding the ApoE gene is predominantly AI (60.6%) and the ε4 allele is significantly associated with increased risk of AD in the Peruvian population (odds ratio = 5.02, confidence interval: 2.3-12.5, p-value = 2e-4). Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic white populations. Given the high admixture of AI ancestry in the Peruvian population, it suggests that the AI genetic ancestry local to the ApoE gene is contributing to a strong risk for AD in ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene.

Distribution of the CAG Triplet Repeat in ATXN1, ATXN3, and CACNA1A Loci in Peruvian Population.

Spinocerebellar ataxia subtypes 1, 3, and 6 (SCA1, MJD/SCA3, and SCA6) are among the most prevalent autosomal dominant cerebellar ataxias worldwide, but their relative frequencies in Peru are low. Frequency of large normal (LN) alleles at spinocerebellar ataxia-causative genes has been proposed to be associated with disease prevalence. To investigate the allelic distribution of the CAG repeat in ATXN1, ATXN3, and CACNA1A genes in a Peruvian mestizo population and examine their association with the relative frequency of SCA1, MJD/SCA3, and SCA6 across populations. We genotyped 213 healthy mestizo individuals from Northern Lima, Peru, for ATXN1, ATXN3, and CACNA1A using polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE). We compared the frequency of LN alleles and relative disease frequency between populations. We also tested 40 samples for CAT repeat interruptions within the CAG tract of ATXN1. We found no association between disease frequency and population frequency of LN alleles at ATXN1 and ATXN3. All 40 ATXN1 samples tested for CAT interruptions were positive. Frequency of LN alleles at CACNA1A correlates with SCA6 frequency across several populations, but this effect was largely driven by data from a single population. Low frequency of SCA1 and MJD/SCA3 in Peru is not explained by frequency of LN alleles at ATXN1 and ATXN3, respectively. The observed correlation between CACNA1A LN alleles and SCA6 frequency requires further assessment.

ATXN10 Microsatellite Distribution in a Peruvian Amerindian Population.

Spinocerebellar ataxia type 10 (SCA10) is a repeat expansion disease occurring mostly in Latin America, suggesting that the mutation spread with the peopling of the Americas, or that Amerindian populations, have a higher ATXN10 mutability. High frequency of large normal alleles is associated with prevalence and relative frequency of other repeat expansion diseases. To test whether the allele distribution of the SCA10-causing ATXN10 microsatellite in an Amerindian Peruvian population differs from that of other populations. The ATXN10 allele distribution in a Quechua Peruvian population from Puno, Peru, is similar to that of Finland. Mean allele size and mode were also similar to those of Mexico, Japan, and white Europeans. ATXN10 allele distribution in a healthy Amerindian population from Peru does not differ from that of other populations.

Haplotype Study in SCA10 Families Provides Further Evidence for a Common Ancestral Origin of the Mutation.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas. However, the ancestral origin of SCA10 mutation remains under speculation. Samples of SCA10 patients from two Latin American countries were analysed, being 16 families from Brazil (29 patients) and 21 families from Peru (27 patients) as well as 49 healthy individuals from Indigenous Quechua population and 51 healthy Brazilian individuals. Four polymorphic markers spanning a region of 5.2 cM harbouring the ATTCT expansion were used to define the haplotypes, which were genotyped by different approaches. Our data have shown that 19-CGGC-14 shared haplotype was found in 47% of Brazilian and in 63% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57%), but they are statistically different from Brazilian controls (12%) (p < 0.001). The most frequent expanded haplotype in Quechuas, 19-15-CGGC-14-10, is found in 50% of Brazilian and in 65% of Peruvian patients with SCA10. These findings bring valuable evidence that ATTCT expansion may have arisen in a Native American chromosome.

The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America.

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent. HD in Peru occurs most frequently on the A1 HTT haplotype (73%), as in Europe, but on an unexpected indigenous variant also found in Amerindian controls. This Amerindian A1 HTT haplotype predominates over the European A1 variant among geographically disparate Latin American controls and in HD families from across Latin America, supporting an indigenous origin of the HD mutation in mestizo American populations. We also show that a proportion of HD mutations in Peru occur on a C1 HTT haplotype of putative Amerindian origin (14%). The majority of HD mutations in Latin America may therefore occur on haplotypes of Amerindian ancestry rather than on haplotypes resulting from European admixture. Despite the distinct ethnic ancestry of Amerindian and European A1 HTT, alleles on the parent A1 HTT haplotype allow for development of identical antisense molecules to selectively silence the HD mutation in the greatest proportion of patients in both Latin American and European populations.

Homocistinuria, una enfermedad metabólica de diagnóstico tardío en el Perú / Homocystinuria, a metabolic disease of late diagnosis in Peru

La Homocistinuria, es un desorden metabólico autosómico recesivo, cuya forma clásica es causada por deficiencia de cistationina β-sintasa, debido a mutaciones en el gen CBS (Cr 21q22.3). Se describe el caso de un varón de 17 años con hipopigmentación de piel y faneras, retraso psicomotor moderado, hábito marfanoide, miopía severa, subluxación del cristalino bilateral, que además presentó eventos psicóticos y una hemiparesia izquierda secundaria a un infarto lacunar. La determinación de homocisteína en plasma se encontró elevada (>9,9mg/dl), así como niveles altos de nitroprusiato de sodio en orina (4+) que confirmaron el diagnóstico clínico de homocistinuria. La homocistinuria clásica genera múltiples complicaciones a nivel dérmico, oftalmológico, cognitivo, osteoarticular y psiquiátrico; que podrían evitarse con un diagnóstico y tratamiento oportuno a través del tamizaje neonatal, aún no disponible en la mayoría de centros asistenciales en el Perú...

Homocystinuria is an autosomal-recessive metabolic disorder whose classical phenotype is caused by a deficiency of cystathionine β-synthase, due to mutations within the CBS gene (Cr21q22.3). Herein we report a 17 year old man with hypopigmented skin and hair, mental retardation, marfanoid habitus, severe myopia, bilateral lens subluxation, psychotic episodes, and left-sided hemiparesis secondary to a lacunar brain infarction. Laboratory tests showed increased levels of homocysteine (>9.9mg/dl) in plasma and high levels of urinary sodium nitroprusside (4+), consistent with the clinical diagnosis of classical homocystinuria. This systemic disorder includes dermal, ophthalmic, cognitive, osteoarticular and psychiatric alterations, all of which could be potentially prevented with early diagnosis and therapy as part of newborn screening, which is still unavailable in Peru...

Clinical and Molecular Features of Late Onset Huntington Disease in a Peruvian Cohort.

BACKGROUND: Late onset cases of Huntington disease (HD), with onset ≥60 years, account for up to 20% of HD cases worldwide. Clinical features include mild motor dysfunction with slow progression and cognitive impairment, frequent absence of family history and low number of CAG repeats. The clinical and molecular features of late onset HD is still understudied in Latin America. OBJECTIVES: To describe the clinical and molecular characteristics of late onset HD in a Peruvian cohort. METHODS: An observational study was carried out by reviewing the HD registry at the Neurogenetics Research Center-INCN from 2000 to 2014. Genotyping of HTT gene …was confirmed using standard PCR and PAGE in accordance to protocols previously established. RESULTS: Thirty-one late onset HD cases from 27 pedigrees were identified (9.42% of total HD cases, n = 329), 51.61% were male. Mean age at onset was 64.1 ± 4.2 and CAG repeats mean was 42.5 ± 2.5. We did not find significant correlation between age at onset and CAG repeats. 33.3% of cases were traced back to Cañete valley. Twenty-two cases had a positive family history, 14 of them with paternal transmission. Choreic movements and cognitive impairment were the main existing manifestations reported in this cohort, with lower frequency of psychiatric disturbances. CONCLUSIONS: This report of late onset HD affected individuals shows a mild phenotype expression of the disease, associated with low range of CAG repeats and up to 30% of cases with absence of clear family history. Cañete valley remains the region with more cases.

Neurogenetics in Peru: clinical, scientific and ethical perspectives.

Neurogenetics, the science that studies the genetic basis of the development and function of the nervous system, is a discipline of recent development in Peru, an emerging Latin American country. Herein, we review the clinical, scientific and ethical aspects regarding the development of this discipline, starting with the first molecular diagnosis of neurogenetic diseases, to family and population-based genetic association studies. Neurogenetics in Peru aims to better explain the epidemiology of monogenic and complex neurodegenerative disorders that will help in implementing public health policies for these disorders. The characterization of Peru and its health system, legal issues regarding rare diseases and the historical milestones in neurogenetics are also discussed.