Japanese Ancestry Research Articles

Development and validation of genome-wide polygenic risk scores for predicting breast cancer incidence in Japanese females: a population-based case-cohort study.

This study aimed to develop an ancestry-specific polygenic risk scores (PRSs) for the prediction of breast cancer events in Japanese females and validate it in a longitudinal cohort study. Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9years) according to the maximal predictive ability by Harrell's C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9years). For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PT = 0.05 and R2 = 0.2) derived from Japanese-ancestry GWAS, the Harrell's C-statistic was 0.598 ± 0.018 in the evaluation dataset. The age-adjusted hazard ratio for breast cancer in females with the highest PRS quintile compared with those in the lowest PRS quintile was 2.47 (95% confidence intervals, 1.64-3.70). The PRS constructed using Japanese-ancestry GWAS demonstrated better predictive performance for breast cancer in Japanese females than that using European-ancestry GWAS (Harrell's C-statistics 0.598 versus 0.586). This study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.

Efficacy and safety of pelacarsen in lowering Lp(a) in healthy Japanese subjects

BackgroundPelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a) [Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively studied. ObjectiveTo assess the effect of pelacarsen, including monthly dosing of 80 mg, in subjects of Japanese ancestry. MethodsA randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The primary objective was to assess the safety and tolerability in healthy Japanese subjects; secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory objective to determine the effect of pelacarsen on plasma Lp(a) levels. ResultsNo serious adverse events or clinically relevant abnormalities in any laboratory parameters were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4 hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were: -55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and 80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days 29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001), -80.0% (p=0.0104) and -55.8% (p=0.0707), respectively. ConclusionsPelacarsen demonstrates an acceptable safety and tolerability profile and potently lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80 mg monthly dose being evaluated in the Lp(a) HORIZON trial.

Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants.

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000mg in fed and fasted states, and as 2×3000-mg doses given 12hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64kg versus ≈80kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.

BOT-3 GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL GERM CELL TUMORS: A COMMON DELETION ATBAK1 ATTENUATES THE ENHANCER ACTIVITY AND CONFERS RISK FOR THE BRAIN TUMORS IN CHILDREN ADOLESCENTS AND YOUNG ADULTS

Abstract Intracranial germ cell tumors (IGCTs) are rare brain tumors that mainly occur in children, adolescents and young adults with a particularly high incidence in East Asian populations. The biological basis of these tumors is still largely unknown. We conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry by using Infinium Asian Screening Array and other molecular biology methods. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. Expression quantitative trait locus (eQTL) analysis using the GTEx dataset reveals that the risk allele of rs3831846 has a down-regulating effect on BAK1 expression in a wide range of tissues. Further in-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity. BAK1 is a pro-apoptotic member of the BCL-2 family, thus our results suggested that the risk allele may contribute to IGCTs predisposition through down-regulating BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman’s ρ = 0.48). Of the 57 loci, 11 exhibit significant association with IGCTs and these loci were implicated in a broad range of biological pathways, including KIT/KITLG signaling, apoptosis regulation, and telomerase activity. The risk allele frequency of rs3831846 is higher in east Asia than Europe (0.49 vs. 0.20), which may provide a partial explanation for the ethnic difference in incidence. Nevertheless, our results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Uncover Marginalized Narratives of Japanese American Incarceration: An Annotation Scheme for Natural Language Processing and Data Analytics

ABSTRACTAround 120,000 people of Japanese ancestry was forced to remove into internment camps in the United States during World War II. Densho Digital Repository curates a collection of oral histories, which mainly includes 904 filmed interviews about “Japanese American incarceration experience from those who lived it”. This study uses web scraping techniques to collect 904 narrators’ bio information and analyzes their demographic information, including race, age, and location. Nisei counts the most of the Japanese American narrators (78.82% of all narrators). 279 (39.35%) of narrators were minors (born between 1926 and 1942) in the year 1942, when the incarceration happened, with over half of them (58.78%) being teenagers (age between 12 and 17). The majority of narrators (82.09% of the total) are from the west coast, namely, Washington State, Oregon State, or California State. This study also constructs a scheme for incarceration oral history, based on which the incarceration historical texts can be manually or/and automatically processed. The annotation scheme includes seven categories: (1) pre‐war background to the incarceration; (2) government's decision to remove ethnic Japanese; (3) life after removal and during the incarceration; (4) military services; (5) returning of ethnic Japanese after WWII; (6) legal challenges; (7) redress movement.

Graphic Deconstruction of Spatially Marked Race in Miné Okubo's Citizen 13660

Miné Okubo's Citizen 13660 is an autobiographical graphic novel about the Japanese concentration camp during the Second World War. From the perspective of an evacuee and Japanese American, Citizen 13660 rewrites Japanese American identity, which confronts the rhetoric of “enemy race” and the frontier myth that normalized the camp. The graphic novel reveals how deeply the War Relocation Authority (WRA) engaged in the spatial and social exclusion of the minority groups and, by doing so, negatively affected their racial identities. Shedding light on Lefebvre’s theory of the spatiality of power, which emphasizes that spatial order reflects the society’s hegemonic power and shapes the dwellers’ identity, this paper will analyze how the state power deindividualized and criminalized people of Japanese ancestry as a homogenous crowd of “enemy race” through spatial control. This paper will also investigate how Citizen 13660 creatively visualizes, reenacts and re-examine the WRA’s spatial politics with its spatial elements (the shape of panels or the arrangements of gutters, panels, lines, and objects), borrowing McCloud’s analysis of the spatiality of the graphic novel. With unique arrangements of spatial elements in Citizen 13660, Okubo asserts the necessity to dismantle the biologically essentialist concept of race, re-individualize people of Japanese ancestry, and challenge the legitimacy of the camp.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Review: Japanese American Incarceration: The Camps and Coerced Labor During World War II, by Stephanie D. Hinnershitz

Stephanie Hinnershitz’s groundbreaking account investigates how the prison labor system was imposed on Japanese Americans and permanent resident non-citizens of Japanese ancestry who were confined in War Relocation Authority (WRA) incarceration camps (formerly “internment” camps) during World War II. The actual internment camps (for non-citizens of Japanese, German, and Italian ancestry, run by the Immigration and Naturalization Service for the Justice Department) are not included in this book.The temporary detention centers (formerly the euphemistic “assembly centers”) that first housed the incarcerees established Work Corps in which prisoners signed up to work in the skilled and unskilled jobs needed to operate the facilities. Wages could not exceed the minimum wage of an American soldier, $21 a month (pp. 42–43). Employing the prisoners meant that costs to operate the detention centers, and later the WRA incarceration camps, were much less than if the workers were Euroamericans hired at prevailing rates. The government established four rationales to explain the purpose and goals of incarceration: Japanese American labor was essential for self-sufficiency, community building, and the “pioneer spirit”; the prisoners needed to prove their loyalty and patriotism; working would build morale; and work was voluntary (pp. 18–19). Some 40 to 60 percent were employed, but unfortunately, and especially for work outside the camps, contracts with the incarcerees were often violated or manipulated, and poor working conditions led to protests, work stoppages, and even strikes. If the incarcerees did not work, they risked being labeled “disloyal or suspect” (p. 60).By 1944, some 33,000 Japanese Americans had signed contracts to work for farmers, especially in the sugar beet fields of Oregon, Idaho, Montana, Nebraska, Utah, and elsewhere (pp. 85–86). The opportunity to leave the camps, even for hard work and poor working conditions, was a big motivator in getting people to sign up for this employment. However, many of the imprisoned Japanese Americans truly wished to contribute to the war effort and would have resisted being characterized, even by implication, as exploited dupes of the U.S. government.The Poston, Arizona, incarceration camp, discussed in detail, was built on land belonging to the Colorado River Indian Reservation. There, the Office of Indian Affairs (OIA) had lost the funding that hired Native Americans to work on reservation infrastructure projects such as clearing and cultivating land and installing irrigation systems. The OIA thus saw the Japanese Americans as the answer to their labor shortage; Poston was therefore unique in that much of the incarcerees’ labor involved the completion of “infrastructure for another colonized and subjugated people” (p. 161).The book’s notes are excellent and comprehensive, but a longer bibliography would have been more helpful than the single page of “Published Primary Sources” (p. 296). Additionally, more rigorous proofreading could have eliminated some regrettable typographical errors, e.g., “payed” (for paid, p. 177), “Minori Yusui” (for Minoru Yasui, pp. 249, 309), and Sue “Kunitoi” (for Kunitomi, p. 275). Still, these and other imperfections do little to detract from this significant contribution to the literature of Japanese American incarceration.

The Political Consequences of Ethnically Targeted Incarceration: Evidence from Japanese American Internment during World War II

What are the downstream political consequences of state activity explicitly targeting an ethnic minority group? This question is well studied in the comparative context, but less is known about the effects of explicitly racist state activity in liberal democracies such as the United States. We investigate this question by looking at an important event in American history—the incarceration of people of Japanese ancestry during World War II. We find that Japanese Americans who were imprisoned or had family who were imprisoned are significantly less politically engaged and that these patterns of disengagement increase with detention length. Using an identification strategy leveraging quasi-random camp assignment, we also find that camp experience matters: those who went to camps that witnessed intragroup violence or demonstrations experienced sharper declines, suggesting that group fragmentation is an important mechanism of disengagement. Taken together, our findings contribute to a growing literature documenting the demobilizing effects of ethnically targeted detention and expand our understanding of these forces within the United States.

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity.

ABSTRACTTreatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population‐specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady‐state AUC0‐τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26–9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4–30.1] ng·h/ml, p < .001) population. In addition to CYP2C19‐poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.

Myopia Genetics and Heredity.

Myopia is the most common eye condition leading to visual impairment and is greatly influenced by genetics. Over the last two decades, more than 400 associated gene loci have been mapped for myopia and refractive errors via family linkage analyses, candidate gene studies, genome-wide association studies (GWAS), and next-generation sequencing (NGS). Lifestyle factors, such as excessive near work and short outdoor time, are the primary external factors affecting myopia onset and progression. Notably, besides becoming a global health issue, myopia is more prevalent and severe among East Asians than among Caucasians, especially individuals of Chinese, Japanese, and Korean ancestry. Myopia, especially high myopia, can be serious in consequences. The etiology of high myopia is complex. Prediction for progression of myopia to high myopia can help with prevention and early interventions. Prediction models are thus warranted for risk stratification. There have been vigorous investigations on molecular genetics and lifestyle factors to establish polygenic risk estimations for myopia. However, genes causing myopia have to be identified in order to shed light on pathogenesis and pathway mechanisms. This report aims to examine current evidence regarding (1) the genetic architecture of myopia; (2) currently associated myopia loci identified from the OMIM database, genetic association studies, and NGS studies; (3) gene-environment interactions; and (4) the prediction of myopia via polygenic risk scores (PRSs). The report also discusses various perspectives on myopia genetics and heredity.

More than Half: Multiracial Families in the World War II Japanese American Incarceration Camps.

In this first-person commentary, the author, an art historian, recounts family explorations of multiraciality and discrimination through her family’s literal journey to 10 camps where Japanese Americans were incarcerated during a period of xenophobia following the bombing of Pearl Harbor in 1942. In addition to Japanese immigrants (Issei) who were banned from becoming U.S. citizens and their American-born children (Nisei), multiracial spouses and children with partial Japanese ancestry were also imprisoned. The War Relocation Authority (WRA) created a series of rules that applied to interracial married couples and multiracial children. Children with Japanese fathers were considered “more than half” Japanese with the belief that the male head of the household would establish and observe the family’s cultural values and practices. Multiracial children with White fathers were treated more sympathetically stemming from a desire to protect them from absorbing Japanese customs and ideas. Within the camps, multiracial families were subject to ostracization by families of Japanese descent as well as military personnel. The author’s children, upon entering public school, endured inquiries, taunts, and microagressions from peers. As parents, the author and her spouse, a fine art photographer, visited the camp locations to understand this dark period of U.S. to explore and document the places, talk with their children about their multiracial identities, and enable growth through experience and knowledge. All of the camps are in desolate locations and most are in ruins, but lingering discrimination from this egregious historical period exist and they affected the author’s children.

Review: Enemies among Us: The Relocation, Internment, and Repatriation of German, Italian, and Japanese Americans during the Second World War, by John E. Schmitz

Review: Enemies among Us: The Relocation, Internment, and Repatriation of German, Italian, and Japanese Americans during the Second World War, by John E. Schmitz

Psychological Distress and Personality Dimensions Associated with Romantic Orientation Among Japanese Adults

Purpose: Evidence is scarce regarding the associations of romantic orientation with mental health and personality. The aims of the present study, therefore, were to examine psychological distress among homoromantic, biromantic, and heteroromantic adults and to investigate how personality dimensions influence their distress. Methods: A cross-sectional survey study was conducted between August 2018 and January 2021. Psychological distress, personality, and romantic orientation were assessed with the 6-item Kessler Psychological Distress Scale (K6), the Ten-Item Personality Inventory (TIPI), and a question about romantic orientation, respectively, in a web-based survey distributed to 11,922 participants. Saliva samples were collected for DNA extraction. After excluding those who did not cluster with Japanese ancestry and those whose genotypic sex did not match their reported sex, 11,662 individuals were included in further analyses. Results: The prevalence of being homoromantic or biromantic was 1.0% and 2.0% for females and 1.5% and 1.2% for males, respectively. Homoromantic males, but not females, had significantly higher K6 scores than their heteroromantic counterparts. Both male and female biromantic participants had significantly higher K6 scores than their heteroromantic counterparts. Furthermore, a significant association was found between romantic orientation and TIPI scores. Accounting for personality profiles did not alter the observed association between romantic orientation and psychological distress. Conclusion: Biromantic adults and homoromantic male adults of genetically confirmed Japanese ancestry living in Japan experienced higher psychological distress than heteroromantic individuals. The mental health disparities of the romantic minority individuals were irrespective of their personality profiles, suggesting the involvement of other factors such as minority stress in Japan.

An Insider’s Response to Racism: Abe Fortas and the Japanese Question during the Asia-Pacific War, 1941–1945

Abstract Abe Fortas (1910–1982) has been best known for service during his legal career as an Associate Justice on the Supreme Court of the United States for four years from 1965 to 1969. His supporters have characterized his life as a lawyer who supported and defended the American Civil Rights Movement during the tumultuous periods of the 1950s and 1960s in the United States. However, observers of his career have paid little attention to the fact that Fortas was one of the few American bureaucrats who took the stand in defense of those of Japanese ancestry in the official hearings in the 1980sinvestigating the internment of Japanese Americans during World War ii. Fortas, as undersecretary in the Department of the Interior from 1942 to 1946, had a close relationship to key U.S. policies dealing with people of Japanese ancestry during the Asia-Pacific War, including the establishment of martial law in Hawai‘i and the ending of the Japanese internment. Fortas’s responses to and critiques of U.S. policy regarding the Japanese American question reveal the intertwined dynamics of how white racism developed and challenges against it at the governmental level.

The Impact of ApoE and FOXO3 Genotype on the Risk of Intracerebral Hemorrhage Among American Men of Japanese Ancestry

This study assessed the impact of APOE e2, e4 minor alleles and the FOXO3 longevity-associated genotype (carrier of SNP rs2802292 “G” allele) on 34-year incidence of intracerebral hemorrhage (ICH). Cox regression models were performed to assess the impact of the APOE e2, e4 and FOXO3 G alleles on the incidence of ICH. A total of 6483 participants were eligible for the analyses. 213 participants developed ICH. Cox-regression model showed neither APOE minor allele vs. common genotype (APOE e3/e3: RR 0.89, 95% CI: 0.64-1.22, p=0.46) nor FOXO3 G carrier status (RR 0.97, 95% CI: 0.72-1.29, p=0.82) was associated with incident ICH. Conversely, both hypertension (RR: 1.46, 95% CI: 1.07-2.00, p=0.02) and low cholesterol level (RR: 0.99, 95% CI: 0.99-1.00, p=0.001) were associated with incident ICH. Carriage of APOE e2 or E4 alleles and the FOXO3 G allele do not appear to impact risk of ICH over 34 years in this cohort.

Evaluation of an ancestry prediction strategy for historical military remains using a World War II-era sample and pedigrees with family-level admixture

ABSTRACT Errors in ancestry prediction for historical military casework result in soldiers unable to be interred to the country they fought and died for. Australian WWII soldiers with varying degrees of European and Asian heritage are expected in the remains recovered in the Asia-Pacific, representing the greatest risk of error for Unrecovered War Casualties-Army (UWC-A). Previous research using the Ghaiyed population-specific panel (GPSP), on a modern British sample, demonstrated less variation in family-level admixture compared to four global ancestry panels. This suggested that the targeting of specific populations of interest may improve accuracy, although an evaluation using a sample of WWII-era European-Australians (W2A) with varying degrees of family-level admixture was required. This paper outlines the development of an ancestry prediction strategy using a W2A sample (non-admixed), and simulation of 4,000 genotypes representing Australian pedigrees with one Japanese ancestor (great-great-grandparent, great-grand-parent, grandparent, and parent). All great-great-grandparent to grandparent profiles were accurately predicted as W2A individuals, and although admixture at the parent level could not be resolved, no profiles were incorrectly assigned Japanese ancestry. The GPSP provided more informative predictions in contrast with the mitochondrial DNA/Y-chromosome lineage approach currently used by UWC-A as the GPSP provides an approximately 75% improvement.

Abstract 9938: Genetic Architecture and Precision Medicine of Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with increased risks of morbidity and mortality. We performed a large-scale genome-wide association study (GWAS) of 150,272 individuals of Japanese ancestry (9,826 cases and 140,446 controls) and identified five new susceptibility loci including Japanese-specific rare variants associated with the pathogenesis of cardiomyopathy. We then conducted a trans-ancestry meta-analysis of more than 1 million individuals including 77,690 cases and discovered 35 novel loci in total. Using the GWAS result, epigenetic-feature and gene-set analyses revealed the transcriptional landscape of AF, elucidating the underlying biological pathways. Additionally, we created polygenic risk scores (PRS) for AF, where PRS derived from trans-ancestry GWAS surpassed those derived from a single population. The PRS was associated with increased risk of long-term cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients, suggesting that it may play an important role in early detection of subclinical AF or the pathophysiology underlying thromboembolism. Our results provide novel biological and clinical insights into AF genetics and broaden its clinical applications.

Physiologically-based pharmacokinetic model predictions of inter-ethnic differences in imatinib pharmacokinetics and dosing regimens.

This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens. A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (Css,min ). The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained Css,min in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400-600 mg/d) to achieve the desirable range of Css,min (1000-3200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600-800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups; however, the clinical data to support this are currently limited. PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.

DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

BackgroundDentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients. MethodsWe performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed. ResultsWe describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 1). ConclusionThe patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.