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1.
Epilepsia ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913524

RESUMO

OBJECTIVE: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population. METHODS: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data. RESULTS: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24. SIGNIFICANCE: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.

2.
Nagoya J Med Sci ; 83(1): 183-194, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33727749

RESUMO

Prostate cancer is emerging as a significant global public health burden. The incidence and prevalence of prostate cancer has increased in Japan, as westernized lifestyles become more popular. Recent advances in genetic epidemiology, including genome-wide association studies (GWASs), have identified considerable numbers of human genetic factors associated with diseases. Several GWASs have reported significant loci associated with serum prostate-specific antigen (PSA) levels. One GWAS, which was based on classic GWAS microarray measurements, has been reported for Japanese so far. In the present study, we conducted a GWAS of serum PSA using 1000Genomes imputed GWAS data (n =1,216) from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, to detect candidate novel genetic loci that influence serum PSA levels in Japanese. The association of SNPs/genetic variants with serum PSA as a continuous variable was tested using the linear Wald test. SNP rs10000006 in SGMS2 (sphingomyelin synthase 2) on chromosome 4 had genome-wide significance (P <5×10-8), and eight variants on three chromosomes (chromosomes 12, 14, 15) had genome-wide suggestive levels of significance (P <1×10-6). With an independent data set from the J-MICC Shizuoka Study (n = 2,447), the association of the SGMS2 SNP with blood PSA levels was not replicated. Although our GWAS failed to detect novel loci associated with serum PSA levels in the Japanese cohort, it confirmed the significant effects of previously reported genetic loci on PSA levels in Japanese. Importantly, our results confirmed the significance of KLK3 SNPs also in Japanese, implying that consideration of individual genetic information in prostate cancer diagnosis may be possible in the future.

3.
Genet Epidemiol ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33739539

RESUMO

Previous genome-wide association studies (GWASs) have been largely focused on European (EUR) populations. However, polygenic risk scores (PRSs) derived from EUR have been shown to perform worse in non-EURs compared with EURs. In this study, we aim to improve PRS prediction in East Asians (EASs). We introduce a rescaled meta-analysis framework to combine both EUR (N = 122,175) and EAS (N = 30,801) GWAS summary statistics. To improve PRS prediction in EASs, we use a scaling factor to up-weight the EAS data, such that the resulting effect size estimates are more relevant to EASs. We then derive PRSs for EAS from the rescaled meta-analysis results of EAS and EUR data. Evaluated in an independent EAS validation data set, this approach increases the prediction liability-adjusted Nagelkerke's pseudo R2 by 40%, 41%, and 5%, respectively, compared with PRSs derived from an EAS GWAS only, EUR GWAS only, and conventional fixed-effects meta-analysis of EAS and EUR data. The PRS derived from the rescaled meta-analysis approach achieved an area under the receiver operating characteristic curve (AUC) of 0.6059, higher than AUC = 0.5782, 0.5809, 0.6008 for EAS, EUR, and conventional meta-analysis of EAS and EUR. We further compare PRSs constructed by single-nucleotide polymorphisms that have different linkage disequilibrium (LD) scores and minor allele frequencies (MAFs) between EUR and EAS, and observe that lower LD scores or MAF in EAS correspond to poorer PRS performance (AUC = 0.5677, 0.5530, respectively) than higher LD scores or MAF (AUC = 0.589, 0.5993, respectively). We finally build a PRS stratified by LD score differences in EUR and EAS using rescaled meta-analysis, and obtain an AUC of 0.6096, with improvement over other strategies investigated.

4.
Clin Transl Sci ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650309

RESUMO

Plasma coproporphyrin-I (CP-I) concentration is used as a sensitive and selective endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B) activity in many studies. CP-I is produced in the process of heme synthesis, but the relationship between plasma CP-I concentrations and heme synthesis activity is unknown. In this study, we evaluated the relationship between plasma CP-I concentration and hemoglobin level as a biomarker of heme synthesis activity. The data of 391 subjects selected from the Japanese general population were analyzed. One hundred twenty-six participants had OATP1B1*15 allele, 11 of whom were homozygous (OATP1B1*15/*15). Multiple regression analysis identified hemoglobin level as an independent variable associated with plasma CP-I concentration (p < 0.0001). A significant positive correlation was observed between hemoglobin level and plasma CP-I concentration in participants without OATP1B1*15 allele (n = 265; rs  = 0.35, p < 0.0001) and with OATP1B1*15 allele (n = 126; rs  =0.27, p = 0.0022). However, Kruskal-Wallis test showed no large difference in Kruskal-Wallis statistics between the distribution of plasma CP-I concentrations and that of ratio of plasma CP-I to hemoglobin among six OATP1B1 polymorphism groups. These findings suggest that the hemoglobin level seems to reflect biosynthesis of CP-I. However, correction by hemoglobin level is not required when using basal plasma CP-I concentration for phenotyping OATP1B activity.

5.
Am J Med Genet A ; 185(5): 1468-1480, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33624935

RESUMO

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.

6.
Jpn J Ophthalmol ; 65(3): 338-343, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33629268

RESUMO

PURPOSE: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. RESULTS: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. CONCLUSION: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

7.
Hum Mol Genet ; 30(5): 356-369, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33555323

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

8.
Br J Nutr ; : 1-9, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33632354

RESUMO

Differences in individual eating habits may be influenced by genetic factors, in addition to cultural, social or environmental factors. Previous studies suggested that genetic variants within sweet taste receptor genes family were associated with sweet taste perception and the intake of sweet foods. The aim of this study was to conduct a genome-wide association study (GWAS) to find genetic variations that affect confection consumption in a Japanese population. We analysed GWAS data on confection consumption using 14 073 participants from the Japan Multi-Institutional Collaborative Cohort study. We used a semi-quantitative FFQ to estimate food intake that was validated previously. Association of the imputed variants with confection consumption was performed by linear regression analysis with adjustments for age, sex, total energy intake and principal component analysis components 1-3. Furthermore, the analysis was repeated adjusting for alcohol intake (g/d) in addition to the above-described variables. We found 418 SNP located in 12q24 that were associated with confection consumption. SNP with the ten lowest P-values were located on nine genes including at the BRAP, ACAD10 and aldehyde dehydrogenase 2 regions on 12q24.12-13. After adjustment for alcohol intake, no variant was associated with confections intake with genome-wide significance. In conclusion, we found a significant number of SNP located on 12q24 genes that were associated with confections intake before adjustment for alcohol intake. However, all of them lost statistical significance after adjustment for alcohol intake.

9.
J Epidemiol ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33612706

RESUMO

BACKGROUND: Inflammation is thought to be a risk factor for kidney disease. However, discussion is controversial whether inflammatory status is either a cause or an outcome of chronic kidney disease. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using mendelian randomization (MR) approaches. METHODS: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. RESULTS: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 95%CI: 0.000, -0.019 to 0.020 and -0.003, -0.019 to 0.014). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 95% CI: -0.005, -0.020 to 0.010 and -0.004, -0.020 to 0.012). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: -0.008, -0.058 to 0.042; IVAsian: 0.001, -0.036 to 0.036). CONCLUSIONS: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

10.
Clin Pharmacol Ther ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33300144

RESUMO

The Nicotine Metabolite Ratio (NMR, 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in non-, former- or intermittent-smokers, for example in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European-ancestry populations (EUR) by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study we developed and replicated an African-ancestry (AFR) wGRS which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

11.
Eur J Clin Nutr ; 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33281188

RESUMO

BACKGROUND/OBJECTIVES: Individual eating habits may be influenced by genetic factors, in addition to environmental factors. Previous studies suggested that adherence to Japanese food patterns was associated with a decreased risk of all-cause and cardiovascular disease mortality. We conducted a genome-wide association study (GWAS) in a Japanese population to find genetic variations that affect adherence to a Japanese food pattern. SUBJECTS/METHODS: We analyzed GWAS data using 14,079 participants from the Japan Multi-Institutional Collaborative Cohort study. We made a Japanese food score based on six food groups. Association of the imputed variants with the Japanese food score was performed by linear regression analysis with adjustments for age, sex, total energy intake, alcohol intake (g/day), and principal components 1-10 omitting variants in the major histocompatibility region. RESULTS: We found one SNP in the 14q11.2 locus that was significantly associated with the Japanese food score with P values <5 × 10-8. Functional annotation revealed that the expression levels of two genes (BCL2L2, SLC22A17) were significantly inversely associated with this SNP. These genes are known to be related to olfaction and obesity. CONCLUSION: We found a new SNP that was associated with the Japanese food score in a Japanese population. This SNP is inversely associated with genes link to olfaction and obesity.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33309985

RESUMO

BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most common cancers in the world. A small proportion of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes. To better understand cancer risk, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations. METHODS: We analyzed the coding regions of 27 cancer-predisposing genes in 12,503 unselected Japanese CRC patients and 23,705 controls by target sequencing and genome-wide SNP chip. Their clinical significance was assessed using ClinVar and the guidelines by ACMG/AMP. RESULTS: We identified 4,804 variants in the 27 genes and annotated them as pathogenic in 397 and benign variants in 941, of which 43.6% were novel. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant. The pathogenic variants of MSH2 (odds ratio (OR) = 18.1), MLH1 (OR = 8.6), MSH6 (OR = 4.9), APC (OR = 49.4), BRIP1 (OR=3.6), BRCA1 (OR = 2.6), BRCA2 (OR = 1.9), and TP53 (OR = 1.7) were significantly associated with CRC development in the Japanese population (P-values<0.01, FDR<0.05). These pathogenic variants were significantly associated with diagnosis age and personal/family history of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes, indicating hereditary cancers. CONCLUSIONS: This largest study of CRC heredity in Asia can contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs.

13.
Environ Health Prev Med ; 25(1): 64, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129280

RESUMO

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.


Assuntos
Demência/epidemiologia , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Demência/etiologia , Demência/genética , Meio Ambiente , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco
14.
Nat Genet ; 52(11): 1169-1177, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33020668

RESUMO

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

15.
J Hum Genet ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106546

RESUMO

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

16.
Clin Transl Sci ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32961019

RESUMO

Coproporphyrin-I (CP-I) in plasma is a sensitive and specific endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B, encoded by SLCO1B). A few small-scale studies suggested that plasma CP-I concentration is affected by OATP1B1 polymorphism, but detailed studies are lacking. In this large-scale study, we measured plasma CP-I concentrations in 391 subjects from the Japanese general population, and evaluated the relationship between plasma CP-I concentrations and OATP1B1 polymorphisms to further assess the utility of plasma CP-I concentrations as an endogenous OATP1B probe. Plasma CP-I concentrations were 0.45 ± 0.12, 0.47 ± 0.16, 0.47 ± 0.20, 0.50 ± 0.15, 0.54 ± 0.14, and 0.74 ± 0.31 ng/mL in participants with OATP1B1*1b/*1b (n = 103), *1a/*1b (n = 122), *1a/*1a (n = 40), *1b/*15 (n = 74), *1a/*15 (n = 41), and *15/*15 (n = 11), respectively, showing an ascending rank order with significant difference (P < 0.0001). Post hoc analysis revealed significant increases in plasma CP-I concentration in OATP1B1*1b/*15 (P = 0.036), *1a/*15 (P = 0.0005), and *15/*15 (P = 0.0003) groups compared with the OATP1B1*1b/*1b group. There was no significant difference among OATP1B genotypes in plasma concentration of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, a uremic toxin reported to decrease OATP1B activity in vivo. These findings confirm the utility of plasma CP-I concentrations as an endogenous biomarker for phenotyping of OATP1B activity. Plasma CP-I concentration is potentially useful for the study of drug-drug interactions via OATP1B or individual dose adjustment of OATP1B substrates.

17.
Commun Biol ; 3(1): 526, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968195

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

18.
Clin Cancer Res ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958699

RESUMO

PURPOSE: Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405. EXPERIMENTAL DESIGN: Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models. RESULTS: The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10-6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10-6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced. CONCLUSIONS: This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.

19.
Eur J Clin Nutr ; 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895509

RESUMO

BACKGROUND/OBJECTIVE: Although benefits of fish consumption for health are well known, a significant percentage of individuals dislike eating fish. Fish consumption may be influenced by genetic factors in addition to environmental factors. We conducted a genome-wide association study (GWAS) to find genetic variations that affect fish consumption in a Japanese population. METHODS: We performed a two-stage GWAS on fish consumption using 13,739 discovery samples from the Japan Multi-Institutional Collaborative Cohort study, and 2845 replication samples from the other population. We used a semi-quantitative food frequency questionnaire to estimate food intake. Association of the imputed variants with fish consumption was analyzed by separate linear regression models per variant, with adjustments for age, sex, energy intake, principal component analysis components 1-10, and alcohol intake (g/day). We also performed conditional analysis. RESULTS: We found 27 single nucleotide polymorphisms (SNPs) located in 12q24 and 14q32.12 that were associated with fish consumption. The 19 SNPs were located at 11 genes including six lead SNPs at the BRAP, ACAD10, ALDH2, NAA25, and HECTD4 regions on 12q24.12-13, and CCDC197 region on 14q32.12. In replication samples, all five SNPs located on chromosome 12 were replicated successfully, but the one on chromosome 14 was not. Conditional analyses revealed that the five lead variants in chromosome 12 were in fact the same signal. CONCLUSION: We found that new SNPs in the 12q24 locus were related to fish intake in two Japanese populations. The associations between SNPs on chromosome 12 and fish intake were strongly confounded by drinking status.

20.
PLoS Genet ; 16(8): e1008915, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776928

RESUMO

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.


Assuntos
Genoma Humano , Herpesvirus Humano 6/genética , Integração Viral , Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 22/genética , Evolução Molecular , Mutação em Linhagem Germinativa , Humanos , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética
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