Koichi Akiyama

National Center for Global Health and Medicine in Japan, Edo, Tōkyō, Japan

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Publications (7)23.39 Total impact

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    ABSTRACT: The reported prevalence of non-alcoholic fatty liver disease (NAFLD) in Asian populations ranges from 5% to 40% [1]. Using stringent ultrasound criteria, we reported that the prevalence of NAFLD in an urban, adult population of Sri Lankans was 32.6% [2]. Familial clustering has suggested that NAFLD is influenced by genetic factors [3,4]. Genome-wide association studies (GWAS) have successfully identified loci associated with susceptibility to NAFLD in populations of European descent, the most consistent being the patatin-like phospholipase domain containing 3 (PNPLA3) gene rs738409 polymorphism [5]. However, no large-scale genetic studies have been reported in South Asian populations. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 06/2014; · 3.87 Impact Factor
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    ABSTRACT: The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.
    PLoS ONE 01/2014; 9(6):e101329. · 3.53 Impact Factor
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    ABSTRACT: Aim: Using general Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with uric acid and gout. The relative contribution of non-genetic and genetic factors to the variances in serum uric acid concentration was then evaluated.Methods: Seven single nucleotide polymorphisms (SNPs) were genotyped from 7 candidate loci robustly confirmed in Europeans. Genotyping was performed in up to 17,226 individuals, from which 237 hyperuricemia cases and 3,218 controls were chosen for a case-control study. For 6 SNPs showing a replication of uric acid association in 17,076 general population samples, we further tested the associations with other metabolic traits (n≤5,745) and with type 2 diabetes (931 cases and 1404 controls) and coronary artery disease (806 cases and 1337 controls).Results: Significant uric acid associations (one-tailed p<0.05) were replicated for 6 loci in Japanese. The strongest association was detected at SLC22A12 rs505802 for uric acid (p=2.4×10(-50)) and ABCG2 rs2231142 for hyperuricemia (p3.6×10(-10)). The combined genetic effect could explain some proportion of inter-individual variation in uric acid (R(2)=0.03) and was more or less comparable to the effect of well-recognized risk factors -BMI (R(2)=0.04) and alcohol intake (R(2)=0.01). The tested SNPs were not significantly associated with cardiovascular risk traits except for GCKR rs780094.Conclusion: Our results confirm that 6 common uric acid variant loci are reproducible in Japanese. Further investigation is warranted to efficiently use the knowledge about genetic factors in combination with modifiable risk factors when we decide an individual's treatment strategy for hyperuricemia.
    Journal of atherosclerosis and thrombosis 12/2012; · 2.93 Impact Factor
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    ABSTRACT: BACKGROUND/OBJECTIVE: The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects. METHODS: In Cdkal1-deficient (Cdkal1(-/-)) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese. PRINCIPAL FINDINGS: On a standard diet, Cdkal1(-/-) mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1(-/-) mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1(-/-) mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1(-/-) mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1(-/-) mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI. CONCLUSIONS: Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.
    PLoS ONE 01/2012; 7(11):e49055. · 3.53 Impact Factor
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    ABSTRACT: An intracranial aneurysm (IA), which results in a subarachnoid hemorrhage with a high mortality on rupture, is a major public health concern. To identify genetic susceptibility loci for IA, we carried out a multistage association study using genome-wide single nucleotide polymorphisms (SNPs) in Japanese case-control subjects. In this study, we assessed evidence for association in standard approaches, and additional tests with adjusting sex effects that act between genetic effect and disease. Consequently, five SNPs (P=1.31 × 10(-5) for rs1930095 of intergenic region; P=1.32 × 10(-5) for rs4628172 of TMEM195; P=2.78 × 10(-5) for rs7781293 of TMEM195; P=4.93 × 10(-5) for rs7550260 of ARHGEF11; and P=3.63 × 10(-5) for rs9864101 of IQSEC1) with probabilities of being false positives <0.5 were associated with IA in Japanese population, and the susceptibility genes could have a role in actin remodeling in the ELN/LIMK pathway. This study indicates the presence of several susceptibility loci that deserve further investigation in the Japanese population.
    Journal of Human Genetics 10/2010; 55(10):656-61. · 2.37 Impact Factor
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    ABSTRACT: Recently, a genome-wide association study identified associations between single nucleotide polymorphisms on chromosome 9p21 and risk of harboring intracranial aneurysm (IA). Aneurysm characteristics or subphenotypes of IAs, such as history of subarachnoid hemorrhage, presence of multiple IAs and location of IAs, are clinically important. We investigated whether the association between 9p21 variation and risk of IA varied among these subphenotypes. We conducted a case-control study of 981 cases and 699 controls in Japanese. Four single nucleotide polymorphisms tagging the 9p21 risk locus were genotyped. The OR and 95% CI were estimated using logistic regression analyses. Among the 4 single nucleotide polymorphisms, rs1333040 showed the strongest evidence of association with IA (P=1.5x10(-6); per allele OR, 1.43; 95% CI, 1.24-1.66). None of the patient characteristics (gender, age, smoking, and hypertension) was a significant confounder or effect modifier of the association. Subgroup analyses of IA subphenotypes showed that among the most common sites of IAs, the association was strongest for IAs of the posterior communicating artery (OR, 1.69; 95% CI, 1.26-2.26) and not significant for IAs in the anterior communicating artery (OR, 1.22; 95% CI, 0.96-1.57). When dichotomizing IA sites, the association was stronger for IAs of the posterior circulation-posterior communicating artery group (OR, 1.73; 95% CI, 1.32-2.26) vs the anterior circulation group (OR, 1.28; 95% CI, 1.07-1.53). Heterogeneity in these ORs was significant (P=0.032). The associations did not vary when stratifying by history of subarachnoid hemorrhage (OR, 1.42; 95% CI, 1.18-1.71 for ruptured IA; OR, 1.27; 95% CI, 1.00-1.62 for unruptured IA) or by multiplicity of IA (OR, 1.57; 95% CI, 1.21-2.03 for multiple IAs; OR, 1.36; 95% CI, 1.15-1.61 for single IA). Our results suggest that genetic influence on formation may vary between IA subphenotypes.
    Stroke 08/2010; 41(8):1593-8. · 6.16 Impact Factor
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) present in probe-target sequences (SPTS) have been shown to be associated with abnormal genoplot images. We explored the effects of SPTS positions on genoplot images using a data set from a genome-wide association study typed on an Illumina Human Hap300 platform. We screened the physical genomic positions of 308,330 autosomal probes to identify SPTS candidates deposited in dbSNP. The genoplot images across 293 individuals were inspected further in SNPs bearing an SPTS candidate. We identified 35,185 SNPs bearing a single SPTS candidate, including 264 SNPs showing abnormal genoplot images. The frequencies of SPTS at distances within 10 bases from the target SNP were significantly higher in the 264 SNPs showing abnormal genoplot images, than in the remaining 34,921 SNPs (49.62 vs 12.87%; Fisher exact test; P = 2.2 x 10(-16)). Of these 264 SNPs, we randomly selected 20 SNPs and resequenced them in 97 individuals. An SPTS within 10 bases of the target SNP was confirmed in all 20 SNPs, except for one SNP with a small deletion (7 bases) in the probe-target sequence. Taken together, these results suggest an association of a proximal SPTS with an abnormal genoplot image, which could result in spurious genotype detections, highlighting the importance of minimizing systematic errors in microarray experiments.
    Genetics and molecular research: GMR 01/2010; 9(1):524-31. · 0.99 Impact Factor