Noriyuki Fuku

Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians.

Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, we performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type 2 diabetes mellitus (T2DM). The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with T2DM and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with T2DM and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups (i.e., F, B, A, N9a, M7a, M7b, G, D4a, D4b, and D5). Multivariate logistic-regression analysis with adjustment for age and sex revealed that the mitochondrial haplogroup N9a was significantly associated with resistance against T2DM (P=.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplogroup might confer resistance against T2DM.

Effects of Isoflavone and Exercise on BMD and Fat Mass in Postmenopausal Japanese Women: A 1-Year Randomized Placebo-Controlled Trial†

The combined intervention of isoflavone intake and walking exercise over 1 year in postmenopausal Japanese women exhibited a trend for a greater effect on prevention of bone loss at the total hip and Wards triangle regions.

Mitochondrial Genome Single Nucleotide Polymorphisms and Their Phenotypes in the Japanese

Abstract: Polymorphisms in the human mitochondrial genome have been used for the elucidation of phylogenetic relationships among various ethnic groups. Because analysis by mitochondrial genetics has detected pathogenic mutations causing mitochondrial encephalomyopathy or cardiomyopathy, most of the mitochondrial single nucleotide polymorphisms (mtSNPs) found in control subjects have been regarded as merely normal variants. However, we cannot exclude the possibility that the mitochondrial functional differences among individuals are ascribable at least in part to the mtSNPs of each individual. Human lifespan in ancient history was much shorter than that at the present time. Therefore, it is reasonable to speculate that certain mtSNPs that predispose one toward susceptibility to adult‐ or elderly‐onset diseases, such as Parkinsons disease and Alzheimers disease, have never been a target for natural selection in the past. Similarly, thrifty mtSNPs that had been advantageous for survival under severe famine or cold climate conditions might turn out to be related to satiation‐related diseases, such as diabetes mellitus and obesity. To examine these hypotheses, we have constructed a mtSNP database by sequencing the entire mitochondrial genomes of 672 subjects: 96 in each of seven groups (i.e., centenarians, young obese or non‐obese subjects, diabetic patients with or without major vascular involvement, patients with Parkinsons disease, and those with Alzheimers disease).

Genomics of elite sporting performance: what little we know and necessary advances.

Numerous reports of genetic associations with performance-related phenotypes have been published over the past three decades but there has been limited progress in discovering and characterising the genetic contribution to elite/world-class performance, mainly owing to few coordinated research efforts involving major funding initiatives/consortia and the use primarily of the candidate gene analysis approach. It is timely that exercise genomics research has moved into a new era utilising well-phenotyped, large cohorts and genome-wide technologies—approaches that have begun to elucidate the genetic basis of other complex traits/diseases. This review summarises the most recent and significant findings from sports genetics and explores future trends and possibilities.

Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study

OBJECTIVE We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to ischemic stroke. METHODS A total of 6341 individuals from three independent populations was examined. Subject panel A comprised 131 individuals with ischemic stroke and 135 controls; subject panel B comprised 790 individuals with ischemic stroke and 3435 controls; and subject panel C comprised 71 individuals with ischemic stroke and 1779 controls. A GWAS for ischemic stroke was performed in subject panel A with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS The relation of 100 single nucleotide polymorphisms (SNPs) selected by the GWAS to ischemic stroke was examined in 705 subjects with ischemic stroke and 3426 controls selected from subject panel B. Three SNPs (rs1671021 of LLGL2, rs9615362 of CELSR1, and rs753307 of RUVBL2) were significantly (P<0.05) associated with ischemic stroke. After DNA sequencing of linkage disequilibrium blocks containing these SNPs, three tag SNPs (rs6007897 of CELSR1, rs1671021 of LLGL2, and rs1062708 of RUVBL2) and a nonsynonymous SNP (rs4044210 of CELSR1) were examined for their relation to ischemic stroke in subject panels B and C. Both rs6007897 (A-->G, Thr2268Ala) and rs4044210 (A-->G, Ile2107Val) of CELSR1 as well as rs1671021 (T-->C, Phe479Leu) of LLGL2 were significantly associated with ischemic stroke in subject panel B. The rs6007897 and rs4044210 polymorphisms of CELSR1 were also significantly associated with ischemic stroke in subject panel C. CONCLUSION CELSR1 is a susceptibility gene for ischemic stroke in Japanese individuals, although the functional relevance of the identified SNPs was not determined.

Mitochondrial DNA Haplogroup D4a Is a Marker for Extreme Longevity in Japan

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99–105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimers and Parkinsons disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain “beneficial” patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

Women With Mitochondrial Haplogroup N9a Are Protected Against Metabolic Syndrome

To identify mitochondrial haplogroups that confer resistance against or susceptibility to metabolic syndrome, we performed a large-scale association study on 1,337 unrelated Japanese individuals, including 871 subjects with metabolic syndrome and 466 control subjects. Metabolic syndrome was diagnosed according to modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using the cutoff point for obesity as a BMI of ≥25 kg/m2 instead of waist circumference. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups, i.e., F, B, A, N9a, M7a, M7b, G1, G2, D5, and D4. Multivariate logistic regression analysis revealed that the haplogroup N9a was significantly associated with resistance against metabolic syndrome in women with an odds ratio (OR) of 0.21 (95% CI 0.07–0.58, P = 0.0042). Women with haplogroups G1 and D5 tended to be resistant against metabolic syndrome with an OR of 0.22 (0.06–0.68, P = 0.0129) for G1 and with an OR of 0.32 (0.10–0.96, P = 0.0469) for D5, respectively. These results indicate that mitochondrial haplogroup N9a may be a protective factor against metabolic syndrome in Japanese women.

An alternative model for the early peopling of southern South America revealed by analyses of three mitochondrial DNA haplogroups.

After several years of research, there is now a consensus that America was populated from Asia through Beringia, probably at the end of the Pleistocene. But many details such as the timing, route(s), and origin of the first settlers remain uncertain. In the last decade genetic evidence has taken on a major role in elucidating the peopling of the Americas. To study the early peopling of South America, we sequenced the control region of mitochondrial DNA from 300 individuals belonging to indigenous populations of Chile and Argentina, and also obtained seven complete mitochondrial DNA sequences. We identified two novel mtDNA monophyletic clades, preliminarily designated B2l and C1b13, which together with the recently described D1g sub-haplogroup have locally high frequencies and are basically restricted to populations from the extreme south of South America. The estimated ages of D1g and B2l, about ∼15,000 years BP, together with their similar population dynamics and the high haplotype diversity shown by the networks, suggests that they probably appeared soon after the arrival of the first settlers and agrees with the dating of the earliest archaeological sites in South America (Monte Verde, Chile, 14,500 BP). One further sub-haplogroup, D4h3a5, appears to be restricted to Fuegian-Patagonian populations and reinforces our hypothesis of the continuity of the current Patagonian populations with the initial founders. Our results indicate that the extant native populations inhabiting South Chile and Argentina are a group which had a common origin, and suggest a population break between the extreme south of South America and the more northern part of the continent. Thus the early colonization process was not just an expansion from north to south, but also included movements across the Andes.

Mitochondrial haplogroups associated with elite Kenyan athlete status.

UNLABELLED The maternal inheritance of mitochondrial DNA (mtDNA) has enabled construction of detailed phylogenies. Analysis of key polymorphisms from these phylogenies allows mtDNA to be assigned to haplogroups, which have been associated with elite endurance performance. PURPOSE To compare the frequencies of mtDNA haplogroups found in elite Kenyan athletes with those in the general Kenyan population. METHODS DNA samples were obtained from 221 national level Kenyan athletes (N), 70 international Kenyan athletes (I), and 85 members of the general Kenyan population (C). mtDNA haplogroups were classified by sequencing 340 bases of hypervariable section (HVS I) and by genotyping known restriction sites. Frequency differences between groups were assessed using exact tests of population differentiation. RESULTS The haplogroup distribution of national (P = 0.023) and international athletes (P < 0.001) differed significantly from controls, with international athletes showing a greater proportion of L0 haplogroups (C = 15%, N = 18%, I = 30%) and lower proportion of L3* haplogroups (C = 48%, N = 36%, I = 26%). Although a high number of international athletes originated from the Rift Valley province relative to controls (C = 20%, N = 65%, I = 81%), subjects from this province did not differ in haplogroup distribution from other regions (P = 0.23). Nor did Bantu subjects differ from Nilotic (P = 0.12) despite an overrepresentation of Nilotic languages among the athletes. CONCLUSIONS International athletes differed in their mtDNA haplogroup distribution relative to the general Kenyan population. They displayed an excess of L0 haplogroups and a dearth of L3* haplogroups. These findings suggest that mtDNA haplogroups are influential in elite Kenyan distance running, although population stratification cannot be ruled out.

Analysis of mitochondrial DNA variants in Japanese patients with schizophrenia.

To test the hypothesis that mitochondrial DNA (mtDNA) variants contribute to the susceptibility to schizophrenia, we sequenced the entire mtDNAs from 93 Japanese schizophrenic patients. Three non-synonymous homoplasmic variants in subunit six of the ATP synthase (MT-ATP6) gene that were detected only in patients but not in controls were suggested to be slightly deleterious, because (1) their original amino acid residues (AA) were highly conserved and (2) the physicochemical differences between the original and altered AA were relatively high. In addition, we detected three novel heteroplasmic variants that were potentially pathogenic. Although functional analysis is needed, rare variants in the mtDNA may convey susceptibility to schizophrenia.