Detailed Analysis of Japanese Population Substructure with a Focus on the Southwest Islands of Japan

Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating FST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study

Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations

AbstractOBJECTIVESWe sought to determine whether the development of left ventricular hypertrophy (LVH) can be demonstrated during adulthood in genetically affected relatives with hypertrophic cardiomyopathy (HCM).BACKGROUNDHypertrophic cardiomyopathy is a heterogeneous cardiac disease caused by mutations in nine genes that encode proteins of the sarcomere. Mutations in cardiac myosin-binding protein C (MyBPC) gene have been associated with age-related penetrance.METHODSTo further analyze dormancy of LVH in patients with HCM, we studied, using echocardiography and 12-lead electrocardiography, the phenotypic expression caused by MyBPC mutations in seven genotyped pedigrees.RESULTSOf 119 family members studied, 61 were identified with a MyBPC mutation, including 21 genetically affected relatives (34%) who did not express the HCM morphologic phenotype (by virtue of showing normal left ventricular wall thickness). Of these 21 phenotype-negative individuals, 9 were children, presumably in the prehypertrophic phase, and 12 were adults. Of the 12 adults with normal wall thickness ≤12 mm (7 also with normal electrocardiograms), 5 subsequently underwent serial echocardiography prospectively over four to six years. Of note, three of these five adults showed development of LVH in mid-life, appearing for the first time at 33, 34 and 42 years of age, respectively, not associated with outflow obstruction or significant symptoms.CONCLUSIONSIn adults with HCM, disease-causing MyBPC mutations are not uncommonly associated with absence of LVH on echocardiogram. Delayed remodeling with the development of LVH appearing de novo in adulthood, demonstrated here for the first time in individual patients with prospectively obtained serial echocardiograms, substantiates the principle of age-related penetrance for MyBPC mutations in HCM. These observations alter prevailing perceptions regarding the HCM clinical spectrum and family screening strategies and further characterize the evolution of LVH in this disease

Gene-gene combination effect and interactions among ABCA1, APOA1, SR-B1, and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population.

BACKGROUND/OBJECTIVE: Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population. METHODS: The study population comprised 1,535 men and 1,515 women aged 35-69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region. PRINCIPAL FINDINGS: Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001). CONCLUSIONS: The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present

Variance components for the J-MICC and the PASNP data.

<p>The total genetic variation is partitioned into variations between two subpopulations (“Among subpopulations”), among individuals within each subpopulation (“Among individuals within subpopulations”) and within individuals. The relative proportions (%) and 95% confidence intervals (95% CI) for variance components are also shown.</p

Geographic locations of the populations studied in Japan.

<p>Kanto-Koshinetsu: the eastern-central region of the main island. Tokai-Hokuriku: the central region of the main island. Kinki: the southern-central region of the main island. Chugoku-Shikoku: the westernmost part of the main island and the fourth largest island. Kyushu: the third largest island, located southwest of the main island. The Amami Islands: a part of the Southwest Islands, located southwest of Kyushu. The black circles represent the approximate geographic positions of the enrollment institutions, and the red-colored islands in the enlarged view of Japan's Southwest Islands (right) represent those used for sampling in the J-MICC study (Tokunoshima and Okinoerabu Islands) and in the survey by the PASNP consortium (the Okinawa Islands).</p

Genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders.

<p>F_ST values were averaged over six SNPs and 95% confidence intervals were computed using 10000 bootstrap resamplings. The mainland population is grouped across all subpopulations in the mainland, <i>i.e.</i>, Kanto-Koshinetsu, Tokai-Hokuriku, Kinki, Chugoku-Shikoku, and Kyushu. Genotype data of the Okinawa Islanders were obtained from the Pan-Asian SNP (PASNP) consortium database.</p

Correspondence analysis plot of the first and second principal components for the mainland population, Amami Islanders and Okinawa Islanders.

<p>Correspondence analysis for the mainland population, Amami Islanders and Okinawa Islanders was conducted using six loci. The scree plot is shown in the upper right corner of this figure.</p