Association of Genetic Variants Influencing Lipid Levels with Coronary Artery Disease in Japanese Individuals

Background/Objective

In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD).

Methods

We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1×10⁻³⁰ in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls.

Principal Findings

Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci–APOB, APOE-C1, CETP, and APOA5–and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3×10⁻⁴¹), CETP rs3764261 for HDL-C (p = 5.2×10⁻²⁴), and APOA5 rs662799 for triglycerides (p = 5.8×10⁻⁵⁴). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7×10⁻⁸), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1×10⁻⁷), and APOE rs7412 (p = 6.1×10⁻¹³).

Conclusions

Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.     

Morphological variation of major human populations based on nonmetric dental traits

The patterns of inter- and intra-regional variation among 12 major geographical groups from around the world were investigated based on 15 nonmetric dental traits. The R-matrix method was applied using a pooled within-group variance-covariance matrix estimated with the maximum likelihood method (tetrachoric correlation matrix) and the threshold value for each trait estimated by univariate probit analysis. Using average heritability rates that range from 0.40 to 1.00, the inter-regional variation represented by Fst falls between 7.19% and 16.23% of the total variance. This range of variation is compatible with those obtained by genetic, craniometric, and odontometric data. Subsaharan Africans show the largest intra-regional diversity among the groups compared. The degree of intra-regional variation shows, moreover, rough clinalities from subsaharan Africa to peripheral regions. The relationship between regional variation and geographic distance from subsaharan Africa supports serial bottlenecks and the founder effect of ancient populations originating in Africa. The variation of East/Northeast Asians is relatively large, suggesting a complex population history such as possible earlier divergence and multiple migrations from outside sources. The present findings are in agreement with both the recent African model for the origin of anatomically modern humans and the current scenario for human migration history suggested by genetic analyses.     

Craniometric variation of the Ainu: an assessment of differential gene flow from northeast Asia into northern Japan, Hokkaido

In and after the latest Neolithic period in Japan (approximately B.P. 2,300 years), there were two distinct waves of migration from eastern Asia. One is well known as successive episodes in which indigenous inhabitants of main-island Japan were intruded on by new arrivals with advanced technology, and of a different genetic stock. Another migration of people and culture, identified as the Okhotsk culture, reached the northeastern part of Hokkaido. As opposed to main-island Japan, the morphological continuity from the Neolithic to recent inhabitants in Hokkaido (Ainu) is notable, so that the evidence of admixture easily could have escaped notice. In this study, the effects of gene flow from an outside source on the pattern of among-group variation of Hokkaido Ainu are examined by means of two models. One is the R-matrix model comparing observed and expected craniometric variation for estimating differential external gene flow into a region. The other is a simple simulation model that estimates admixture in a population with two parental populations. The two approaches give similar results. The results suggest the possibility of admixture between the migrants from Northeast Asia, the Okhotsk culture people, and the indigenous inhabitants in Hokkaido during the 5th to 12th centuries A.D., at least in northeastern Hokkaido. Such gene flow may have a certain degree of effect on the genetic structure of recent Ainu. The findings further suggest morphological heterogeneity in Northeast Asia during the Holocene that has relevance for understanding the morphological heterogeneity seen through time in the New World.     

Gramicidin S identified as a potent inhibitor for cytochrome bd-type quinol oxidase

Gramicidin S, a cationic cyclic decapeptide, exhibits the potent antibiotic activity through perturbation of lipid bilayers of the bacterial membrane. From the screening of natural antibiotics, we identified gramicidin S as a potent inhibitor for cytochrome bd-type quinol oxidase from Escherichia coli. We found that gramicidin S inhibited the oxidase with IC(50) of 3.5 microM by decreasing V(max) and the affinity for substrates but showed the stimulatory effect at low concentrations. Our findings would provide a new insight into the development of gramicidin S analogs, which do not share the target and mechanism with conventional antibiotics.     

Alterations in foraging behavior of Coccinella septempunctata and Propylea japonica mediated by a novel defended prey affect their predatory potential

Generalist aphidophagous coccinellids have to cope with novel prey aphids in environments that are changing rapidly because of anthropogenic activity. The goldenrod aphid, Uroleucon nigrotuberculatum (Olive) (Hemiptera: Aphididae), is a noxious prey, which was recently introduced into Japan. It is a major prey for the native Japanese predators Coccinella septempunctata bruckii Mulsant and Propylea japonica (Thunberg) (both Coleoptera: Coccinellidae) in early summer on patches of solidago, Solidago altissima L. (Asteraceae). Prey preference of these coccinellids between this aphid and a native suitable prey aphid, Megoura crassicauda Mordvilko (Hemiptera: Aphididae), as well as their foraging behavior were studied for a better understanding of the negative impacts of the noxious novel aphid. Coccinella septempunctata initially preferred the novel prey, but later switched to the native prey, M. crassicauda; P. japonica had no preference for either prey. Feeding time of the first instars of C. septempunctata on U. nigrotuberculatum was significantly longer than that of P. japonica. The foraging bouts of fourth instars of C. septempunctata were significantly longer on U. nigrotuberculatum than on M. crassicauda, whereas only the feeding time of fourth instars of P. japonica on U. nigrotuberculatum was significantly longer than on M. crassicauda. Both coccinellids consumed less of U. nigrotuberculatum than of M. crassicauda. Thus, solidago patches infested by U. nigrotuberculatum may present an ecological trap, especially for C. septempunctata.     

Dental and cranial affinities among populations of east Asia and the Pacific: the basic populations in east Asia, IV.

The origins of the four major geographical groups recognized as Australomelanesians, Micronesians, Polynesians, and East and Southeast Asians are still far from obvious. The earliest arrivals in Sahulland may have migrated from Sundaland about 40,000-50,000 years B.P. and begun the Australomelanesian lineage. The aboriginal populations in Southeast Asia may have originated in the tropical rain forest of Sundaland, and their direct descendants may be the modern Dayaks of Borneo and Negritos of Luzon. These populations, the so-called "Proto-Malays," are possible representatives of the lineage leading to not only modern Southeast Asians, but also the Neolithic Jomon populations in Japan. The present study suggests, moreover, that the Polynesians and western Micronesians have closer affinities with modern Southeast Asians than with Melanesians or Jomonese.     

Comparability of multiple data types from the bering strait region: Cranial and dental metrics and nonmetrics,mtDNA, and Y‐chromosome DNA

Different data types have previously been shown to have the same microevolutionary patterns in worldwide data sets. However, peopling of the New World studies have shown a difference in migration paths and timings using multiple types of data, spurring research to understand why this is the case. This study was designed to test the degree of similarity in evolutionary patterns by using cranial and dental metric and nonmetric data, along with Y‐chromosome DNA and mtDNA. The populations used included Inuits from Alaska, Canada, Siberia, Greenland, and the Aleutian Islands. For comparability, the populations used for the cranial and molecular data were from similar geographic regions or had a shared population history. Distance, R and kinship matrices were generated for use in running Mantel tests, PROTEST analyses, and Procrustes analyses. A clear patterning was seen, with the craniometric data being most highly correlated to the mtDNA data and the cranial nonmetric data being most highly correlated with the Y‐chromosome data, while the phenotypic data were also linked. This patterning is suggestive of a possible male or female inheritance, or the correlated data types are affected by the same or similar evolutionary forces. The results of this study indicate cranial traits have some degree of heritability. Moreover, combining data types leads to a richer knowledge of biological affinity. This understanding is important for bioarchaeological contexts, in particular, peopling of the New World studies where focusing on reconciling the results from comparing multiple data types is necessary to move forward. Am J Phys Anthropol 154:334–348, 2014. © 2014 Wiley Periodicals, Inc.     

A simple and rapid determination of biapenem in plasma by high-performance liquid chromatography

A simple, rapid and precise HPLC method using ultrafiltration to remove plasma protein was developed to determine biapenem concentrations in human plasma. Plasma was separated by centrifugation at 4 degrees C from blood collected in heparinized vacuum tubes, and biapenem was stabilized by immediate mixing the plasma with 1M 3-morpholinopropanesulfonic acid (MOPS) buffer (pH 7.0) (1:1). Biapenem was detected by ultraviolet absorbance at 300nm with no interfering plasma peak. The calibration curve of biapenem in human plasma was linear from 0.04 to 50microg/mL. The limit of detection was 0.01microg/mL, which was more than 40-fold lower than that of conventional plasma protein precipitation using ammonium sulfate. The assay has been clinically applied to pharmacokinetic studies in patients.