Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.

BACKGROUND: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. METHODS: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. RESULTS: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (± 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (± 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (± 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). CONCLUSION: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.

Genetic heterogeneity in a susceptible region for essential hypertension among demographically different local populations in Japan.

OBJECTIVE: The aim of the study was to investigate genetic heterogeneity among local Japanese populations. METHODS: We performed a single nucleotide polymorphism (SNP) study of four demographically distinct local populations (population 1: a large city; population 2: isolated islands; populations 3 and 4: rural areas). Seventy SNPs in a region spanning 5 Mb of chromosome 17 known to be a candidate region for essential hypertension were genotyped and linkage disequilibrium analyses were performed. RESULTS: Statistical analyses of SNP allele frequencies and haplotype distribution showed significant divergence among the populations, mostly between population 2 and the other populations. Pairwise D' declined with increasing population size, and smaller populations retained a high linkage disequilibrium. CONCLUSION: Population 2 is likely to have a different ancestry from the majority of the Japanese population, whereas the heterogeneity among the other populations may result from differences in population size or geographic background.

Comparative study of polymorphisms on genes associated with lifestyle related diseases in Asian and Pacific populations.

An increase in prevalence of lifestyle related diseases becomes one of the main threats to human health in Asia-Pacific regions. Especially Pacific countries face the marked epidemic of obesity and related disorders. Understanding of the genetic basis for these diseases is awaited. We investigated frequencies of 106 single nucleotide polymorphisms (SNPs) in genes associated with lifestyle related diseases in 1,878 individuals from five Asia-Pacific countries including Japan, China, Mongolia, Thailand, and Palau. Population genetic analyses revealed that disease susceptible variants of SNPs in TRIB3, PTGS2, ADIPOR1, DGAT1, UCP2, FOXC2, and ESR1 were overrepresented in the Palau population in comparison with the Asian populations. These gene variants likely contribute to the high prevalence of obesity and related diseases in Pacific populations. The present results would be helpful in coping with the lifestyle related diseases and may provide a new insight into the human dispersal in Asia-Pacific regions.

Aly/ REF, a factor for mRNA transport, activates RH gene promoter function.

The rhesus (Rh) blood group antigens are of considerable importance in transfusion medicine as well as in newborn or autoimmune hemolytic diseases due to their high antigenicity. We identified a major DNaseI hypersensitive site at the 5' flanking regions of both RHD and RHCE exon 1. A 34 bp fragment located at -191 to -158 from a translation start position, and containing the TCCCCTCCC sequence, was involved in enhancing promoter activity, which was assessed by luciferase reporter gene assay. A biotin-labelled 34 bp probe isolated an mRNA transporter protein, Aly/REF. The specific binding of Aly/REF to RH promoter in erythroid was confirmed by chromatin immunoprecipitation assay. The silencing of Aly/REF by siRNA reduced not only the RH promoter activity of the reporter gene but also transcription from the native genome. These facts provide second proof of Aly/REF as a transcription coactivator, initially identified as a coactivator for the TCRalpha enhancer function. Aly/REF might be a novel transcription cofactor for erythroid-specific genes.