title: 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.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. Supichaya.boon@gmail.com.
authors.forename: Supichaya
authors.initials: S
authors.lastname: Boonvisut
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. nakayama@jichi.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. s1305@jichi.ac.jp.
authors.forename: Saho
authors.initials: S
authors.lastname: Makishima
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. kwatanabe@jichi.ac.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Jichi Medical University Health Care Center, Shimotsuke, Tochigi, 329-0498, Japan. hrsm@jichi.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyashita
authors.affiliation: School of Medicine, Mongolian National University, Bayagol district, 11th khoroo, Ulaanbaatar-city, Mongolia. Munkhtulga_l@yahoo.com.
authors.forename: Munkhtulga
authors.initials: M
authors.lastname: Lkhagvasuren
authors.affiliation: High Technology Research Center, Kagawa Nutrition University, Sakado, Saitama, 350-0288, Japan. kagawa@eiyo.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. siwamoto@jichi.ac.jp.
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
mesh_terms: D044466:Asian People / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008055:Lipids / Q000097:blood*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D044468:Native Hawaiian or Pacific Islander / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D008055:Lipids; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D058580:Neurocan; C109878:cytoplasmic linker protein 115; C076817:NCAN protein, human