Genetic association study of pulmonary function, metabolic syndrome and obesity in populations in Northeast Asia

다국어 초록 (Multilingual Abstract)

Genetic studies including, genome-wide association study (GWAS) have been used extensively to identify genetic variants linked to complex traits, but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between genotypes and several complex traits in northeast Asian population.
In the first part of this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. The spirometric measurement of pulmonary function forced expiratory volume in one second (FEV1) is a heritable trait that reflects physiological condition of the lung and airways. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the five loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.
In the second part of this study, we aimed to evaluate the association between metabolic syndrome (MetS) and previously reported SNPs, and their interaction with health-related behavior in Korean men. Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1,193 men who enrolled in the study at Seoul National University Hospital. We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG), and low levels of high-density lipoprotein (HDL), while rs769450 was associated with a decreased risk of TG. Risk alleles in both SNPs were more frequent in Korean men than in Europeans. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men. We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.
In the third part of this study, we tested association between copy number variation (CNV) of salivary amylase gene (AMY1) and obesity indices in 2 groups of Korean (KRSA 1035 and KRFM 2049 individuals) and two population of Mongolia (MND 411 and MON 400 individuals). CNV have recently been considered as important human genomic variant, which associated with phenotypic difference and disorder. The copy number of AMY1 have been shown to be related with ethnic difference of starch diet. We estimated copy number by duplex TaqMan real-time PCR method. The average copy number of each group was 6.29 and 6.27 in Korean, 5.78 and 6.23 in Mongolia populations, respectively. The Mongolia Dashbalbar population (MND) show significantly low copy number which was composed of 88.7% of Buryat ethnics. Buryat have geographical similarity with Yakut ethnic group which have been previously as reported low starch diet population with AMY1 low copy. In the test of association between AMY1 copy number and obesity phenotype, AMY1 copy number are not associated with obesity, but had weak and positive trend in Korean population. In Mongolian population, AMY1 copy number had weak but negative association with obesity phenotype. These might result from different dependence on starch diet and populational difference of genomic variation may affect the different obesity phenotypes.

목차 (Table of Contents)

• Chapter 1 1
• Introduction 2
• Materials and Methods 4
• Study design and population 4
• Phenotype measurement 6
• Genome-wide SNP genotyping 7
• Statistics 8
• Replication test 9
• Results 10
• Population characteristics 10
• Association of discovery stage 12
• Result without known respiratory disease 17
• Replication stage 19
• Discussion 23
• Chapter 2 29
• Introduction 30
• Material and Methods 32
• Study design and population 32
• Phenotype measurement 35
• SNP selection and genotyping 37
• Statistics 39
• Results 40
• Population characteristics 40
• Genetic associations 41
• Health-related behavior and genotype-stratified analysis 48
• 1. Smoking status and genotype interaction 49
• 2. Alcohol and genotype interaction 50
• 3. Physical activity and genotype interaction 51
• Discussion 56
• Chapter 3 61
• Introduction 61
• Material and Methods 64
• Study subjects of SNUH-HPC 64
• Study subjects of GENDISCAN study 65
• Study subjects of Japanese and Chinese 66
• Anthropometric measurement 67
• Copy number estimation 69
• SNP genotyping and imputation 70
• Linkage disequilibrium (LD) analysis in the AMY1 region 71
• Results and Discussion 72
• Comparison of AMY1 copy number for each population 73
• Comparison of copy number estimation accuracy 74
• Association of AMY1 copy number with obesity in Korean population 77
• Association of AMY1 copy number with obesity in Mongolian population 86
• SNP-AMY1 copy number correlation 94
• Total Summary 100
• References 103
• Abstract in Korean 120