• 대한의생명과학회지
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• 제26권1호
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• pp.28-36
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• 2020

High blood pressure (HTN) is a condition in which blood pressure is kept higher than normal. Blood pressure trait measures systolic blood pressure (SBP) which is the highest pressure and diastolic blood pressure (DBP) which is the lowest blood pressure. Pulse pressure (PP) is the difference between systolic and diastolic blood pressure. Hypertension is known as a disease caused by the interaction of the environment and genetic factors. To date, studies have been conducted to find genes associated with hypertension. Genome-Wide Association Study (GWAS) analysis using European data from the UK Biobank reported new 535 loci were associated with blood pressure trait. Among them, 12 genes have been reported to have a significant correlation with SBP, DBP and PP. In the study, 12 genes polymorphisms were extracted based on KARE (Korean association resource) and then we performed linear regression of blood pressure trait. As a result, 6 SNPs of the 3 genes (rs12355413 and rs11006736 of ARMC4, rs2290883, rs2290884 and rs11039014 of LRP4, rs7234941 of BCL2) showed statistically significant correlation (P<0.05) with blood pressure trait. Of the 3 genes, 6 SNPs in 2 genes (rs9651357, rs12355413, rs11006736, rs1889522 of ARMC4 and rs4987774, rs7234941 of BCL2) showed significant correlation with hypertension. These results suggest that genetic polymorphisms of ARMC4, LRP4 and BCL2 genes are associated with blood pressure traits and hypertension in Korean population. Moreover, we expected to help understand the pathogenesis of hypertension.

• 대한의생명과학회지
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• 제18권4호
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• pp.377-383
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• 2012

Recent genome-wide association studies (GWAS) have identified a number of common variants associated with blood pressure homeostasis and hypertension in population. In the previous study, single nucleotide polymorphisms (SNPs) in the SLC4A4 gene have been reported to be associated with hypertension in Han Chinese population. We aimed to confirm whether the genetic variation of SLC4A4 gene influence the susceptibility to blood pressure and hypertension in Korean population. We genotyped variants in or near SLC4A4 in a population-based cohort including 7,551 unrelated Korean from Ansan and Ansung. Here, we performed association analysis to elucidate the possible relations of genetic polymorphisms in SLC4A4 gene with blood pressure traits. By examining genotype data of a total of 7,551 subjects in the Korean Association REsource (KARE) study, we discovered the SLC4A4 gene polymorphisms are associated with blood pressure and hypertension. The common and highest significant polymorphism was rs6846301 (${\beta}$=0.839, additive P=0.032) with systolic blood pressure (SBP), rs6846301 (${\beta}$=0.588, additive P=0.027) with diastolic blood pressure (DBP), and rs6846301 (OR=1.23, CI: 1.09~1.40, additive $P=1.2{\times}10^{-3}$) with hypertension. Furthermore, the SNP rs6846301 was consistently associated with both blood pressure and hypertension. Consequently, we found statistically significant SNPs in SLC4A4 gene that are associated with both blood pressure and hypertension traits. In addition, these results suggest that the individuals with the minor alleles of the SNP in the SLC4A4 gene may be more susceptible to the development of hypertension in the Korean population.

• 대한의생명과학회지
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• 제18권2호
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• pp.87-95
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• 2012

Hypertension is a complex disease that results from the interaction of genetic and environmental influences and heritability is influenced by about one-third to one-half. However, the specific genetic variants determining risk for hypertension are still largely unknown. Here, we performed association analysis to elucidate the possible relations of genetic polymorphisms in ESR1 gene with blood pressure traits. By examining genotype data of a total of 3,804 women in the Korean Association REsource (KARE) study, we discovered the ESR1 gene polymorphisms are associated with blood pressure and hypertension. The highest significant polymorphisms were rs2982571 (${\beta}=-1.56$, $P=6.8{\times}10^{-3}$) with systolic blood pressure (SBP), rs9322335 (${\beta}=-0.61$, P=0.013) with diastolic blood pressure (DBP), and rs851985 (OR=0.78, CI: 0.65~0.94, $P=8.6{\times}10^{-3}$) with hypertension. In the 5 SNPs (rs2982571, rs851985, rs851983, rs851981, and rs851980), their ${\beta}$-values in SBP and/or DBP showed consistent trends with the odds ratios (ORs) of hypertension, and these 5 SNPs were composed with one LD block. Consequently, we found statistically significant SNPs in ESR1 gene that are associated with both blood pressure and hypertension traits. These results suggested that the individuals with the minor alleles of the 5 SNPs in the ESR1 gene may be less susceptible to the development of hypertension in the Korean women.

• Genomics & Informatics
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• 제8권3호
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• pp.103-107
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• 2010

The imputation of untyped SNPs enables researchers to validate association findings across SNP arrays and also enables them to test a large number of SNPs to reveal the fine structure of the association peak, facilitating interpretation of the results and the location of causal polymorphisms. In this study, we applied the imputation method to a genomewide association study and recapitulated the previously associated gene loci of blood pressure traits in Korean cohorts. A total of 1,827,004 SNPs were imputed by the IMPUTE program, and we conducted a genomewide association study for systolic and diastolic blood pressure. While no SNPs passed the Bonferroni correction p-value (p=$2.74{\times}10^{-8}$ for 1,827,004 SNPs), 12 novel loci for systolic blood pressure and 16 novel loci for diastolic blood pressure were detected by imputed SNPs, with $10^{-5}$ < p-value < $10^{-4}$. Moreover, 7 regions (ATP2B1, 10p15.1, ARHGEF12, ALX4, LIPC, 7q31.1, and TCF7L2) out of 14 genetic loci that were previously reported revealed that the imputed SNPs had lower p-values than those of genotyped SNPs. Moreover, a nonsynonymous SNP in the CSMD1 gene, one of the 14 genes, was found to be associated with systolic blood pressure (p<0.05). These results suggest that the imputation method can facilitate the discovery of novel SNPs as well as enhance the fine structure of the association peak in the loci.

• Genomics & Informatics
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• 제11권3호
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• pp.129-134
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• 2013

Orthostatic hypotension (OH) is defined by a 20-mm Hg difference of systolic blood pressure (dtSBP) and/or a 10-mm Hg difference of diastolic blood pressure (dtDBP) between supine and standing, and OH is associated with a failure of the cardiovascular reflex to maintain blood pressure on standing from a supine position. To understand the underlying genetic factors for OH traits (OH, dtSBP, and dtDBP), genome-wide association studies (GWASs) using 333,651 single nucleotide polymorphisms (SNPs) were conducted separately for two population-based cohorts, Ansung (n = 3,173) and Ansan (n = 3,255). We identified 8 SNPs (5 SNPs for dtSBP and 3 SNPs for dtDBP) that were repeatedly associated in both the Ansung and Ansan cohorts and had p-values of < $1{\times}10^{-5}$ in the meta-analysis. Unfortunately, the SNPs of the OH case control GWAS did not pass our p-value criteria. Four of 8 SNPs were located in the intergenic region of chromosome 2, and the nearest gene (CTNNA2) was located at 1 Mb of distance. CTNNA2 is a linker between cadherin adhesion receptors and the actin cytoskeleton and is essential for stabilizing dendritic spines in rodent hippocampal neurons. Although there is no report about the function in blood pressure regulation, hippocampal neurons interact primarily with the autonomic nervous system and might be related to OH. The remaining SNPs, rs7098785 of dtSBP trait and rs6892553, rs16887217, and rs4959677 of dtDBP trait were located in the PIK3AP1 intron, ACTBL2-3' flanking, STAR intron, and intergenic region, respectively, but there was no clear functional link to blood pressure regulation.

• Genomics & Informatics
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• 제8권3호
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• pp.142-149
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• 2010

In recent years, genome-wide association (GWA) studies have successfully led to many discoveries of genetic variants affecting common complex traits, including height, blood pressure, and diabetes. Although GWA studies have made much progress in finding single nucleotide polymorphisms (SNPs) associated with many complex traits, such SNPs have been shown to explain only a very small proportion of the underlying genetic variance of complex traits. This is partly due to that fact that most current GWA studies have relied on single-marker approaches that identify single genetic factors individually and have limitations in considering the joint effects of multiple genetic factors on complex traits. Joint identification of multiple genetic factors would be more powerful and provide a better prediction of complex traits, since it utilizes combined information across variants. Recently, a new statistical method for joint identification of genetic variants for common complex traits via the elastic-net regularization method was proposed. In this study, we applied this joint identification approach to a large-scale GWA dataset (i.e., 8842 samples and 327,872 SNPs) in order to identify genetic variants of obesity for the Korean population. In addition, in order to test for the biological significance of the jointly identified SNPs, gene ontology and pathway enrichment analyses were further conducted.

• Genomics & Informatics
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• 제9권4호
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• pp.152-160
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• 2011

Hypertension is the major factor of most death and high blood pressure (BP) can lead to stroke, myocardial infarction and cardiac failure. Moreover, hypertension is strongly correlated with body mass index (BMI). Although the exact causes of hypertension are still unclear, some of genetic loci were discovered from genome-wide association study (GWAS). Therefore, it is essential to study genetic variation for finding more genetic factor affecting hypertension. The purpose of our study is to conduct a CNV association study for hypertension-related traits, BP and BMI, in Korean individuals. We identified 2,206 CNV regions from 3,274 community-based Korean participants using the Affymetrix Genome-Wide Human SNP Array 6.0 platform and performed a logistic regression analysis of CNVs with two hypertension-related traits, BP and BMI. Moreover, the 4,692 participants in an independent cohort were selected for respective replication analyses. GWAS of CNV identified two loci encompassing previously known hypertension-related genes: LPA (lipoprotein) on 6q26, and JAK2 (Janus kinase 2) on 9p24, with suggestive p-values (0.0334 for LPA and 0.0305 for JAK2 ). These two positive findings, however, were not evaluated in the replication stage. Our result confirmed the conclusion of CNV study from the WTCCC suggesting weak association with common diseases. This is the first study of CNV association study with BP and BMI in Korean population and it provides a state of CNV association study with common human diseases using SNP array.

• Genomics & Informatics
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• 제8권3호
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• pp.108-115
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• 2010

Hypertension is the most prevalent disease worldwide and is itself a risk factor for cerebral, cardiac, and renal diseases. The inconsistency of candidate genes suggested by previous genomewide association studies (GWASs) may be due to not only differences in study design and genetic or environmental background but also the difference in the power of analysis between continuous traits and discrete traits. We analyzed 352,228 single nucleotide polymorphisms (SNPs) in 8842 unrelated Koreans obtained from Ansan and Ansung cohorts. We performed a series of GWA analyses using three different phenotype models; young hypertensive cases (278 subjects) versus elderly normotensive controls (680 subjects); the upper 25% (2211 hypertensive cases) versus the lower 25% of the SBP distribution (2211 hypotensive controls); and finally SBP and DBP as continuous traits (8842 subjects). The numbers of young hypertensive cases and elderly normotensive controls were not large enough to achieve genomewide significance. The model comparing the upper 25% subjects to the lower 25% of subjects showed a power that was approximate to that of QTL analysis. Two neighboring SNPs of the ATP2B1 gene, rs17249754 (SBP, p=$2.53^{-10}$; DBP, p=$1.28{\times}10^{-8}$) and rs7136259 (SBP, p=$1.30{\times}10^{-9}$; DBP, p=$6.41{\times}10^{-8}$), were associated with both SBP and DBP. Interestingly, a SNP of the RPL6 gene, rs11066280, revealed a significant genomewide association with SBP in men only (p=$3.85{\times}10^{-8}$), and four SNPs located near the MAN2A1 gene showed a strong association with DBP only in elderly men aged 60-70 years (e.g., rs6421827, p=$4.86{\times}10^{-8}$). However, we did not observe any gene variant attaining genomewide significance consistently in the three phenotype models except for the ATP2B1 gene variants. In general, the association signal with blood pressure was stronger in women than in men. Genes identified in GWASs are expected to open the way for prevention, early diagnosis, and personalized treatment of hypertension.

• 한국식품영양과학회지
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• 제15권2호
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• pp.191-200
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• 1986

It is now generally accepted that individuals at increased risk for cardiovascular disease may be identified by certain traits or habbits. The factors such as high blood pressure, elevated blood cholestrol, age, sex and obesity are associated with increseaed frequency of disease. The blood cholesterol level lowering will decrease cardiovascular disease risk. The regression of atherosclerosis can be achieved by lowering the level of circulating cholesterol. Those things are connected with the quantity and quality of protein, fats, carbohydrates, especially soluble and non-soluble fiber, magnesium and calcium. The lipoprotein and lipid metabolism are connected with the lipid transport. The factors on lipid absorption and blood serum lipid pattern of human are exist. The factors have a variety of materials with different chemical and physical properties. The soluble fiber diet make a low blood and liver lipids. Many kind of soluble fiber results in a lowering of blood cholesterol and triglyceride levels. The cholesterol lowering effects of dietery fiber may be a results of alterations of in intestinal handling of fats, hepatic metabolism of fatty acid or triglyceride acid metabolism of lipoprotein. It is investigated that the high density lipoprotein (HDL) is inversely related to coronary artery disease. It has been postulated that HDL may be an important factor in cholesterol efflux from the tissues, therby reducing the amount of cholesterol deposited there. Alternatively, the HDL may pick up cholestyl ester and phospholipid during normal VLDL lipolysis in the plasma. The HDL levels are relatively insensitive to diet. At present time, the cause-and -diet effect of HDL's inverse relation to CHD remains unclear.

• Genomics & Informatics
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• 제8권3호
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• pp.101-102
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• 2010

During the last decade, large community cohorts have been established by the Korea National Institutes of Health (KNIH), and enormous epidemiological and clinical data have been accumulated. Using these information and samples in the cohorts, KNIH set out to do a large-scale genome-wide association study (GWAS) in 2007, and the Korea Association REsource (KARE) consortium was launched to analyze the data to identify the underlying genetic risk factors of diseases and diverse health indexes, such as blood pressure, obesity, bone density, and blood biochemical traits. The consortium consisted of 6 research divisions, formed by 25 principal investigators in 19 organizations, including 18 universities, 2 institutes, and 1 company. Each division focused on one of the following subjects: the identification of genetic factors, the statistical analysis of gene-gene interactions, the genetic epidemiology of gene-environment interactions, copy number variation, the bioinformatics related to a GWAS, and a GWAS of nutrigenomics. In this special issue, the study results of the KARE consortium are provided as 9 articles. We hope that this special issue might encourage the genomics community to share data and scientists, including clinicians, to analyze the valuable Korean data of KARE.