Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies

Yamada, Yoshiji; Sakuma, Jun; Takeuchi, Ichiro; Yasukochi, Yoshiki; Kato, Koichi; Oguri, Mitsutoshi; Fujimaki, Tetsuo; Horibe, Hideki; Muramatsu, Masaaki; Sawabe, Motoji; Fujiwara, Yoshinori; Taniguchi, Yu; Obuchi, Shuichi; Kawai, Hisashi; Shinkai, Shoji; Mori, Seijiro; Arai, Tomio; Tanaka, Masashi

doi:10.18632/oncotarget.17159

Cited by 7 publications

(11 citation statements)

References 40 publications

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“…The associations of eight of the nine SNPs [rs7771335 (P=1.00×10 −7 ), rs2071653 (P=1.61×10 −5 ), rs2853969 (P= 6.16×10 −8 ), rs2269704 (P=2.92×10 −7 ), rs2269703 (P=3.67×10 −7 ), rs495089 (P= 0.0 0 01), rs2269702 (P=5.13×10 −7 ) and rs1233399 (P=0.0009)] with hyper-LDL-cholesterolemia were replicated in the present study. Although the association of most SNPs with dyslipidemia identified in our previous study ( 28 ) was replicated, genetic variants associated with hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia appear to differ, at least in part, between early- and late-onset forms of the diseases.…”

Section: Discussionmentioning

confidence: 62%

“…Our group has previously reported that two, three and nine SNPs were associated with hypertriglyceridemia (P<1.71×10 −4 ), hypo-HDL-cholesterolemia (P<1.44×10 −4 ), and hyper-LDL-cholesterolemia (P<1.10×10 −4 ), respectively, as determined by multivariable logistic regression analysis with adjustment for age and sex, following an initial EWAS screening of allele frequencies among subjects with early- or late-onset forms of these conditions ( 28 ). The associations of the two SNPs [rs10790162 (P=3.58×10 −24 ) and rs7350481 (P=7.94×10 −23 )] with hypertriglyceridemia were replicated (P<0.05) in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, the median age of subjects with hypertriglyceridemia, hypo-HDL-cholesterolemia or hyper-LDL-cholesterolemia was 64, 68 or 62 years, respectively ( 28 ). Therefore, in the present study, early-onset dyslipidemia was defined as that occurring at an age of ≤65 years.…”

Section: Methodsmentioning

confidence: 99%

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Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia

et al. 2018

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The circulating concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, and low density lipoprotein (LDL)-cholesterol have a substantial genetic component, and the heritability of early-onset dyslipidemia might be expected to be higher compared with late-onset forms. In the present study, exome-wide association studies (EWASs) were performed for early-onset hypertriglyceridemia, hypo-HDL-cholesterolemia, and hyper-LDL-cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ≤65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo-HDL-cholesterolemia (974 cases and 7,085 controls), and hyper-LDL-cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia, respectively, was examined with Fisher’s exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni’s correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo-HDL-cholesterolemia and hyper-LDL-cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo-HDL-cholesterolemia and hyper-LDL-cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL-cholesterol, or LDL-cholesterol, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C-TMOD4, LPGAT1, EHD3, COL6A3, ZNF860-CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo-HDL-cholesterolemia, and three loci (KIAA0319-FAM65B, UBD, LOC105375015) for hyper-LDL-cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early-onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia in the Japanese population.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia

et al. 2018

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“…One explanation for the difference between these two studies could be that they were conducted in people of different ethnicities and ages. A recent exome-wide association study (EWAS) (Yamada et al 2017) performed in a Japanese population indicated that APOA4 rs5104 located in this gene was associated with the serum TG concentration. A genome-wide association study (GWAS) conducted in Chinese people (Zhou et al 2013) showed that rs651821 presented a strong association with TG levels.…”

Section: Discussionmentioning

confidence: 99%

Peer Review #2 of "Functional polymorphisms of the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster are associated with dyslipidemia in a sex-specific pattern (v0.1)"

2019

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Background. Dyslipidemia contributes to the risk of many diseases, including stroke, cardiovascular disease and metabolic-related diseases. Previous studies have indicated that single nucleotide polymorphisms (SNPs) are associated with different levels of serum lipid. Therefore, this study explored the relationship between the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster gene polymorphisms and dyslipidemia in the total sample population and stratified by genders in a northeast Chinese population. Methods. A total of 3850 participants from Jilin Province, China, were enrolled in our study, and their serum lipid levels were measured. Six functional SNPs (APOA1 rs5072, APOC3 rs5128, APOA4 rs5104, APOA5 rs651821, ZPR1 rs2075294 and BUD13 rs10488698) were genotyped using polymerase chain reaction and MALDI-TOF-MS. Logistic regression analysis was performed to explore the relationship of APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster gene polymorphisms with dyslipidemia. Linkage disequilibrium and haplotype analyses were performed with SNPStats program and Haploview software. Results. All SNPs conformed to Hardy-Weinberg Equilibrium. Logistic regression analysis revealed that rs5072, rs5128 and rs651821 were associated with hypertriglyceridemia, rs5104 and rs651821 were associated with low-HDL cholesterolemia in overall group. rs651821 was associated with hypertriglyceridemia and low-HDL cholesterolemia in both the male and female group. However, among females, rs5072 was observed to be associated with hypertriglyceridemia. Haplotype analysis showed that haplotypes TGCCGC and CAGCGC were associated with dyslipidemia in the overall, male and female groups. Conclusion. SNPs in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster were associated with dyslipidemia. Furthermore, the association of APOA1 rs5072 in this gene cluster with dyslipidemia differed between genders; thus, additional studies are needed to confirm this conclusion, and the mechanisms underlying these results warrant further exploration.

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“…We applied the selection criteria for subjects used in a similar study in a Japanese cohort published in 2017 (Yamada et al, ) to compare our results with theirs. The case and control groups for hypertriglyceridemia, hypo‐HDL‐cholesterolemia, hyper‐LDL‐cholesterolemia, and dyslipidemia were classified based on the classification criteria specified by Yamada et al ().…”

Section: Methodsmentioning

confidence: 99%

Exome chip‐driven association study of lipidemia in >14,000 Koreans and evaluation of genetic effect on identified variants between different ethnic groups

Han

Hwang

Yoon

et al. 2019

Genetic Epidemiology

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Lipid levels in blood are widely used to diagnose and monitor chronic diseases. It is essential to identify the genetic traits involved in lipid metabolism for understanding chronic diseases. However, the influence of genetic traits varies depending on race, sex, age, and ethnicity. Therefore, research focusing on populations of individual countries is required, and the results can be used as a basis for comparison of results of other studies at the cross-racial and crosscountry levels. In the present study, we selected lipid-related variants and evaluated their effects on lipid-related diseases in more than 14,000 subjects of three cohorts using the Illumina Human Exome Beadchip. A genome-wide association study was conducted using EPACTs after adjusting for age, sex, and recruitment area. A genome-wide significance cutoff was defined as p < 5E−08 in all the three cohorts. Sixteen variants represented the lipid traits and were classified as vulnerable to borderline hypertriglyceridemia, hyper-LDL-cholesterolemia, or hypo-HDL-cholesterolemia. Moreover, we compared the genetic effects of the 16 variants between ethnic groups and identified the missense variants in apolipoprotein A-V, cholesterol ester transfer protein, and apolipoprotein E as Asian-specific. Our study provides candidate genes as markers for chronic diseases through the evaluation of genetic effects.

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Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies

Cited by 7 publications

References 40 publications

Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia

Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia

Peer Review #2 of "Functional polymorphisms of the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster are associated with dyslipidemia in a sex-specific pattern (v0.1)"

Exome chip‐driven association study of lipidemia in >14,000 Koreans and evaluation of genetic effect on identified variants between different ethnic groups

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