Dataset Information

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins.

ABSTRACT: Dyslipidemia represents a strong and independent risk factor for cardiovascular disease. Plasma cholesterol, such as total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C), is the common indicator of diagnosing dyslipidemia. Here based on 382 Chinese twin pairs, we explored the magnitude of genetic impact on TC, HDL-C, LDL-C variation and further searched for genetic susceptibility loci for them using genome-wide association study (GWAS). The ACE model was the best fit model with additive genetic parameter (A) accounting for 26.6%, common or shared environmental parameter (C) accounting for 47.8%, unique/non-shared environmental parameter (E) accounting for 25.6% for the variance in HDL-C. The AE model was the best fit model for TC (A: 61.4%; E: 38.6%) and LDL-C (A: 65.5%; E: 34.5%). While no SNPs reached the genome-wide significance level (P < 5 × 10-8), 8, 14, 9 SNPs exceeded the suggestive significance level (P < 1 × 10-5) for TC, HDL-C, LDL-C, respectively. The promising genetic regions for TC, HDL-C, LDL-C were on chromosome 11 around rs7107698, chromosome 5 around rs12518218, chromosome 2 around rs10490120, respectively. Gene-based analysis found 1038, 1033 and 1090 genes nominally associated with TC, HDL-C, LDL-C (P < 0.05), especially FAF1, KLKB1 for TC, KLKB1 for HDL-C, and NTRK1, FAF1, SNTB2 for LDL-C, respectively. The number of common related genes among TC, HDL-C and LDL-C was 71, including FAF1, KLKB1, etc. Pathway enrichment analysis discovered known related pathways-zinc transporters, metal ion SLC transporters for TC, cell adhesion molecules CAMs, IL-6 signaling for HDL, FC epsilon RI signaling pathway, NFAT pathway for LDL, respectively. In conclusion, the TC and LDL-C level is moderately heritable and the HDL-C level is lowly heritable in Chinese population. The genomic loci, functional genes and pathways are identified to account for the heritability of plasma cholesterol level. Our findings provide important insights into plasma cholesterol molecular physiology and expect future research to replicate and validate our results.

SUBMITTER: Liu H

PROVIDER: S-EPMC6249314 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins.

Liu Hui H Wang Weijing W Zhang Caixia C Xu Chunsheng C Duan Haiping H Tian Xiaocao X Zhang Dongfeng D

Frontiers in endocrinology 20181115

Dyslipidemia represents a strong and independent risk factor for cardiovascular disease. Plasma cholesterol, such as total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C), is the common indicator of diagnosing dyslipidemia. Here based on 382 Chinese twin pairs, we explored the magnitude of genetic impact on TC, HDL-C, LDL-C variation and further searched for genetic susceptibility loci for them using genome-wide association study (G ...[more]

PMID: 30498476

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Project description:BackgroundCurrently, diabetes has become one of the leading causes of death worldwide. Fasting plasma glucose (FPG) levels that are higher than optimal, even if below the diagnostic threshold of diabetes, can also lead to increased morbidity and mortality. Here we intend to study the magnitude of the genetic influence on FPG variation by conducting structural equation modelling analysis and to further identify specific genetic variants potentially related to FPG levels by performing a genome-wide association study (GWAS) in Chinese twins.ResultsThe final sample included 382 twin pairs: 139 dizygotic (DZ) pairs and 243 monozygotic (MZ) pairs. The DZ twin correlation for the FPG level (rDZ = 0.20, 95% CI: 0.04-0.36) was much lower than half that of the MZ twin correlation (rMZ = 0.68, 95% CI: 0.62-0.74). For the variation in FPG level, the AE model was the better fitting model, with additive genetic parameters (A) accounting for 67.66% (95% CI: 60.50-73.62%) and unique environmental or residual parameters (E) accounting for 32.34% (95% CI: 26.38-39.55%), respectively. In the GWAS, although no genetic variants reached the genome-wide significance level (P < 5 × 10- 8), 28 SNPs exceeded the level of a suggestive association (P < 1 × 10- 5). One promising genetic region (2q33.1) around rs10931893 (P = 1.53 × 10- 7) was found. After imputing untyped SNPs, we found that rs60106404 (P = 2.38 × 10- 8) located at SPATS2L reached the genome-wide significance level, and 216 SNPs exceeded the level of a suggestive association. We found 1007 genes nominally associated with the FPG level (P < 0.05), including SPATS2L, KCNK5, ADCY5, PCSK1, PTPRA, and SLC26A11. Moreover, C1orf74 (P = 0.014) and SLC26A11 (P = 0.021) were differentially expressed between patients with impaired fasting glucose and healthy controls. Some important enriched biological pathways, such as β-alanine metabolism, regulation of insulin secretion, glucagon signaling in metabolic regulation, IL-1 receptor pathway, signaling by platelet derived growth factor, cysteine and methionine metabolism pathway, were identified.ConclusionsThe FPG level is highly heritable in the Chinese population, and genetic variants are significantly involved in regulatory domains, functional genes and biological pathways that mediate FPG levels. This study provides important clues for further elucidating the molecular mechanism of glucose homeostasis and discovering new diagnostic biomarkers and therapeutic targets for diabetes.

Project description:Serum uric acid (SUA), as the end product of purine metabolism, has proven emerging roles in human disorders. Here based on a sample of 379 middle and old-aged Chinese twin pairs, we aimed to explore the magnitude of genetic impact on SUA variation by performing sex-limitation twin modeling analyses and further detect specific genetic variants related to SUA by conducting a genome-wide association study. Monozygotic (MZ) twin correlation for SUA level (rMZ = 0.56) was larger than for dizygotic (DZ) twin correlation (rDZ = 0.39). The common effects sex-limitation model provided the best fit with additive genetic parameter (A) accounting for 46.3%, common or shared environmental parameter (C) accounting for 26.3% and unique/nonshared environmental parameter (E) accounting for 27.5% for females and 29.9, 33.1, and 37.0% for males, respectively. Although no SUA-related genetic variants reached genome-wide significance level, 25 SNPs were suggestive of association (P < 1 × 10-5). Most of the SNPs were located in an intronic region and detected to have regulatory effects on gene transcription. The cell-type specific enhancer of skeletal muscle was detected which has been reported to implicate SUA. Two promising genetic regions on chromosome 17 around rs2253277 and chromosome 14 around rs11621523 were found. Gene-based analysis found 167 genes nominally associated with SUA level (P < 0.05), including PTGR2, ENTPD5, well-known SLC2A9, etc. Enrichment analysis identified one pathway of transmembrane transport of small molecules and 20 GO gene sets involving in ion transport, transmembrane transporter activity, hydrolase activity acting on acid anhydrides, etc. In conclusion, SUA shows moderate heritability in women and low heritability in men in the Chinese population and genetic variations are significantly involved in functional genes and regulatory domains that mediate SUA level. Our findings provide clues to further elucidate molecular physiology of SUA homeostasis and identify new diagnostic biomarkers and therapeutic targets for hyperuricemia and gout.

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Dataset Information

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins.

Publications

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins.

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