Heritability and Genome-Wide Association Analyses of Serum Uric Acid in Middle and Old-Aged Chinese Twins.
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ABSTRACT:
SUBMITTER: Wang W
PROVIDER: S-EPMC5845532 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Heritability and Genome-Wide Association Analyses of Serum Uric Acid in Middle and Old-Aged Chinese Twins.
Wang Weijing W Zhang Dongfeng D Xu Chunsheng C Wu Yili Y Duan Haiping H Li Shuxia S Tan Qihua Q
Frontiers in endocrinology 20180306
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 ( ...[more]
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Project description:BackgroundAge-related hearing impairment (ARHI) is considered an unpreventable disorder. We aimed to detect specific genetic variants that are potentially related to ARHI via genome-wide association study (GWAS).MethodsA sample of 131 dizygotic twins was genotyped for single-nucleotide polymorphism- (SNP-) based GWAS. Gene-based test was performed using VEGAS2. Pathway enrichment analysis was conducted by PASCAL.ResultsThe twins are with a median age of 49 years, of which 128 were females and 134 were males. rs6633657 was the only SNP that reached the genome-wide significance level for better ear hearing level (BEHL) at 2.0 kHz (P = 1.19 × 10-8). Totally, 9, 10, 42, 7, 17, and 5 SNPs were suggestive evidence level for (P < 1 × 10-5) BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and pure tone average (PTA), respectively. Several promising genetic regions in chromosomes (near the C20orf196, AQPEP, UBQLN3, OR51B5, OR51I2, OR52D1, GLTP, GIT2, and PARK2) nominally associated with ARHI were identified. Gene-based analysis revealed 165, 173, 77, 178, 170, and 145 genes nominally associated with BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and PTA, respectively (P < 0.05). For BEHLs at 0.5, 1.0, and 2.0 kHz, the main enriched pathways were phosphatidylinositol signaling system, regulation of ornithine decarboxylase, eukaryotic translation initiation factor (EIF) pathway, amine compound solute carrier (SLC) transporters, synthesis of phosphoinositides (PIPS) at the plasma membrane, and phosphatidylinositols (PI) metabolism.ConclusionsThe genetic variations reported herein are significantly involved in functional genes and regulatory domains that mediate ARHI pathogenesis. These findings provide clues for the further unraveling of the molecular physiology of hearing functions and identifying novel diagnostic biomarkers and therapeutic targets of ARHI.
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Project description:BACKGROUND:Currently, 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. RESULTS:The 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 ?-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. CONCLUSIONS:The 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.
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Project description: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.
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Project description:AimThe role of uric acid as a risk factor for cardio-cerebrovascular diseases is controversial. In this study, we aimed to investigate the relationship between serum uric acid level and the risk of cardio-cerebrovascular events in middle-aged and non-obese Chinese men.MethodsWe included 3152 participants from the health examination center of Tongji Hospital from June 2007 to June 2010. Clinical examination and medical records were collected at the annual health examination. The hazard ratios (HRs) of uric acid for cardio-cerebrovascular events were calculated by Cox proportional hazards models. Generalized additive model and threshold effect analysis were used to explore the non-linear relationship between serum uric acid level and the incidence of cardio-cerebrovascular event.ResultThe mean follow-up time was 52 months. When the participants were classified into four groups by the serum acid quarter (Q1-Q4), the HRs (95% CI) of Q2-Q4 for cardio-cerebrovascular events were 1.26 (0.83, 1.92), 1.97 (1.33, 2.91) and 2.05 (1.40, 3.01), respectively, compared with the reference (Q1). The actual incidence and conditional incidence of cardio-cerebrovascular events in the high serum acid group were higher than those in the low serum acid group, which were stratified by the turning point (sUA = 372 μmol/L). We also showed a strong prognostic accuracy of the multiple variable-based score in 3 years and 5 years, with area under the receiver operating characteristic (ROC) curve of 0.790 (0.756-0.823) and 0.777 (0.749-0.804), respectively.ConclusionSerum uric acid level is a strong risk factor for cardio-cerebrovascular events.
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Project description:As the world's population ages, the age-related cognitive decline presents a great challenge to world's healthcare systems. One of the molecular mechanisms implicated in cognitive ageing is DNA methylation, an epigenetic modification known to be a key player in memory formation, maintenance, and synaptic plasticity. Using the twin design we performed an epigenome-wide association study (EWAS) in a population of 486 middle-aged monozygotic twins (mean age at follow-up 65.9, SD = 6.1) and correlated their blood DNA methylation to their level (cross-sectional analysis) and change in cognitive abilities over 10 years (longitudinal analysis). We identified several CpG sites where cross-sectional cognitive functioning was associated with DNA methylation levels. The top identified loci were located in ZBTB46 (p = 5.84 × 10-7), and TAF12 (p = 4.91 × 10-7). KEGG's enrichment analyses of the most associated findings identified "Neuroactive ligand-receptor interaction" as the most enriched pathway (p = 0.0098). Change in cognitive functioning over 10 years was associated with DNA methylation levels in AGBL4 (p = 9.01 × 10-7) and SORBS1 (p = 5.28 × 10-6), with the first gene playing an important role in neuronal survival and the latter gene implicated before in Alzheimer's disease and ischemic stroke. Our findings point to an association between changes in DNA methylation of genes related to neuronal survival and change of cognitive functioning in aging individuals.
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Project description:OBJECTIVE:Serum uric acid (SUA) has been associated with cardiovascular diseases, including atherosclerosis and carotid artery stenosis. However, data on the relationship between SUA level and proximal extracranial artery stenosis (PEAS) are limited. Therefore, this study investigates the association between SUA levels and the risk of PEAS in asymptomatic Chinese population. SETTING:This community-based cross-sectional study was conducted in Jidong Community Hospital, Tangshan, Hebei, China between July 2013 and August 2014. PARTICIPANTS:The study examined 3325 asymptomatic participants (40-60?years) to evaluate the risk of PEAS. RESULTS:For the participants stratified into quartiles based on gender-specific SUA levels, the prevalence of PEAS increased from Q1 to Q4 from 12.3% to 29.8% in the vertebral artery (VA), and from 2.8% to 5.8% in the common carotid artery. The proportion of PEAS relative to the detected number of arterial stenosis was lower in Q1 than in Q2-Q4. The multivariable ORs and 95% CI of PEAS in the second through fourth compared with the lowest quartiles for arterial stenosis were 1.278 (0.980 to 1.665), 1.117 (0.851 to 1.468) and 1.375 (1.033 to 1.830) (ptrend=0.0399); and for VA stenosis, 1.285 (0.966 to 1.709), 1.085 (0.808 to 1.457) and 1.439 (1.061 to 1.952) (ptrend=0.0235). CONCLUSION:Elevated SUA concentration is significantly associated with PEAS in an asymptomatic middle-aged Chinese population, and vertebral arteries appeared to be the most vulnerable vessels.
| S-EPMC6112387 | biostudies-literature
Project description:BACKGROUND:Observational studies have highlighted an association between serum uric acid (SUA) levels and cardiovascular risk factors. Despite the growing body of evidences, several studies were conducted in older individuals or in carriers of diseases susceptible to affect SUA levels and cardiometabolic risk markers. OBJECTIVE:To evaluate the relationship of SUA with body adiposity, metabolic profile, oxidative stress, inflammatory biomarkers, blood pressure and endothelial function in healthy young and middle-aged adults. METHODS:149 Brazilian adults aged 20-55 years, both sexes, underwent evaluation of body adiposity, SUA, fasting glucose and insulin, lipid profile, malondialdehyde (MDA), high sensitivity C-reactive protein (hs-CRP), adiponectin, blood pressure and endothelial function. Endothelial function was assessed by the reactive hyperemia index (RHI) derived from peripheral arterial tonometry method. Participants were allocated in two groups according to SUA levels: control group (CG; n = 130; men ? 7 mg/dL, women ? 6 mg/dL) and hyperuricemia group (HG; n = 19; men > 7 mg/dL, women > 6 mg/dL). A P-value < 0.05 was considered statistically significant. RESULTS:After adjustment for confounders, participants in HG compared with those in CG displayed higher body mass index (BMI): 34.15(33.36-37.19) vs.31.80 (26.26-34.42) kg/m2,p = 0.008, higher MDA: 4.67(4.03-5.30) vs. 3.53(3.10-4.07) ng/mL, p < 0.0001 and lower RHI: 1.68 ± 0.30 vs. 2.05 ± 0.46, p = 0.03). In correlation analysis adjusted for confounders, SUA was positively associated (p < 0.05) with BMI, waist circumference, LDL-cholesterol, triglycerides and MDA, and negatively associated (p < 0.05) with HDL-cholesterol, adiponectin and RHI. CONCLUSIONS:This study suggests that in healthy young and middle-aged adults higher SUA levels are associated with higher body adiposity, unfavorable lipid and inflammatory phenotype, higher oxidative stress and impaired endothelial function.
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