Dataset Information

A Key GWAS-Identified Genetic Variant Contributes to Hyperlipidemia by Upregulating miR-320a.

ABSTRACT: It has been unclear whether the elevated levels of the circulating miR-320a in patients with coronary artery disease is due to environmental influence or genetic basis. By recombinant adeno-associated virus (rAAV)-mediated loss- and gain-of-function studies in the mouse liver, we revealed that elevated miR-320a is sufficient to aggravate diet-induced hyperlipidemia and hepatic steatosis. Then, we analyzed the data from published genome-wide association studies and identified the rs12541335 associated with hyperlipidemia. We demonstrated that the rs13282783 T allele indeed obligated the silencer activity by preventing the repressor ZFP161 and co-repressor HDAC2 from binding to DNA that led to miR-320a upregulation. We further confirmed this genetic connection on an independent population and through direct genome editing in liver cells. Besides environmental (diet) influence, we established a genetic component in the regulation of miR-320a expression, which suggest a potential therapeutic avenue to treat coronary artery disease by blocking miR-320a in patient liver.

SUBMITTER: Yin Z

PROVIDER: S-EPMC7689551 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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A Key GWAS-Identified Genetic Variant Contributes to Hyperlipidemia by Upregulating miR-320a.

Yin Zhongwei Z Zhao Yanru Y Du Hengzhi H Nie Xiang X Li Huaping H Fan Jiahui J He Mengying M Dai Beibei B Zhang Xudong X Yuan Shuai S Wen Zheng Z Chen Chen C Wang Dao Wen DW

iScience 20201110 12

It has been unclear whether the elevated levels of the circulating miR-320a in patients with coronary artery disease is due to environmental influence or genetic basis. By recombinant adeno-associated virus (rAAV)-mediated loss- and gain-of-function studies in the mouse liver, we revealed that elevated miR-320a is sufficient to aggravate diet-induced hyperlipidemia and hepatic steatosis. Then, we analyzed the data from published genome-wide association studies and identified the rs12541335 assoc ...[more]

PMID: 33294796

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Project description:miRNAs are small non-coding RNAs modulating gene expression, and variants in miRNA genes are involved in the pathogenesis of ischemic stroke (IS). However, the effect of miR-34a polymorphisms on IS susceptibility has rarely been reported. In the present study, we investigated the association between rs12128240, rs2666433, and rs6577555 of the miR-34a gene and IS susceptibility. Snapshot assay was used to detect miR-34a polymorphisms in 548 IS patients and 560 controls. Relative expression of miR-34a was measured by quantitative real-time PCR. We found that rs2666433 was associated with a significantly increased risk of IS (AA vs. GG: OR = 1.61, 95% CI = 1.05-2.52, P = 0.031; AA vs. GG+GA: OR = 1.58, 95% CI = 1.05-2.45, P = 0.026). For the IS subtypes, rs2666433 was associated with large artery atherosclerosis (AA vs. GG: OR = 2.09, 95% CI = 1.16-3.51, P = 0.007; AA vs. GG+GA: OR = 2.02, 95% CI = 1.15-3.33, P = 0.007; A vs. G: OR = 1.36, 95% CI = 1.07-1.81, P = 0.021). Additionally, the level of miR-34a was significantly up-regulated in IS patients compared to the controls (P < 0.001), and patients with rs2666433 AA genotype had a higher level of miR-34a than those with GG+GA genotypes (P < 0.001). Furthermore, increased level of homocysteine was observed in IS patients compared to the controls (P < 0.001), especially in patients carrying the rs2666433AA genotype compared to those carrying the rs2666433 GG+GA genotypes (P < 0.001). However, no significant association between rs12128240 or rs6577555 and IS was found. Collectively, our study found the association between miR-34a polymorphisms and the risk of IS among the Chinese population. The results may provide an explanation for etiology of IS and a potential biomarker or therapeutic target for IS. HIGHLIGHTS-MiR-34a rs2666433 polymorphism was associated with an increased risk of ischemic stroke.-The level of miR-34a was significantly up-regulated in ischemic stroke patients compared with controls, and patients with rs2666433 AA genotype had a higher level miR-34a than those with GG+GA genotypes.-Furthermore, increased level of homocysteine was showed in IS patients compared to controls, and in patients carrying the rs2666433AA compared to those carrying the rs2666433 GG+GA.

Project description:Study questionDo genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry?Summary answerMany genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner.What is known and what this paper addsPrior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women.Participants and settingWe evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche.Main resultsFor 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10(-6), binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results.Study funding/competing interestsThis study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.

Dataset Information

A Key GWAS-Identified Genetic Variant Contributes to Hyperlipidemia by Upregulating miR-320a.

Publications

A Key GWAS-Identified Genetic Variant Contributes to Hyperlipidemia by Upregulating miR-320a.

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