Lower Circulating Folate Induced by a Fidgetin Intronic Variant Is Associated With Reduced Congenital Heart Disease Susceptibility

Wang, Dan; Wang, Feng; Shi, Kai-Hu; Tao, Hui; Yang, Li; Zhao, Rui; Lu, Han; Duan, Wei; Qiao, Bin; Zhao, Shimin; Wang, Hongyan; Zhao, Jin

doi:10.1161/circulationaha.116.025164

Cited by 54 publications

(40 citation statements)

References 42 publications

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“…It is not surprising that such variants have only moderate contribution to risk and progression of cancers, if any, particularly compared to germline mutations that are associated with some distinct disease phenotypes. This is particularly true for a single locus change such as the MTOR rs2536 T > C change, which is similar to other functional studies focused on single germline variant . The effect of such germline variants on gene expression is also likely to be affected by other molecular events that govern gene expression regulation, such as long coding RNAs and circular RNAs that are competing endogenous RNAs (ceRNAs), which may disrupt the binding of miRNA to 3′UTR of the genes.…”

Section: Discussionmentioning

confidence: 53%

“…This is particularly true for a single locus change such as the MTOR rs2536 T > C change, which is similar to other functional studies focused on single germline variant. [43][44][45] The effect of such germline variants on gene expression is also likely to be affected by other molecular events that govern gene expression regulation, such as long coding RNAs and circular RNAs that are competing endogenous RNAs (ceRNAs), 46,47 which may disrupt the binding of miRNA to 3 0 UTR of the genes. This might be the reason for the relatively less strong impact of miRNA-150 on modulating the MTOR expression associated with the MTOR rs2536 T > C change.…”

Section: Discussionmentioning

confidence: 99%

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Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Cheng

Qiu

Zhang

et al. 2018

Intl Journal of Cancer

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We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Cheng

Qiu

Zhang

et al. 2018

Intl Journal of Cancer

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“…The same study observed that the depletion of FIGN resulted in alterations in the structure of mitotic centrosomes. However, Wang et al 49 have recently identified a FIGN intronic variant (rs2119289) that has a protective role against congenital heart disease. This finding is compatible with the role of FIGN as contributing to modulating HPAH penetrance.…”

Section: Discussionmentioning

confidence: 99%

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

et al. 2019

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BackgroundMapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.MethodsWe performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.ResultsWe identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene.ConclusionOur results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.

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“…FIGN 491 encodes fidgetin, a microtubule-severing enzyme most highly expressed in the pituitary 492 gland and ovary (50). A genetic variant in FIGN was found to reduce the risk of congenital 493 heart disease in Han Chinese by modulating transmembrane folate transport (67,68). The 494 TAD encompassing the association signal in this locus includes FIGN and extends upstream 495 to the GRB14 gene (Fig 9).…”

Section: Subtypes In Pcos Families 398mentioning

confidence: 99%

Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

Dapas¹,

Lin²,

Nadkarni

et al. 2019

Preprint

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AD) 20 ghayes@northwestern.edu (MGH) 21 22 DISCLOSURE STATEMENT: The authors have nothing to disclose. 23 metabolic subtype (KCNH7/FIGN, P=1.0×10 -8 ). We have previously reported that rare 47 variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS 48 quantitative traits in a family-based whole genome sequencing analysis. We classified the 49 reproductive and metabolic subtypes in this family-based PCOS cohort and found that the 50 subtypes tended to cluster in families and that carriers of rare DENND1A variants were 51 significantly more likely to have the reproductive subtype of PCOS. Limitations of our study 52 were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, 53 the sample sizes for the subtype GWAS were small, and the GWAS findings were not 54 replicated. 55 56 Conclusions 57In conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, 58 these subtypes were associated with novel susceptibility loci. Our results suggest that these 59 subtypes are biologically relevant since they have distinct genetic architectures. This study 60 demonstrates how precise phenotypic delineation can be more powerful than increases in 61 sample size for genetic association studies. 62 63Understanding the genetic architecture of complex diseases is a central challenge in 64 human genetics (1-3). Often defined according to arbitrary diagnostic criteria, complex 65 diseases can represent the phenotypic convergence of numerous genetic etiologies (4)(5)(6)(7)(8). 66Recent studies in type 2 diabetes support the concept that there are disease subtypes with 67 distinct genetic architecture (7,8). Identifying and addressing genetic heterogeneity in 68 complex diseases could increase power to detect causal variants and improve treatment 69 efficacy (9). 70Polycystic ovary syndrome (PCOS) is a highly heritable, complex genetic disorder 71 affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic 72 criteria applied (10). It is characterized by a variable constellation of reproductive and 73 metabolic abnormalities (Fig 1). It is the leading cause of anovulatory infertility and a major 74 risk factor for type 2 diabetes (T2D) in women (11). Despite these substantial morbidities, 75 the etiology(ies) of PCOS remains unknown (12). Accordingly, the commonly-used 76 diagnostic criteria for PCOS, the National Institutes of Health (NIH) criteria (13) and the 77 Rotterdam criteria (14,15), are based on expert opinion, rather than mechanistic insights, and 78 are designed to account for the diverse phenotypic presentations of PCOS. The NIH criteria 79 require the presence of hyperandrogenism (HA) and chronic oligo/anovulation or ovarian 80 dysfunction (OD) (13). The Rotterdam criteria include polycystic ovarian morphology 81 (PCOM) and require the presence of at least two of these three key reproductive traits, 82 resulting in three different affected phenotypes: HA and OD with or without PCOM, also 83 known as NIH PCOS, as w...

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Lower Circulating Folate Induced by a Fidgetin Intronic Variant Is Associated With Reduced Congenital Heart Disease Susceptibility

Cited by 54 publications

References 42 publications

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

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