A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Wang, Binbin; Bao, Suying; Zhang, Zhigang; Zhou, Xueya; Wang, Jing; Fan, Yanhui; Zhang, Yan; Li, Yan; Chen, Luhua; Jia, Yizhen; Jiang, Li; Li, Miaoxin; Zheng, Wenhua; Ma, Nan; Wang, Liqiu; Yu, Zhe; Wong, Dana S.M.; Zhang, Yalun; Kwan, Joseph; Mak, Henry Ka‐Fung; Ambalavanan, Amirthagowri; Zhou, Sirui; Cai, Wangwei; Zheng, Jin; Huang, Shishu; Rouleau, Guy A.; Yang, Wanling; Rogaeva, Ekaterina; Ma, Xu; George-Hyslop, Peter St; Chu, Leung Wing; Song, You‐Qiang

doi:10.1016/j.neurobiolaging.2018.03.006

Cited by 30 publications

(29 citation statements)

References 31 publications

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“…Cerhan et al have performed clinic‐based case‐control study using the Affymetrix Immune and Inflammation SNP panel which revealed the association of variants in RIP3 gene with risk of Non‐Hodgkin lymphoma. A rare variant in MLKL, as a functional substrate of RIP3, was found to be associated with risk of late‐onset AD . Thus, our study firstly demonstrated the association of variant in RIP3 gene with the prognosis of HF.…”

Section: Discussionmentioning

confidence: 99%

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

Huang

et al. 2019

J Cellular Molecular Medi

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Receptor‐interacting protein kinase 3 (RIP3) is a key determinant of necroptosis and participates in ischaemia—and oxidative stress‐induced necroptosis, myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in RIP3 gene were associated with the risk and prognosis of HF in the Chinese Han population. By re‐sequencing and luciferase assays, we identified a common functional variant in the RIP3 promoter region. The rs3212247‐T allele suppressed RIP3 promoter activity by facilitating transcription factor SOX17 binding, but not the C allele. We further recruited 2961 control participants and 3194 HF patients who underwent a mean follow‐up of 19 months (6‐31 months) for this study. Rs3212247 and another missense variant rs3212254 were genotyped. Although rs3212247 did not significantly associate with increased risk of HF (odds ratio = 1.00, 95% CI = 0.92‐1.08, P = 0.91), it raised the risk for cardiovascular death and cardiac transplantation (hazard ratio = 1.47, 95% CI = 1.13‐1.91, P = 0.004). Moreover, participants carrying the rs3212247 CC genotype had higher plasma levels of RIP3 than those carrying the TT or TC genotype (p for trend = 0.02) in New York Heart Association class III HF group. No association was found between the RIP3 missense variant rs3212254 and risk or prognosis of HF after adjustment for traditional risk factors. In conclusion, genetic variant in RIP3 promoter region is associated with increased RIP3 transcription, thus contributed to the poor prognosis of HF patients. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1 . Unique identifier: NCT03461107.

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Section: Discussionmentioning

confidence: 99%

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

Huang

et al. 2019

J Cellular Molecular Medi

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“…Multiple factors, including amyloid beta (Aβ) plaques, hyperphosphorylated tau tangles in the brain, synaptic dysfunction, neuronal loss, gut microbiota and neuroinflammatory, were recognized to be associated with the development and progression of AD 39-41 . This dataset contained 246 ApoE ε4-negative AD patients and 172 healthy elderly controls sequenced at exomes. The detailed sample information can be seen in the original paper 42 . RUNNER also showed approximately uniformly-distributed p-values at the most majority genes for the rare variant mutation burden test ( Figure S2).…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases

Jiang

Dai

et al. 2020

Preprint

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AbstractThe identification of rare variants that contribute to complex diseases is challenging due to low statistical power. Here we propose a novel and powerful rare variants association test based on the deviation of the observed mutational burden in a genomic region from a baseline mutation burden predicted by weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association methods (including SKAT, CMC and KBAC), while maintaining correct type 1 error rates under population stratification and in small samples. Applied to real data, RUNNER “rediscovered” known genes of Hirschsprung disease missed by current methods, and detected promising new candidate genes, including NXPE4 for Hirschsprung disease and CXCL16 for Alzheimer’s disease. The proposed approach provides a powerful and robust method to identify rare risk variants for complex diseases.

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“…The study cohorts included 106 TNBC patients recruited from this study and 287 cancer-free elderly women (CTRL) over 80 years old from an open dataset (43), which served as the control.…”

Section: Study Participantsmentioning

confidence: 99%

“…Written informed consent was obtained from all participants for the use of banked tissues (including white blood cells and buccal cells), collection of pathological data and clinical follow-up data. The SNP data on CTRL was gathered from a previous report (43).…”

Section: Study Participantsmentioning

confidence: 99%

“…To lay the foundation, we first analyzed whole exome sequencing (WES) data of rare nonsynonymous germline mutations from a cohort of 287 cancer free elderly women over 80 years old (287 subjects from LOAD cohort (43)) that used as the CTRL cohort, whom we postulate the germline genetics begets the natural resistant against TNBC to throughout evolution. After obtaining the features of their pathway spectra, we observed an intriguing phenomenon that all individuals exhibit either one of two typical differentiated pathway spectrum patterns that we identified as Type A and Type B ( Fig.…”

Section: Tnbc Patients Significantly Differentiated From Healthy Subjmentioning

confidence: 99%

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Rare non-synonymous germline mutations systematically define the risk of triple negative breast cancer

Yang

Fan

et al. 2018

Preprint

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Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types.Significance: We identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers.

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A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population

Cited by 30 publications

References 31 publications

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding

Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases

Rare non-synonymous germline mutations systematically define the risk of triple negative breast cancer

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