Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension

Chang, Tien-Jyun; Wang, Wen Chang; Hsiung, Chao A.; He, Chih-Tsueng; Lin, Ming; Sheu, Wayne Huey Herng; Chang, Yi‐Cheng; Quertermous, Thomas; Chen, Ida; Rotter, Jerome I.; Chuang, Lee‐Ming

doi:10.1097/md.0000000000002970

Cited by 15 publications

(9 citation statements)

References 52 publications

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“…A significant association between a polymorphism of the threonine/alanine amino acid substitution at codon 228 (Thr228Ala) of SORBS1 and insulin resistance, obesity, and type 2 diabetes was already detected in a prior case-control study [46]. Furthermore, a recent study found other genetic variants of Sorbs1 significantly associated with blood pressure and hypertension, providing also a possible correlation with insulin resistance [47]. …”

Section: Discussionmentioning

confidence: 91%

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

Giuranna¹,

Volckmar²,

Heinen³

et al. 2018

Obes Facts

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Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level. Methods: We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student’s t-test for independent samples was applied and effect sizes using Cohen’s d were calculated. Results: In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 (Cap1 (150Arg; d = 7.48), Mapk1(343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)). Conclusion: The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.

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Section: Discussionmentioning

confidence: 91%

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

Giuranna¹,

Volckmar²,

Heinen³

et al. 2018

Obes Facts

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“…The same phenomenon was observed to carry over generations from grandparents to grandchildren, though less robustly [60]. In addition to observed heritability patterns in population studies, specific genetic determinants have been identified for early onset hypertension in several studies [61][62][63][64][65].…”

Section: Age Of Hypertension Onsetmentioning

confidence: 84%

Longitudinal blood pressure patterns and cardiovascular disease risk

et al. 2020

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Observational and interventional studies have unequivocally demonstrated that "present", i.e. single-occasion, blood pressure is one of the key determinants of cardiovascular disease risk. Over the past two decades, however, numerous publications have suggested that longitudinal blood pressure data and assessment of long-term blood pressure exposure provide incremental prognostic value over present blood pressure. These studies have used several different indices to quantify the overall exposure to blood pressure, such as time-averaged blood pressure, cumulative blood pressure, blood pressure trajectory patterns, and age of hypertension onset. This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal blood pressure changes can be measured and used to improve cardiovascular disease risk prediction. KEY MESSAGESNumerous recent publications have examined the relation between cardiovascular disease and long-term blood pressure (BP) exposure, quantified using indices such as time-averaged BP, cumulative BP, BP trajectory patterns, and age of hypertension onset. This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal BP changes can be measured and used to improve cardiovascular disease risk prediction. Although longitudinal BP indices seem to predict cardiovascular outcomes better than present BP, there are considerable differences in the clinical feasibility of these indices along with a limited number of prospective data.

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“…SORBS1 is an adaptor protein involved in insulin signalling. Polymorphisms in the SORBS1 gene have been associated with various, non-lung related, diseases,11 12 but its role in lung disease is unexplored. The new SORBS1 splice variant includes an additional exon encoding for an atrophin-1 domain.…”

Section: Resultsmentioning

confidence: 99%

Integrated proteogenomic approach identifying a protein signature of COPD and a new splice variant of SORBS1

Brandsma

Guryev

Timens

et al. 2020

Thorax

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Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD.

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Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension

Abstract: Supplemental Digital Content is available in the text

Cited by 15 publications

References 52 publications

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

Longitudinal blood pressure patterns and cardiovascular disease risk

Integrated proteogenomic approach identifying a protein signature of COPD and a new splice variant of SORBS1

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