A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol

Tomaszewski, Maciej; Charchar, Fadi J.; Barnes, Timothy; Gawron-Kiszka, Magdalena; Sedkowska, Agnieszka; Podolecka, Ewa; Kowalczyk, Jacek; Rathbone, Wendy E.; Kalarus, Zbigniew; Grzeszczak, W; Goodall, Alison H.; Samani, Nilesh J.; Żukowska-Szczechowska, E

doi:10.1161/atvbaha.109.185355

Cited by 37 publications

(40 citation statements)

References 33 publications

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“…We also replicated the new (FGFBP1) and previously shown (FGF1) associations in an independent population recruited in the same region where the primary cohort was collected. 5,12 More importantly, we discovered an additive effect of both FGFBP1 and FGF1 alleles on the risk of hypertension. Finally, we determined that, similar to FGF1, 5 FGFBP1 is up-regulated in the hypertensive kidney and that this up-regulation is apparent mainly (but not exclusively) within the glomerulus.…”

Section: Discussionmentioning

confidence: 76%

“…We also appreciate that criteria of inclusion to SHS and SCS were not identical (hypertension in SHS and cardiovascular disease or its risk factors in SCS), which is clearly less optimal than having two populations selected for the same disease. However, we should stress that hypertension was a leading criterion of inclusion into SCS, 12 and the overall demographic and clinical characteristics of 807 subjects in SCS was similar to the age-matching parental generation of SHS. We are aware that our pathway analysis did not capture other FGFs with a potential relevance to hypertension (i.e., FGF5).…”

Section: Discussionmentioning

confidence: 97%

“…12 Briefly, the phenotyping included collecting clinical information (using coded questionnaires), anthropometric measurements, and biochemical studies. 12 BP was measured in triplicate using an oscillometric method according to the guidelines. 27 Hypertension was defined as BP Ն140/90 mmHg measured on at least two separate occasions and/or taking anti-hypertensive medication.…”

Section: Subjectsmentioning

confidence: 99%

“…27 Hypertension was defined as BP Ն140/90 mmHg measured on at least two separate occasions and/or taking anti-hypertensive medication. 12 For the purpose of replication analysis, all biologically unrelated subjects (807 individuals) were selected from this cohort for genotyping.…”

Section: Subjectsmentioning

confidence: 99%

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Pathway Analysis Shows Association between FGFBP1 and Hypertension

Tomaszewski¹,

Charchar²,

Nelson³

et al. 2011

Journal of the American Society of Nephrology

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Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P ϭ 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5-and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P ϭ 0.04 and P ϭ 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. 22: 947-955, 201122: 947-955, . doi: 10.1681 Essential hypertension is a complex, multifactorial, heritable disease. The contribution of genetic factors to the development of hypertension is estimated at 30 to 50%, but the causative alleles and related molecular mechanisms remain largely elusive. However, it is becoming increasingly clear that genes underlying familial susceptibility to essential hypertension may not necessarily reside within the most obvious pathways involved in BP regulation. 1 Indeed, a substantial proportion of novel alleles associated with hypertension and BP in the recent genome-wide association scans map to genes that do not belong to classical systems of BP regulation (such as the sympathetic nervous system or renal sodium handling). 2,3 Fibroblast growth factor (FGF) family is an example of a novel group of mole- J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Section: Subjectsmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

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Pathway Analysis Shows Association between FGFBP1 and Hypertension

Tomaszewski¹,

Charchar²,

Nelson³

et al. 2011

Journal of the American Society of Nephrology

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“…Five populations (Silesian Cardiovascular Study 29 ; Victorian Family Heart Study 30 ; Prevention of Renal and Vascular End-stage Disease Study 31,32 ; Genetic Regulation of Arterial Pressure of Humans in the Community Study (GRAPHIC) 5,33 ; and Young Men Cardiovascular Association Study 34 ) with relevant genetic (directly genotyped rs152524 SNP) and phenotypic (clinic BP) information were included in the genetic association analysis. All individuals were of white European ethnicity.…”

Section: Populationsmentioning

confidence: 99%

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

Tomaszewski

Eales

Denniff

et al. 2015

Journal of the American Society of Nephrology

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The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65310 25) and diastolic BP (P=7.61310 23) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0310 23). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP. Essential hypertension is a net product of genetic factors and environmental exposure acting together on regulatory systems in key organs for BP homeostasis. The kidney is central to BP regulation and drives the development of hypertension through numerous mechanisms including glomerular hemodynamics, tubular reabsorption of sodium, actions of the renin-angiotensin system, and natriuretic peptides. 1 Rare genetic variants that affect expression of molecules and pathways operating within the kidney lead to elevated BP in monogenic forms of hypertension. 2 Several common variants in genes associated with BP and/or susceptibility to hypertension are also believed to act through the

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The role of Lrp5/6 in cardiac valve disease: LDL‐density‐pressure theory

Rajamannan

2011

J of Cellular Biochemistry

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Atherosclerosis and osteoporosis are the leading causes of mortality and morbidity in the World. Recent epidemiologic studies have demonstrated that these disease processes develop in parallel. Evidence indicates that hyperlipidemia plays a paradoxical role in both disease processes. However, the mechanism is not understood. This prospectus hypothesizes the role of lipids activate atherosclerosis within the bone and the heart to initiate the development of diseases in both of these tissues. The Prospectus on the Lrp 5/6 receptors provides a foundation for the mechanisms involved in the Lrp5/6 mediated disease biology. The LDL-Density-Pressure theory: the Role of Lrp5/6 provides a biological and a hemodynamic approach towards understanding the development of valvular heart disease and the implications in the field of bone molecular biology. This prospectus will review the current literature, provide a basis for the development of valve disease and indicate future therapeutic pathways for this disease process in the future.

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A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol

Cited by 37 publications

References 33 publications

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

The role of Lrp5/6 in cardiac valve disease: LDL‐density‐pressure theory

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