- Büsst, Cara, Bloomer, Lisa, Scurrah, Katrina, Ellis, Justine, Barnes, Timothy, Charchar, Fadi, Braund, Peter, Hopkins, Paul, Samani, Nilesh, Hunt, Steven, Tomaszewski, Maciej, Harrap, Stephen
- Authors: Büsst, Cara , Bloomer, Lisa , Scurrah, Katrina , Ellis, Justine , Barnes, Timothy , Charchar, Fadi , Braund, Peter , Hopkins, Paul , Samani, Nilesh , Hunt, Steven , Tomaszewski, Maciej , Harrap, Stephen
- Date: 2011
- Type: Text , Journal article
- Relation: Hypertension Vol. 58, no. 6 (2011), p. 1073-1078
- Full Text: false
- Reviewed:
- Description: Variants in the gene encoding the y-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination. © 2011 American Heart Association, Inc.
- Charchar, Fadi, Kaiser, Michael, Bingham, Andrew, Fotinatos, Nina, Ahmady, Fahima, Tomaszewski, Maciej, Samani, Nilesh
- Authors: Charchar, Fadi , Kaiser, Michael , Bingham, Andrew , Fotinatos, Nina , Ahmady, Fahima , Tomaszewski, Maciej , Samani, Nilesh
- Date: 2010
- Type: Text , Journal article
- Relation: Hypertension Vol. 55, no. 5 (2010), p. 1231-1238
- Full Text: false
- Reviewed:
- Description: Copy number variation has emerged recently as an important genetic mechanism leading to phenotypic heterogeneity. The aim of our study was to determine whether copy number variants (CNVs) exist between the spontaneously hypertensive rat (SHR) and its control strain, the Wistar-Kyoto rat, whether these map to quantitative trait loci in the rat and whether CNVs associate with gene expression or blood pressure differences between the 2 strains. We performed a comparative genomic hybridization assay between SHR and Wistar-Kyoto strains using a whole-genome array. In total, 16 CNVs were identified and validated (6 because of a relative loss of copy number in the SHR and 10 because of a relative gain). CNVs were present on rat autosomes 1, 3, 4, 6, 7, 10, 14, and 17 and varied in size from 10.0 kb to 1.6 Mb. Most of these CNVs mapped to chromosomal regions within previously identified quantitative trait loci, including those for blood pressure in the SHR. Transcriptomic experiment! s confirmed differences in the renal expression of several genes (including Ms4a6a, Ndr3, Egln1, Cd36, Sema3a, Ugt2b, and Idi21) located in some of the CNVs between STIR and Wistar-Kyoto rats. In F-2 animals derived from an SHRXWistar-Kyoto cross, we also found a significant increase in blood pressure associated with an increase in copy number in the Egln1 gene. Our findings suggest that, CNVs may play a role in the susceptibility to hypertension and related trails in the SHR. (Hypertension. 2010;55:1231-1238.)
Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study
- Fox, Ervin, Young, J. Hunter, Li, Yali, Dreisbach, Albert, Charchar, Fadi
- Authors: Fox, Ervin , Young, J. Hunter , Li, Yali , Dreisbach, Albert , Charchar, Fadi
- Date: 2011
- Type: Text , Journal article
- Relation: Human molecular genetics Vol. 20, no. 11 (June 2011), p. 2273
- Full Text:
- Reviewed:
- Description: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
- Authors: Fox, Ervin , Young, J. Hunter , Li, Yali , Dreisbach, Albert , Charchar, Fadi
- Date: 2011
- Type: Text , Journal article
- Relation: Human molecular genetics Vol. 20, no. 11 (June 2011), p. 2273
- Full Text:
- Reviewed:
- Description: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
Genetics of blood pressure : Time to curate the collection
- Harrap, Stephen, Charchar, Fadi
- Authors: Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Editorial
- Relation: Journal of Hypertension Vol. 35, no. 7 (2017), p. 1360-1362
- Full Text: false
- Reviewed:
- Description: The genetics of blood pressure (BP) is all about discovery and understanding, but it is certainly not for the faint hearted. Despite heroic effort, the question we posed nearly 15 years ago [1] regarding the whereabouts of BP genes remains largely unanswered.
DMD-associated dilated cardiomyopathy : genotypes, phenotypes, and phenocopies
- Johnson, Renee, Otway, Robyn, Chin, Ephrem, Horvat, Claire, Ohanian, Monique, Wilcox, Jon, Su, Zheng, Prestes, Priscilla, Smolnikov, Andrei, Soka, Magdalena, Guo, Guanglan, Rath, Emma, Chakravorty, Samya, Chrzanowski, Lukasz, Hayward, Christopher, Keogh, Anne, MacDonald, Peter, Giannoulatou, Eleni, Chang, Alex, Oates, Emily, Charchar, Fadi, Seidman, Jonathan, Seidman, Christine, Hegde, Madhuri, Fatkin, Diane
- Authors: Johnson, Renee , Otway, Robyn , Chin, Ephrem , Horvat, Claire , Ohanian, Monique , Wilcox, Jon , Su, Zheng , Prestes, Priscilla , Smolnikov, Andrei , Soka, Magdalena , Guo, Guanglan , Rath, Emma , Chakravorty, Samya , Chrzanowski, Lukasz , Hayward, Christopher , Keogh, Anne , MacDonald, Peter , Giannoulatou, Eleni , Chang, Alex , Oates, Emily , Charchar, Fadi , Seidman, Jonathan , Seidman, Christine , Hegde, Madhuri , Fatkin, Diane
- Date: 2023
- Type: Text , Journal article
- Relation: Circulation: Genomic and Precision Medicine Vol. 16, no. 5 (2023), p. 421-430
- Full Text:
- Reviewed:
- Description: Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management. © 2023 American Heart Association, Inc.
- Authors: Johnson, Renee , Otway, Robyn , Chin, Ephrem , Horvat, Claire , Ohanian, Monique , Wilcox, Jon , Su, Zheng , Prestes, Priscilla , Smolnikov, Andrei , Soka, Magdalena , Guo, Guanglan , Rath, Emma , Chakravorty, Samya , Chrzanowski, Lukasz , Hayward, Christopher , Keogh, Anne , MacDonald, Peter , Giannoulatou, Eleni , Chang, Alex , Oates, Emily , Charchar, Fadi , Seidman, Jonathan , Seidman, Christine , Hegde, Madhuri , Fatkin, Diane
- Date: 2023
- Type: Text , Journal article
- Relation: Circulation: Genomic and Precision Medicine Vol. 16, no. 5 (2023), p. 421-430
- Full Text:
- Reviewed:
- Description: Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management. © 2023 American Heart Association, Inc.
Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics
- Rowland, Joshua, Akbarov, Artur, Eales, James, Xu, Xiaoguang, Dormer, John, Guo, Hui, Denniff, Matthew, Jiang, Xiao, Ranjzad, Parisa, Nazgiewicz, Alicja, Prestes, Priscilla, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Zukowska-Szczechowska, Ewa, Bogdanski, Pawel, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
- Full Text:
- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
- Authors: Rowland, Joshua , Akbarov, Artur , Eales, James , Xu, Xiaoguang , Dormer, John , Guo, Hui , Denniff, Matthew , Jiang, Xiao , Ranjzad, Parisa , Nazgiewicz, Alicja , Prestes, Priscilla , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Zukowska-Szczechowska, Ewa , Bogdanski, Pawel , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2019
- Type: Text , Journal article
- Relation: Kidney International Vol. 95, no. 3 (2019), p. 624-635
- Full Text:
- Reviewed:
- Description: Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.
Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- Surendran, Praveen, Feofanova, Elena, Lahrouchi, Najim, Ntalla, Ionna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi, Cartwright, James, Hellwege, Jacklyn, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang, Prins, Bram, Stewart, Isobel, Cabrera, Claude, Eales, James, Akbarov, Artur, Auer, Paul, Charchar, Fadi, Howson, Joanna, LifeLines Cohort, Study, Epic, C. V. D., Epic InterAct, Understanding Society Scientific, Group, Million Veteran, Program
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
- Full Text:
- Reviewed:
- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
- Authors: Surendran, Praveen , Feofanova, Elena , Lahrouchi, Najim , Ntalla, Ionna , Karthikeyan, Savita , Cook, James , Chen, Lingyan , Mifsud, Borbala , Yao, Chen , Kraja, Aldi , Cartwright, James , Hellwege, Jacklyn , Giri, Ayush , Tragante, Vinicius , Thorleifsson, Gudmar , Liu, Dajiang , Prins, Bram , Stewart, Isobel , Cabrera, Claude , Eales, James , Akbarov, Artur , Auer, Paul , Charchar, Fadi , Howson, Joanna , LifeLines Cohort, Study , Epic, C. V. D. , Epic InterAct , Understanding Society Scientific, Group , Million Veteran, Program
- Date: 2020
- Type: Text , Journal article
- Relation: Nature Genetics Vol. 52, no. 12 (2020), p. 1314-1332
- Full Text:
- Reviewed:
- Description: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. There are 286 authors of this articles not all are listed in this record.
- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Gawron-Kiszka, Magdalena, Sedkowska, Agnieszka, Podolecka, Ewa, Kowalczyk, Jacek, Rathbone, Wendy, Kalarus, Zbigniew, Grzeszczak, Wladyslaw, Goodall, Alison, Samani, Nilesh, Zukowska-Szczechowska, Ewa
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Gawron-Kiszka, Magdalena , Sedkowska, Agnieszka , Podolecka, Ewa , Kowalczyk, Jacek , Rathbone, Wendy , Kalarus, Zbigniew , Grzeszczak, Wladyslaw , Goodall, Alison , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2009
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 29, no. 9 (2009), p. 1316-1321
- Full Text: false
- Reviewed:
- Description: Objective-A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C). Methods and Results-Twelve common ( minor allele frequency >= 0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (P=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (P=0.0268, P=0.0476, and P=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05, P=0.0038). Conclusions-Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation. (Arterioscler Thromb Vasc Biol. 2009;29:1316-1321.)
- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Maric, Christine, Zukowska-Szczechowska, Ewa, Samani, Nilesh
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
- Date: 2010
- Type: Text , Conference paper
- Relation: Paper presented at British Cardiovascular Society Annual Conference 2010, Manchester Central, Manchester, UK : 7th-9th June 2010
- Full Text: false
- Description: Essential hypertension is a complex, multifactorial disease with a strong genetic component. Fibroblast growth factor 1 gene (FGF1) is one of the most relevant candidates having been associated not only with familial susceptibility to hypertension but also with up-regulation within the glomerulus of the human hypertensive kidney/Circulation 2007;116:1915e24/. We have hypothesised that systematic analysis of genes interacting with FGF1 may uncover novel variants underlying essential hypertension. Seventy-nine common (minor allele frequency$0.1) tagging (r2$0.8) and functional single nucleotide polymorphisms (SNPs) spanning eight critical components of the FGF (fibroblast growth factor) pathway (FGF2, FGFR1, FGFR2, FGFR3, FGFR4, FGFBP1, FIBP, SPRY1) were genotyped by MALDI-TOF mass spectrometry in 629 subjects from 207 Polish hypertensive families (Silesian Hypertension Study d SHS). 83.5% of genotyped SNPs that passed quality control filters provided 92.9% genetic coverage of FGF pathway loci. Family-based analysis in SHS revealed that alleles of three SNPs (rs2956724, rs2245964 and rs16892645) in two loci (FGFR1 and FGFBP1) were transmitted to hypertensive offspring more frequently than expected by chance. However, only one association survived correction for multiple testing e major allele of rs16892645 in FGFBP1 was over-transmitted from heterozygous parents to hypertensive offspring more frequently than expected by chance (p¼0.0048, false discovery rate<0.25). The association between rs16892645 and hypertension was replicated in an independent cohort of 807 Polish subjects from Silesian Cardiovascular Study d each major allele copy of rs16892645 increased the odds of hypertension approximately by 1.5 (odds ratio: 1.5; 95% CI: 1.1 to to 2.2, p¼0.04). Association between FGFBP1 and hypertension was also apparent at the protein expression level d compared with normotensive patients, hypertensives from Silesian Renal Tissue Bank showed approximately 1.4-fold higher renal abundance of FGFBP1 in Western blotting (p¼0.001). Immunohistochemical analysis revealed that hypertension-related up-regulation of FGFBP1 was exclusive to renal glomeruli. These data show that FGFBP1da gene that encodes a carrier protein for FGF1 d is associated with human hypertension. We also reveal that up-regulation of FGFBP1 maps to the same histological compartment where FGF1 was shown to be most abundant (renal glomeruli). Our study also proves that systematic genetic analysis of signalling pathways is a strategy with a potential to identify novel molecular mechanisms underlying blood pressure elevation.
- Tomaszewski, Maciej, Debiec, Radoslaw, Braund, Peter, Nelson, Christopher, Hardwick, Robert, Christofidou, Paraskevi, Denniff, Matthew, Codd, Veryan, Rafelt, Suzanne, van der Harst, Pim, Waterworth, Dawn, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Zukowska-Szczechowska, Ewa, Burton, Paul, Mooser, Vincent, Charchar, Fadi, Thompson, John, Tobin, Martin, Samani, Nilesh
- Authors: Tomaszewski, Maciej , Debiec, Radoslaw , Braund, Peter , Nelson, Christopher , Hardwick, Robert , Christofidou, Paraskevi , Denniff, Matthew , Codd, Veryan , Rafelt, Suzanne , van der Harst, Pim , Waterworth, Dawn , Song, Kijoung , Vollenweider, Peter , Waeber, Gerard , Zukowska-Szczechowska, Ewa , Burton, Paul , Mooser, Vincent , Charchar, Fadi , Thompson, John , Tobin, Martin , Samani, Nilesh
- Date: 2010
- Type: Text , Journal article
- Relation: Hypertension Vol. 56, no. 6 (2010), p. 1069-U146
- Full Text: false
- Reviewed:
- Description: Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains approximate to 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2 x 10(-8)). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 x 10(-6)). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: <0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.
Genetics of human essential hypertension - from single mutations to quantitative trait loci
- Tomaszewski, Maciej, Brain, Nick, Charchar, Fadi, Dominiczak, Anna
- Authors: Tomaszewski, Maciej , Brain, Nick , Charchar, Fadi , Dominiczak, Anna
- Date: 2006
- Type: Text , Book chapter
- Relation: Molecular mechanisms in hypertension Chapter p. 241-247
- Full Text: false
- Description: 2003007414
Kidney omics in hypertension: from statistical associations to biological mechanisms and clinical applications
- Tomaszewski, Maciej, Morris, Andrew, Howson, Joanna, Franceschini, Nora, Eales, James, Xu, Xiaoguang, Dikalov, Sergey, Guzik, Tomasz, Humphreys, Benjamin, Harrap, Stephen, Charchar, Fadi
- Authors: Tomaszewski, Maciej , Morris, Andrew , Howson, Joanna , Franceschini, Nora , Eales, James , Xu, Xiaoguang , Dikalov, Sergey , Guzik, Tomasz , Humphreys, Benjamin , Harrap, Stephen , Charchar, Fadi
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Kidney International Vol. 102, no. 3 (2022), p. 492-505
- Full Text:
- Reviewed:
- Description: Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage. © 2022 International Society of Nephrology
- Authors: Tomaszewski, Maciej , Morris, Andrew , Howson, Joanna , Franceschini, Nora , Eales, James , Xu, Xiaoguang , Dikalov, Sergey , Guzik, Tomasz , Humphreys, Benjamin , Harrap, Stephen , Charchar, Fadi
- Date: 2022
- Type: Text , Journal article , Review
- Relation: Kidney International Vol. 102, no. 3 (2022), p. 492-505
- Full Text:
- Reviewed:
- Description: Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage. © 2022 International Society of Nephrology
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