Browsing by Author "Kuivaniemi, Helena"

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    Association of simple renal cysts and chronic kidney disease with large abdominal aortic aneurysm
    (BMC (part of Springer Nature), 2020-05-29) Miszczuk, Milena; Müller, Verena; Althoff, Christian E.; Stroux, Andrea; Widhalm, Daniela; Dobberstein, Andy; Greiner, Andreas; Kuivaniemi, Helena; Hinterseher, Irene
    Background: Abdominal aortic aneurysms (AAA) primarily affect men over 65 years old who often have many other diseases, with similar risk factors and pathobiological mechanisms to AAA. The aim of this study was to assess the prevalence of simple renal cysts (SRC), chronic kidney disease (CKD), and other kidney diseases (e.g. nephrolithiasis) among patients presenting with AAA. Methods: Two groups of patients (97 AAA and 100 controls), with and without AAA, from the Surgical Clinic Charité, Berlin, Germany, were selected for the study. The control group consisted of patients who were evaluated for a kidney donation (n = 14) and patients who were evaluated for an early detection of a melanoma recurrence (n = 86). The AAA and control groups were matched for age and sex. Medical records were analyzed and computed tomography scans were reviewed for the presence of SRC and nephrolithiasis. Results: SRC (74% vs. 57%; p<0.016) and CKD (30% vs. 8%; p<0.001) were both more common among AAA than control group patients. On multivariate analysis, CKD, but not SRC, showed a strong association with AAA. Conclusions: Knowledge about pathobiological mechanisms and association between CKD and AAA could provide better diagnostic and therapeutic approaches for these patients.
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    Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals
    (BioMed Central, 2017) Holzinger, Emily R.; Verma, Shefali S.; Moore, Carrie B.; Hall, Molly; De, Rishika; Gilbert-Diamond, Diane; Lanktree, Matthew B.; Pankratz, Nathan; Amuzu, Antoinette; Burt, Amber; Dale, Caroline; Dudek, Scott; Furlong, Clement E.; Gaunt, Tom R.; Kim, Daniel Seung; Riess, Helene; Sivapalaratnam, Suthesh; Tragante, Vinicius; Van Iperen, Erik P. A.; Brautba, Ariel; Carrell, David S.; Crosslin, David R.; Jarvik, Gail P.; Kuivaniemi, Helena; Kullo, Iftikhar J.; Larson, Eric B.; Rasmussen-Torvik, Laura J.; Tromp, Gerard; Baumert, Jens; Cruickshanks, Karen J.; Farrall, Martin; Hingorani, Aroon D.; Hovingh, G. K.; Kleber, Marcus E.; Klein, Barbara E.; Klein, Ronald; Koenig, Wolfgang; Lange, Leslie A.; Mӓrz, Winfried; North, Kari E.; Onland-Moret, N. Charlotte; Reiner, Alex P.; Talmud, Philippa J.; Van Der Schouw, Yvonne T.; Wilson, James G.; Kivimaki, Mika; Kumari, Meena; Moore, Jason H.; Drenos, Fotios; Asselbergs, Folkert W.; Keating, Brendan J.; Ritchie, Marylyn D.
    Background: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Results: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. Conclusions: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
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    Editorial: FDA-Approved Drug Repositioning for P-Glycoprotein Overexpressing Resistant Cancer
    (Frontiers Media S.A, 2021-03) Yoon, Sungpil; Wang, Xiaoju; Vongpunsawad, Sompong; Tromp, Gerard; Kuivaniemi, Helena
    Anticancer drugs are an essential part of cancer treatment. Cancer cells can, however, develop resistance to these drugs by e.g., P-glycoprotein 1 (P-gp) overexpression or accumulation of mutations in the genes part of growth signaling pathways, apoptotic pathways, or repair system. Intrinsically, metastatic cancers, advanced-stage cancers, or stem cell-like cancers are usually drug-resistant and difficult to treat using current anticancer drugs. The overexpression of P-gp, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1), is one of the well-known mechanisms of resistance to anticancer drugs. Stem cell-like cancers often overexpress P-gp on their membranes, which results in inefficient treatment using the currently available anticancer drugs (1). It is, therefore, important to investigate novel therapeutic options to treat the P-gp overexpressing drug-resistant cancer cells. Identifying the mechanisms for targeting these cancers can overcome the inefficiencies of current anticancer drugs and lead to better outcomes for patients with P-gp overexpressing cancers.
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    eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants
    (BioMed Central, 2016) Verma, Anurag; Verma, Shefali S.; Pendergrass, Sarah A.; Crawford, Dana C.; Crosslin, David R.; Kuivaniemi, Helena; Bush, William S.; Bradford, Yuki; Kullo, Iftikhar; Bielinski, Suzette J.; Li, Rongling; Denny, Joshua C.; Peissig, Peggy; Hebbring, Scott; De Andrade, Mariza; Ritchie, Marylyn D.; Tromp, Gerard
    Background: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy. Results: In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272. 1 “Disorder of Lipoid metabolism” (pdiscovery = 2.59x10-6, preplicating = 2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 “Acquired Hypothyroidism” (pdiscovery = 5.31x103, preplicating = 1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 “Complications peculiar to certain specified procedures” (pdiscovery = 8. 65x103, preplicating = 4.16x10-3).
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    Genetic association of lipids and lipid drug targets with abdominal aortic aneurysm : a meta-analysis
    (American Medical Association, 2018) Harrison, Seamus C.; Holmes, Michael V.; Burgess, Stephen; Asselbergs, Folkert W.; Jones, Gregory T.; Baas, Annette F.; Van 't Hof, F. N.; De Bakker, Paul I. W.; Blankensteijn, Jan D.; Powell, Janet T.; Saratzis, Athanasios; De Borst, Gert J.; Swerdlow, Daniel I.; Van der Graaf, Yolanda; Van Rij, Andre M.; Carey, David J.; Elmore, James R.; Tromp, Gerard; Kuivaniemi, Helena; Sayers, Robert D.; Samani, Nilesh J.; Bown, Matthew J.; Humphries, Steve E.
    Importance Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants Genetic risk scores, composed of lipid trait–associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10−9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10−5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10−7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C–reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C–raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10−7). Finally, the LDL-C–lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C–lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). Conclusions and Relevance The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
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    Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm
    (Nature Research, 2019-09-17) Sharma, Neekun; Dev, Rishabh; Ruiz-Rosado, Juan de Dios; Partida-Sanchez, Santiago; Guerau-de-Arellano, Mireia; Dhakal, Pramod; Kuivaniemi, Helena; Hans, Chetan P.
    ENGLISH ABSTRACT: Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.
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    Phenome-wide association study to explore relationships between immune system related genetic loci and complex traits and diseases
    (Public Library of Science, 2016) Verma, Anurag; Basile, Anna O.; Bradford, Yuki; Kuivaniemi, Helena; Tromp, Gerard; Carey, David; Gerhard, Glenn S.; Crowe, James E.; Ritchie, Marylyn D.; Pendergrass, Sarah A.
    This study highlights the utility of using PheWAS in conjunction with EHRs to discover new genotypic-phenotypic associations for immune-system related genetic loci.
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    Smooth muscle cell-specific Notch1 haploinsufficiency restricts the progression of abdominal aortic aneurysm by modulating CTGF expression
    (Public Library of Science, 2017) Sachdeva, Jaspreet; Mahajan, Advitiya; Cheng, Jeeyun; Baeten, Jeremy T.; Lilly, Brenda; Kuivaniemi, Helena; Hans, Chetan P.
    Aims: Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development. Methods and results: Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF. Conclusions: Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.
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    Systematic review of genetic factors in the etiology of esophageal squamous cell carcinoma in African populations
    (Frontiers Media, 2019) Simba, Hannah; Kuivaniemi, Helena; Lutje, Vittoria; Tromp, Gerard; Sewram, Vikash
    Background: Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most divergence in cancer incidence globally, with high prevalence reported in East Asia, Southern Europe, and in East and Southern Africa. Its etiology is multifactorial, with lifestyle, environmental, and genetic risk factors. Very little is known about the role of genetic factors in ESCC development and progression among African populations. The study aimed to systematically assess the evidence on genetic variants associated with ESCC in African populations. Methods: We carried out a comprehensive search of all African published studies up to April 2019, using PubMed, Embase, Scopus, and African Index Medicus databases. Quality assessment and data extraction were carried out by two investigators. The strength of the associations was measured by odds ratios and 95% confidence intervals. Results: Twenty-three genetic studies on ESCC in African populations were included in the systematic review. They were carried out on Black and admixed South African populations, as well as on Malawian, Sudanese, and Kenyan populations. Most studies were candidate gene studies and included DNA sequence variants in 58 different genes. Only one study carried out whole-exome sequencing of 59 ESCC patients. Sample sizes varied from 18 to 880 cases and 88 to 939 controls. Altogether, over 100 variants in 37 genes were part of 17 case-control genetic association studies to identify susceptibility loci for ESCC. In these studies, 25 variants in 20 genes were reported to have a statistically significant association. In addition, eight studies investigated changes in cancer tissues and identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. Two genes were assessed for both genetic association and somatic mutation. Conclusions: Comprehensive large-scale studies on the genetic basis of ESCC are still lacking in Africa. Sample sizes in existing studies are too small to draw definitive conclusions about ESCC etiology. Only a small number of African populations have been analyzed, and replication and validation studies are missing. The genetic etiology of ESCC in Africa is, therefore, still poorly defined.
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    Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients
    (BioMed Central, 2020-02-04) Oluwole, Oluwafemi G.; Kuivaniemi, Helena; Abrahams, Shameemah; Haylett, William L.; Vorster, Alvera A.; Van Heerden, Carel J.; Kenyon, Colin P.; Tabb, David L.; Fawale, Michael B.; Sunmonu, Taofiki A.; Ajose, Abiodun; Olaogun, Matthew O.; Rossouw, Anastasia C.; Van Hillegondsberg, Ludo S.; Carr, Jonathan; Ross, Owen A.; Komolafe, Morenikeji A.; Tromp, Gerard; Bardien, Soraya
    Background: The prevalence of Parkinson’s disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. Methods: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2’s protein structure was investigated by molecular modelling. Results: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. Conclusions: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.
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    A trans-ethnic genome-wide association study of uterine fibroids
    (Frontiers Media, 2019) Edwards, Todd L.; Giri, Ayush; Hellwege, Jacklyn N.; Hartmann, Katherine E.; Stewart, Elizabeth A.; Jeff, Janina M.; Pendergrass, Sarah A.; Torstenson, Eric S.; Keaton, Jacob M.; Jones, Sarah H.; Gogoi, Radhika P.; Kuivaniemi, Helena; Jackson, Kathryn L.; Kho, Abel N.; Kullo, Iftikhar J.; McCarty, Catherine A.; Im, Hae Kyung; Pacheco, Jennifer A.; Pathak, Jyotishman; Williams, Marc S.; Tromp, Gerard; Kenny, Eimear E.; Peissig, Peggy L.; Denny, Joshua C.; Roden, Dan M.; Edwards, Digna R. Velez
    ENGLISH ABSTRACT: Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10−⁵) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10−⁸), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10−⁹) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10−⁸). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10−²⁴). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het- between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10−⁸), OBFC1 in esophageal mucosa (P = 8.7 × 10−⁸), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10−⁶), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10−⁶) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.