Estimating Haplotype Effects on Dichotomous Outcome for Unphased Genotype Data Using a Weighted Penalized Log-Likelihood Approach

Souverein, Olga W.; Zwinderman, Aeilko H.; Tanck, Michael W.T.

doi:10.1159/000093476

Cited by 14 publications

(11 citation statements)

References 43 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From the obtained unphased SNP genotype data, haplotype frequencies and their effects on risk of ISR, repeat PCI, TLR, or MACE were estimated with weighted Cox regression as described. 19 Variables depicted by Cox proportional-hazard analysis to be predictive for ISR, repeat PCI, TLR, or MACE (PϽ0.05) and known predictive variables were entered into the model (control of confounding). We adjusted for multiple testing with the Bonferroni correction.…”

Section: Genotyping and Statistical Analysis Of The Genetic Associatimentioning

confidence: 99%

Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

et al. 2010

Self Cite

View full text Add to dashboard Cite

Background— Restenosis is the major drawback of percutaneous coronary interventions involving excessive activation and proliferation of vascular smooth muscle cells (SMCs). The nuclear receptor Nurr1 is an early response gene known mainly for its critical role in the development of dopamine neurons. In the present study, we investigated Nurr1 in human and experimental vascular restenosis. Methods and Results— In a prospective cohort of 601 patients undergoing percutaneous coronary intervention, including stent placement, we found a strong association between Nurr1 haplotypes and in-stent restenosis risk. Furthermore, Nurr1 is specifically expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor-α. Lentivirus-mediated gain- and loss-of-function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27 Kip1 , whereas Nurr1 silencing enhanced SMC growth. The tumor necrosis factor-α–induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 expression. Consistent with our in vitro data, endogenous Nurr1 reduced wire injury–induced proliferation and vascular lesion formation in carotid arteries of ApoE −/− mice. Conclusion— Nurr1 haplotypes are associated with human restenosis risk, and Nurr1 is expressed in human in-stent restenosis. In SMCs, Nurr1 inhibits proliferation and inflammatory responses, which explains the inhibition of SMC-rich lesion formation in mice. The recently identified small-molecule drugs that enhance the activity of Nurr1 reveal this nuclear receptor as an attractive novel target for (local) intervention in restenosis.

show abstract

Section: Genotyping and Statistical Analysis Of The Genetic Associatimentioning

confidence: 99%

Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Note that rare SNPs are already penalized through the group penalty. The concept is similar to that used by Souverein et al [9], who used a ridge penalty scaled by the haplotype frequency.…”

Section: Methodsmentioning

confidence: 99%

Penalized-regression-based multimarker genotype analysis of Genetic Analysis Workshop 17 data

2011

View full text Add to dashboard Cite

Testing for association between multiple markers and a phenotype can not only capture untyped causal variants in weak linkage disequilibrium with nearby typed markers but also identify the effect of a combination of markers. We propose a sliding window approach that uses multimarker genotypes as variables in a penalized regression. We investigate a penalty with three separate components: (1) a group least absolute shrinkage and selection operator (LASSO) that selects multimarker genotypes in a gene to be included in or excluded from the model, (2) an allele-sharing penalty that encourages multimarker genotypes with similar alleles to have similar coefficients, and (3) a penalty that shrinks the size of coefficients while performing model selection. The penalized likelihood is minimized with a cyclic coordinate descent algorithm, allowing quick coefficient estimation for a large number of markers. We compare our method to single-marker analysis and a gene-based sparse group LASSO on the Genetic Analysis Workshop 17 data for quantitative trait Q2. We found that all of the methods were underpowered to detect the simulated rare causal variants at the low false-positive rates desired in association studies. However, the sparse group LASSO on multi-marker genotypes seems to provide some advantage over the sparse group LASSO applied to single SNPs within genes, giving further evidence that there may be an advantage to modeling combinations of rare variant alleles over modeling them individually.

show abstract

“…17 For the GEISHA study, from the obtained unphased SNP genotype data, haplotype frequencies and their effect on risk of TLR were estimated using weighted Cox regression as described. 18 On the basis of inferred haplotypes, we grouped patients as those having 1 or no copies of the risk haplotype (TCG) and as those having 2 copies of the risk haplotype. Differences were considered statistically significant at P<0.05, as determined by paired 2-sided Student t test (experiments with 2 groups) or 1-way or 2-way ANOVA followed by Bonferroni or Dunnett test (experiments with >2 groups).…”

Section: Genotyping Of Snpsmentioning

confidence: 99%

Genetic Variants in CCNB1 Associated With Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

Silvestre-Roig¹,

Fernández²,

Mansego³

et al. 2014

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Background-The development of diagnostic tools to assess restenosis risk after stent deployment may enable the intervention to be tailored to the individual patient, for example, by targeting the use of drug-eluting stent to highrisk patients, with the goal of improving safety and reducing costs. The CCNB1 gene (encoding cyclin B1) positively regulates cell proliferation, a key component of in-stent restenosis. Therefore, we hypothesized that single-nucleotide polymorphisms in CCNB1 may serve as useful tools in risk stratification for in-stent restenosis. The incidence of restenosis is highly influenced by clinical, biological, and procedural and lesion-related risk factors. 4 However, information on restenosis biomarkers is scarce. Single-nucleotide polymorphisms (SNPs) are recognized as suitable markers of disease predisposition. Methods and Results-We5 SNPs in the human genome occur on average once every 300 nucleotides (≈10 million SNPs), making them the most common type of genetic variation. SNPs reported to influence restenosis risk affect platelet activation, leukocyte recruitment, the inflammatory response, metalloproteinases, lipid metabolism, oxidative stress, nitric oxide, the renin-angiotensin system, and cell proliferation. 4,6,7 Interestingly, the 838C>A SNP in CDKN1B (encoding the tumor suppressor p27 Kip1 ) has been associated with restenosis risk after coronary stenting, which might be because of augmented vascular smooth muscle cell proliferation caused by reduced CDKN1B promoter activity in patients carrying the risk allele.8 However, other SNPs in CDKN1B or TP53 (encoding the tumor suppressor p53) showed lack of association with restenosis risk. 8,9 In the present study, we investigated a potential association of restenosis risk with SNPs in the CCNB1 gene (encoding cyclin B1). Cyclin B1 is essential for cell proliferation, and its ablation in the mouse is embryonically lethal.10 Several regulatory mechanisms are necessary to ensure that cyclin B1 protein accumulates appreciably only during the G2/M cell cycle transition, and deregulated CCNB1 transcription leading to aberrantly high levels of cyclin B1 throughout the cell cycle is associated with excessive hyperplasia in several human cancers.11 Several lines of evidence indicate that cyclin B1 is also important in the context of cardiovascular disease: its expression has been reported in human restenotic tissue obtained by directional coronary atherectomy, 12 it is induced in balloon-injured rat carotid artery, 13,14 and its inhibition reduces neointimal thickening in this animal model. 15 Herein, we present evidence from 2 independent cohorts of patients undergoing coronary stent deployment (Clinica Mediterranea and Genetic risk factors for In-Stent Hyperplasia study Amsterdam [GEISHA]) 8 cohorts showing that alleles of the SNPs rs350099, rs350104, and rs164390, located in regulatory regions of CCNB1, are associated with higher CCNB1 mRNA expression and increased risk of in-stent restenosis (ISR) after PCI. Furthermore, we identify mole...

show abstract

Estimating Haplotype Effects on Dichotomous Outcome for Unphased Genotype Data Using a Weighted Penalized Log-Likelihood Approach

Cited by 14 publications

References 43 publications

Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

Penalized-regression-based multimarker genotype analysis of Genetic Analysis Workshop 17 data

Genetic Variants in CCNB1 Associated With Differential Gene Transcription and Risk of Coronary In-Stent Restenosis

Contact Info

Product

Resources

About