Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

Dungan, Jennifer R.; Qin, Xuejun; Horne, Benjamin D.; Carlquist, John F.; Singh, Abanish; Hurdle, Melissa; Grass, Elizabeth; Haynes, Carol; Gregory, Simon G.; Shah, Svati H.; Hauser, Elizabeth R.; Kraus, William E.

doi:10.1371/journal.pone.0154856

Cited by 6 publications

(11 citation statements)

References 54 publications

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“…Outside CNS, the highest expression level was observed for Lsamp 1b transcript in the heart, which is in line with considerable evidence suggesting that IgLONs, specifically Lsamp and Ntm , may have additional functions in the human cardiovascular system (Wang et al, 2008 ; Luukkonen et al, 2012 ; Cao et al, 2015 ; Dungan et al, 2016 ). However, data from knockout mouse models has demonstrated that deletion of either Lsamp, Ntm , or Opcml individually, or Opcml and Ntm together as a double heterozygote, does not result in apparent cardiac phenotype (Innos et al, 2011 ; Ye et al, 2014 ).…”

Section: Discussionsupporting

confidence: 76%

Promoter-Specific Expression and Genomic Structure of IgLON Family Genes in Mouse

et al. 2017

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IgLON family is composed of five genes: Lsamp, Ntm, Opcml, Negr1, and Iglon5; encoding for five highly homologous neural adhesion proteins that regulate neurite outgrowth and synapse formation. In the current study we performed in silico analysis revealing that Ntm and Opcml display similar genomic structure as previously reported for Lsamp, characterized by two alternative promotors 1a and 1b. Negr1 and Iglon5 transcripts have uniform 5′ region, suggesting single promoter. Iglon5, the recently characterized family member, shares high level of conservation and structural qualities characteristic to IgLON family such as N-terminal signal peptide, three Ig domains, and GPI anchor binding site. By using custom 5′-isoform-specific TaqMan gene-expression assay, we demonstrated heterogeneous expression of IgLON transcripts in different areas of mouse brain and several-fold lower expression in selected tissues outside central nervous system. As an example, the expression of IgLON transcripts in urogenital and reproductive system is in line with repeated reports of urogenital tumors accompanied by mutations in IgLON genes. Considering the high levels of intra-family homology shared by IgLONs, we investigated potential compensatory effects at the level of IgLON isoforms in the brains of mice deficient of one or two family members. We found that the lack of IgLONs is not compensated by a systematic quantitative increase of the other family members. On the contrary, the expression of Ntm 1a transcript and NEGR1 protein was significantly reduced in the frontal cortex of Lsamp-deficient mice suggesting that the expression patterns within IgLON family are balanced coherently. The actions of individual IgLONs, however, can be antagonistic as demonstrated by differential expression of Syp in deletion mutants of IgLONs. In conclusion, we show that the genomic twin-promoter structure has impact on both anatomical distribution and intra-family interactions of IgLON family members. Remarkable variety in the activity levels of 1a and 1b promoters both in the brain and in other tissues, suggests complex functional regulation of IgLONs by alternative signal peptides driven by 1a and 1b promoters.

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Section: Discussionsupporting

confidence: 76%

Promoter-Specific Expression and Genomic Structure of IgLON Family Genes in Mouse

et al. 2017

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“…However, with an increasing focus on the genetic context of subsequent CHD 5 , a more specific question has arisen about the impact of selection bias in studying those who have been selected on and have survived a potentially fatal index event. While some studies have examined the impact of selection bias on effect estimates in case-control studies 18,19 , to our knowledge this question has not been addressed for time to event analysis of longitudinal cohort studies exploring associations with recurrent or subsequent CHD events.…”

Section: Discussionmentioning

confidence: 99%

Impact of Selection Bias on Estimation of Subsequent Event Risk

Schmidt

Dudbridge

et al. 2017

Circ Cardiovasc Genet

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Background Studies of recurrent or subsequent disease events may be susceptible to bias due to selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio (HR) for risk of subsequent events among those with established coronary heart disease (CHD). The extent of selection bias was determined by the magnitudes of genetic and non-genetic effects on the indexing (first) CHD event. Unless the genetic HR was unrealistically large (> 1.6 per allele) and assuming the sum of all non-genetic HRs was less then 10, bias was usually less than 10% (downward towards the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size due to increasing precision. Importantly, false positive rates were not affected by selection bias. Conclusions In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, due to undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of CHD, the false positive rates of association tests will be close to nominal.

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“…We included only self-reported White participants for two reasons: First, the frequency of self-reported Black/African American individuals with CAD in the extant GWAS datasets was insufficient for stratified analyses (n = 126 and 124 for the discovery and replication cohorts, respectively). Second, our goal is for the present GWA screen to be comparable to the findings of our prior work as we look to build genomic convergence for this phenotype, and the sample for our earlier candidate gene study of survivorship with CAD comprised White individuals (Dungan et al, 2016).…”

Section: Inclusion Criteriamentioning

confidence: 99%

“…We defined time to event as the number of days from study enrollment (time at coronary catheterization and blood collection) to death from any cause. Data from surviving individuals were censored on the date of the last follow-up, consistent with our "survivorship with CAD" phenotype (Dungan et al, 2016). For our analyses of SNPs, we assumed an additive genetic model based on preliminary data demonstrating additive genetic effects (Dungan et al, 2016).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…We identified SNPs in LSAMP that had varied allelic effects on hazards of all-cause mortality, with some alleles conferring significantly increased hazard of allcause mortality and others significantly improved likelihood of survival. Notably, these observed allelic effects were specific to CAD cases, having shown no significant association among Abbreviations: AIP1, apoptosis signal regulating kinase 1; ASK1, apoptosis signal-regulating kinase 1; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; CATHGEN, catheterization genetics biorepository; CHD, coronary heart disease; CI, confidence interval; DAB2IP, disabled homolog 2 interacting protein; DNA, deoxyribonucleic acid; EARP, endosome-associated recycling protein; EIPR1, EARP complex and GARP complex interacting protein 1; GWAS, genome-wide association study; HR, hazard ratio; LSAMP, limbic system-associated membrane protein; MAF, minor allele frequency; MI, myocardial infarction; MYT1L, myelin transcription factor 1like; Ras/GAP, ras/GTPase activating protein; SNP, single nucleotide polymorphism; TSSC1, tumor-suppressing subtransferable fragment candidate gene 1. non-CAD controls (Dungan et al, 2016). Following up on our prior candidate-gene results with an agnostic, genome-wide association analysis is an appropriate next step in the search for genomic variation that contributes to long-term survival outcomes among people with CAD.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

et al. 2021

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ObjectiveCoronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach.Approach and ResultsWe performed discovery (n = 1,099), replication (n = 404), and meta-analyses (N = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were p × 10–8 for the discovery phase and Bonferroni-calculated p-values for the replication (p < 5.3 × 10–4) and meta-analysis (p < 1.6 × 10–3) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive p-value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, LINC01250, which resides between MYTIL and EIPR1, conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17–1.86, p(adj) = 1.07 × 10–3 (discovery), p(adj) = 0.03 (replication), p(adj) = 9.53 × 10–5 (meta-analysis)]. MYT1L is involved in neuronal differentiation. TSSC1 is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to DAB2IP was associated with increased survival time [HR 0.65, 95% CI 0.51–0.83, p(adj) = 4.79 × 10–4 (discovery), p(adj) = 0.02 (replication), p(adj) = 2.25 × 10–5 (meta-analysis)]. DAB2IP is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. DAB2IP has multiple lines of evidence for protection against atherosclerosis.ConclusionReplicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci LINC01250 (rs13007553) and biologically relevant candidate DAB2IP (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.

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Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

Cited by 6 publications

References 54 publications

Promoter-Specific Expression and Genomic Structure of IgLON Family Genes in Mouse

Promoter-Specific Expression and Genomic Structure of IgLON Family Genes in Mouse

Impact of Selection Bias on Estimation of Subsequent Event Risk

Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

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