title: Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship.
abstract: Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs-rs1462845 and rs6788787-using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01-1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69-0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08-1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05-1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype ('A/A') fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.
authors.affiliation: Duke University School of Nursing, Durham, NC, United States of America.
authors.forename: Jennifer R
authors.identifier: 0000-0002-4863-1616
authors.initials: JR
authors.lastname: Dungan
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT, United States of America.|Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT, United States of America.|Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.affiliation: Behavioral Medicine Research Center, Duke University Medical Center, Durham, NC, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Abanish
authors.initials: A
authors.lastname: Singh
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hurdle
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grass
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.
authors.forename: Carol
authors.initials: C
authors.lastname: Haynes
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America.|Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.affiliation: Duke University Department of Medicine, Durham, NC, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D012720:Severity of Illness Index; D012737:Sex Factors; D016019:Survival Analysis; D055815:Young Adult