Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus
Bibliographic record
Abstract
BACKGROUND Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( P <5.0×10 -8 ): rs147138607 (intergenic variant between CACNA1E and ZNF648 ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 – 1.32, P =3.6×10 -9 , rs11444867 (intergenic variant near HS3ST1 ) with HR 1.89, 95% CI 1.52 – 2.35, P =9.9×10 -9 , and rs335407 (intergenic variant between TFB1M and NOX3 ) HR 1.25, 95% CI 1.16 – 1.35, P =1.5×10 -8 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P <0.05, and 5 were significant after Bonferroni correction ( P <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 – 1.16) per 1 standard deviation increase ( P =1.0×10 -16 ). CONCLUSIONS The data point to novel and known genomic regions associated with incident CVD among individuals with T2D. CLINICAL PERSPECTIVE What is new? We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between CACNA1E and ZNF648 ), rs11444867 (intergenic variant near HS3ST1 ), and rs335407 (intergenic variant between TFB1M and NOX3 ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. What are the clinical implications? There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D. In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.007 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.004 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".