TABLE 2.
Association Results for Ejection Fraction Response
| Phase I* | Phase II† | Combined | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SNP | Minor Allele | Candidate Gene | Source‡ | ΔEF ≥20%§ (n = 29) MAF | Transplant (n = 37)‖ MAF | OR | p Value | ΔEF ≥10%§ (n = 137) MAF | ΔEF <10% (n = 454) MAF | OR | p Value | p Value |
| Top Overall SNPs ¶ | ||||||||||||
| rs7767652 | T# | HCRTR2 | D | 0.14 | 0.36 | 0.28 | 0.0040 | 0.11 | 0.24 | 0.394 | 3.29 × 10−5 | 9.04 × 10−6 |
| rs2527366 | G | GTF2I | A | 0.45 | 0.26 | 2.35 | 0.016 | 0.39 | 0.29 | 1.728 | 0.00065 | 0.0003 |
| rs4901426 | A | DDHD1 | D | 0.31 | 0.63 | 0.27 | 0.0025 | 0.52 | 0.43 | 1.54 | 0.00383 | 0.0085 |
| rs1936602 | A | HTR7 | D | 0.60 | 0.30 | 3.60 | 0.0020 | 0.38 | 0.49 | 0.67 | 0.00650 | 0.0177 |
| rs3813089 | T | MRO | B | 0.22 | 0.18 | 1.36 | 0.465 | 0.31 | 0.23 | 1.60 | 0.00748 | 0.0062 |
| rs1546120 | T | MAD2L1 | A | 0.12 | 0.30 | 0.32 | 0.0130 | 0.19 | 0.27 | 0.61 | 0.00799 | 0.0037 |
| Top Curated SNPs ** | ||||||||||||
| rs8096199 | G | DLGAP1 | C-Can | — | — | — | — | 0.220 | 0.161 | 1.616 | 0.00902 | 0.0090 |
| rs1799983 | T | NOS3 | C-Can | — | — | — | — | 0.359 | 0.277 | 1.449 | 0.01504 | 0.01504 |
| rs767757 | G | PRKCH | C-Path | 0.362 | 0.216 | 2.057 | 0.0485 | 0.448 | 0.385 | 1.367 | 0.042 | 0.0254 |
| rs7220007 | A | PRKCA | C-Can | 0.603 | 0.378 | 2.5 | 0.0151 | 0.528 | 0.444 | 1.362 | 0.04335 | 0.0263 |
| rs12623467 | T | NRXN1 | C-GWA | — | — | — | — | 0.171 | 0.128 | 1.612 | 0.0267 | 0.0267 |
| rs7903146 | T | TCF7L2 | C-GWA | 0.362 | 0.284 | 1.432 | 0.364 | 0.354 | 0.292 | 1.377 | 0.04691 | 0.0381 |
| rs10511311 | T | CD200 | C-GWA | — | — | — | — | 0.409 | 0.336 | 1.342 | 0.04834 | 0.04834 |
| Replication†† Penn Heart Failure Study | ||||||||||||
| EF ≥35% (n = 333) MAF | EF <35% (n = 464) MAF | OR | p Value | |||||||||
| rs7767652 | T‡‡ | HCRTR2 | Penn | .209 | 0.247 | 0.769 | 0.021 | |||||
Phase I cohort was age-, sex-, and race-matched.
Phase II analyses were adjusted for age, sex, and race.
Source = group from which the variant was selected for placement on the customized array: D = top intergenic SNPs from phase I GWAS; A = top weighted SNPs from phase I GWAS; B-Hub = coexpression network analysis gene hub; C-can = candidate SNPs from prior studies; C-Path = variant in gene responsible for important disease pathway, C-GWA = SNPs associated with relevant phenotypes in prior studies.
ΔEF ≥20% and ΔEF ≥10% represent patients whose EF improved by an absolute value >20 or 10 percentage points, respectively.
Transplant patients are those with decompensation in their clinical status despite medical intervention and required heart transplantation.
Top Overall SNPs = the common variants from the customized heart failure gene array with the lowest p values.
21 of 591 Stanford Phase II heart failure patients were homozygous for the minor allele.
Top Curated SNPs = the variants with the lowest p values from a subset of variants on the customized array that had been manually pre-selected.
The Penn Heart Failure replication analysis was adjusted for age, sex, hypertension, diabetes, renal function (glomerular filtration rate), and body mass index.
59 of 767 Penn Heart Failure patients were homozygous for the minor allele.
GWAS = genome-wide association study; MAF = minor allele frequency; OR = odds ratio per minor allele; SNP = single nucleotide polymorphism; other abbreviations as in Table 1.