Table 4.
Genetic associations with plasma proteins.
| Protein | Locus (p value) | Location | Effect | Gene expression |
|---|---|---|---|---|
| Vascular messengers | ||||
| Nt-proBNP | 1p36 (5 × 10−9)* | cis | 2% | NPPB (heart) |
| Matrix remodeling | ||||
| TSP2 | 6q27 (2 × 10−47) | cis | 13% | THBS2 (heart) |
| Immune system | ||||
| CXCL13 | — | — | — | — |
| CRP | 1q23 (6 × 10−10) | cis | 2% | — |
| IL-1R antagonist protein | 2q13 (9 × 10−17) | cis | 5% | IL1RN (multiple) |
| IL-18 receptor 1 | 2q12 (9 × 10−135) | cis | 37% | IL18R1 (heart) |
| Complement system | ||||
| C5a |
9q33 (3 × 10−10) * 1q31 (2 × 10−10) |
cis trans |
1% 3% |
C5 (multiple) CFH (multiple) |
| C9 | 5p13 (4 × 10−10) | cis | 5% | — |
| Coagulation system | ||||
| Protein C |
2q14 (2 × 10−19) 20q11 (2 × 10−57) |
cis trans |
6% 15% |
PROC (liver, atria) PROCR (multiple) |
| tPA | 8p11 (1 × 10−7) * | cis | 1% | PLAT (multiple) |
| Intracellular or membrane-bound | ||||
| Gelsolin | 9q33 (2 × 10−9) * | cis | 1% | GSN (blood) |
| Carbonic anhydrase 13 | 8q21 (2 × 10−19) | cis | 6% | CA13 (multiple) |
| Contactin-1 |
12q12 (2 × 10−11) 16p13 (1 × 10−17) |
cis trans |
3% 5% |
CNTN1 (multiple) TMEM8A (multiple) |
| DUSP3 | — | — | — | — |
| PRKACA | — | — | — | — |
| Netrin receptor UNC5D | 8p12 (1 × 10−6) * | cis | 1% | — |
Index SNPs at loci associated with the 16 heart failure proteins at genome-wide significance (p < 5 × 10−8). p values from linear regression models are presented for associations in cis (within 500 kb) and trans. Effects of each SNP are expressed as proportion of variability explained. Association of index SNPs at each locus with gene expression was explored in publically available eQTL data using PhenoScanner31, with results presented for transcripts below a Bonferroni-corrected threshold for the total nr of SNPs (p < 0.05/15). Proteins associated with heart failure, grouped according to functional annotations. *Asterisk indicates that the locus was discovered in the second stage of discovery, in a meta-analysis of two cohorts focused on cis-windows (±500 kb from the transcription start site), with a lower number of SNPs tested in each window, resulting in a more permissive significance threshold (2 × 10−5)