Table 2.
Landmark forward genetics studies in Group 1 PAH. Abbreviations: BMPR2—Bone morphogenic protein receptor type 2; ENG—Endoglin; ACVRL1—Activin A Receptor Like Type 1; SMAD—SMAD Family Member; CAV1—Caveolin 1; KCNK3—Potassium Two Pore Domain Channel Subfamily K Member 3; TBX4—T-Box Transcription Factor 4; EIF2AK4—Eukaryotic Translation Initiation Factor 2 α Kinase 4; GDF2—Growth Differentiation Factor 2; SOX17—SRY-Box Transcription Factor 17; ATP13A3—ATPase 13A3; AQP1—Aquaporin 1; ABCC8—ATP Binding Cassette Subfamily C Member 8; BMP10—Bone Morphogenetic Protein 10; KLK1—Kallikrein 1; GCCX—γ-Glutamyl Carboxylase; KDR—Kinase insert domain receptor; TET2—Tet Methylcytosine Dioxygenase 2; FBLN2—Fibulin 2; PDGFD—Platelet-Derived Growth Factor D.
| Study (Reference) | Genes | Study Design | Sample | Ethnicity | Method | Reference Genome |
|---|---|---|---|---|---|---|
| Lane et al. 2000, [101] | BMPR2 | Case-level data | Cases: n = 8 PPH kindreds for candidate gene mutational analysis | Not stated | TS | H.sapiens mRNA for BMPR-II: Genbank Z48923 |
| Thomson 2000, [102] | BMPR2 | Case-level data | Cases: n = 50 PPH | Not stated | TS | Not stated |
| Trembath et al. 2001, [103] | ACVRL1 | Case-level data | Cases: 5 kindreds plus 1 individual patient with HHT, including n = 10 cases with PH | Not stated | TS | Not stated |
| Chaouat 2004, [104] | ENG | Case-level data | Case: n=1 HHT, PPH with history of anorexigen use | Not stated | TS | Not stated |
| Harrison et al. 2005, [105] | ACVRL1, ENG | Case-level data | Cases: n = 18 I/APAH | Not stated | TS | Not stated |
| Shintani et al. 2009, [106] | SMAD9 (SMAD8) | Case-level data | Cases: n = 23 IPAH | Japanese | TS | Not stated |
| Nasim et al. 2011, [54] | SMAD1, SMAD4, SMAD9 | Case-level data | Cases: n = 324 IPAH/APAH/CTEPH; Controls: n = 1584 | European & Japanese | TS | Not stated |
| Austin et al. 2012, [74] | CAV1 | Case-level data | Cases: 3-generation family, 6 with PAH; Additional cohort: n = 260 unrelated I/HPAH cases; Controls: n = 1000 | European | WES | GRCh37 |
| Ma et al. 2013, [107] | KCNK3 | Case-level data | Cases: Family in which multiple members had PAH | Not stated | WES | GRCh37 |
| Kerstjens-Frederikse et al. 2013, [108] | TBX4 | Case-level data | Cases: n = 20 childhood-onset I/HPAH; n = 49 adult-onset I/HPAH; n = 23 SPS | Not stated | TS | Not stated |
| Eyries et al. 2014, [109] | EIF2AK4 | Case-level data | Cases: n = 13 PVOD families | Not stated | WES | GRCh37 |
| Best et al. 2017, [110] | EIF2AK4 | Case-level data | Cases: n = 81 I/HPAH | Not stated | TS | Not stated |
| Hadinnapola et al. 2017, [111] | EIF2AK4 | Case-control data | Cases: n = 880 I/FPAH, PVOD/PCH; Controls: n = 7134 non-PAH controls and their relatives recruited to NBR | European: 84.6% | WGS | GRCh37 |
| Gräf et al. 2018, [24] | GDF2, SOX17, ATP13A3, AQP1 | Case-control data | Cases: n = 1048 I/F/PAH, PVOD/PCH; Controls: n = 7979 non-PAH controls and their relatives recruited to NBR | European: 84.6% | WGS | GRCh37 |
| Zhu et al. 2018, [75] | SOX17 | Case-control data | Cases: n = 256 I/FPAH-CHD; Additional cohort: n = 413 I/FPAH screened for rare variants in SOX17; Controls: n = 7509 gnomAD | Not stated | WES | GRCh37 |
| Hiraide et al. 2018, [112] | SOX17 | Case-level data | Cases: n = 12 IPAH and 12 family members; Additional cohort: n = 128 I/HPAH screened for SOX17 mutations | Japanese: 100% | WES | Not stated |
| Bohnen et al. 2018, [113] | ABCC8 | Case-control data | Cases: n = 913; Controls: n = 33,369 European adults from ExAC & n = 49,630 Europeans from the Regeneron-Geisinger DiscovEHR study | Not stated | WES, WGS | GRCh37 |
| Wang et al. 2019, [26] | GDF2 | Case-control data | Cases: n = 331 IPAH; Controls: n = 10,508 from available reference data sets | East Asian: 100% | WES, WGS | GRCh37 |
| Eyries et al. 2019, [114] | BMP10 | Case-level data | Cases: n = 268 I/HPAH, PVOD/PCH | European: > 90% | TS | GRCh37 |
| Hodgson et al. 2020, [115] | BMP10 | Case-level data | Cases: n = 1048 I/FPAH, PVOD/PCH | European: 84.6% | WGS | GRCh37 |
| Zhu et al. 2019, [25] | KLK1, GCCX | Case-control data | Cases: n = 2572 Group 1 PAH; Controls: n = 12,771 | European: 72% | WES | GRCh38 |
| Rhodes et al. 2019, [116] | HLA-DPA1/DPB1, SOX17 enhancer | Case-control data | Cases: n = 2085 cases; Controls: n = 9659 | European: 100% | WGS | GRCh37 |
| Swietlik et al. 2019, [30] | KDR | Case-control data | Cases: n = 1122 PAH; Controls: n = 11,889 non-PAH NBR | European: 84% | WGS | GRCh37 |
| Eyries et al. 2020, [117] | KDR | Case-level data | Cases: n = 311 unrelated PAH | Not stated | TS | Not stated |
| Potus et al. 2020, [55] | TET2 | Case-control data | Cases: n = 2572; Controls: n = 7509 non-Finnish European subjects from gnomAD | European: 72% | WES | GRCh38 |
| Zhu et al. 2020, [118] | FBLN2, PDGFD | Case-control data | Cases: n = 4175; Controls: n = 18,819 from SPARK and gnomAD cohorts | European: 54.5% | WES | GRCh38 |