Table 2.
Main findings and characteristics of genome-wide approaches to study the genetic factors involved in AEs conducted from 15th November, 2018 to 1st October, 2022.
| Type of study | rsID (Gene) | Subjects | Phenotype | EA | Effect size (95%CI) or (SE) | P | PMID [reference] |
|---|---|---|---|---|---|---|---|
|
| |||||||
| GWAS | rs56151658 (HLA-DQB1) | Discovery: 34,167 white British adults with asthma Replication: 2,645 Hispanic/Latino children with asthma |
ER/Hosp/OCS | A | ORDiscovery:1.36 (1.22, 1.52) ORReplication: 1.19 (0.99, 1.42)*† |
3.11×10−8 5×10−3* |
32890573 [71] |
|
| |||||||
| GWAS | rs2253681 (LINC03033) | 4,010 Hispanic/Latino youth with asthma | ER/Hosp/OCS | A | OR: 1.55 (1.34,1.79) | 6.3×10−9 | 33093117 [72] |
|
| |||||||
| GWAS | rs4952375 (LINC01913) | Children with asthma. Discovery: 3,310 Hispanics/Latinos; replication: 1,043 African Americans. | ER/Hosp/OCS | A | ORDiscovery: 1.37 (1.20,1.55) ORReplication: 1.53 (1.12 ,2.08) |
1.24×10−6; 7.43×10−3 | 32841424 [73] |
|
| |||||||
| GWAS | rs721992318 (GSDMB) | Discovery: 2,866 European children experiencing severe AE between ages 2 and 6 years, and 65,415 non-asthmatic controls. Replication: 1,118 children. |
Discovery: Asthma with Hosp; Replication: Asthma | T | OR: 1.65 (1.56,1.75) | 1.6×10−68 | 33328473 [74] |
| rs696733010 (CDHR3) | A | OR: 1.41 (1.32,1.51) | 2.1×10−23 | ||||
| rs107163018 (HLA-DQA1) | C | OR: 1.25 (1.18,1.32) | 8.0×10−14 | ||||
| rs34093366 (IL33) | G | OR: 1.37 (1.26,1.49) | 1.6×10−13 | ||||
| rs134232666 (IL33) | C | OR: 1.31 (1.22,1.40) | 1.7×10−13 | ||||
| rs1018962918 (IL1RL1) | C | OR: 1.40 (1.27,1.54) | 7.7×10−12 | ||||
| rs104382818 (WDR36) | C | OR: 1.20 (1.14,1.27) | 1.0×10−10 | ||||
| rs2054118 (IL13) | A | OR: 1.21 (1.13,1.29) | 1.0×10−8 | ||||
| rs281379 (FUT2/MAMSTR) | G | ORDiscovery 1.18 (1.11,1.25) ORReplication: 1.43 (1.16,1.79) |
2.6×10−9; 1.1×10−3 | ||||
|
| |||||||
| GWAS | rs10519519 (MYT1L) | 1-year longitudinal study of 20 non-smoking and 188 smoking Korean patients with asthma | Annual rate of episodes of increased dyspnea, wheezing, or coughing with a >20%decrease in FEV1 |
A | β: 0.60 (0.11) | 8.32×10−7 | 35606283 [75] |
|
| |||||||
| GWAS | rs12091010 (VCAM1/EXTL2) | Discovery (4,989 subjects with asthma): 53.1% Europeans, 23.2% Hispanics/Latinos, 13.3% Singaporean Chinese, and 10.3% African Americans. Replication: 36,477 European and 1078 non-European asthma patients |
ACC/ER/Hosp/OCS/SA | T | ORDiscovery: 0.82 (0.75–0.90) ORReplication: 0.89 (0.82–0.97) |
9.05×10−6; 5.35×10−3 | 35754128 [76] |
| rs943126 (PANK1) | Children with asthma. Discovery: 854 Hispanic/Latino, 493 African Americans. Replication: 1,697 Europeans | ER/Hosp/OCS despite ICS use | C | ORDiscovery: 0.85 (0.78,0.92) ORReplication: 0.92 (0.86,0.98) |
3.10×10−5; 1.30×10−2 | ||
|
| |||||||
| PGWAS (ICS) | rs5995653 (APOBEC3B/APOBEC3C) | Children with asthma. Discovery: 854 Hispanic/Latino and 493 African Americans. Replication: 1,697 Europeans | ER/Hosp/OCS despite ICS use | A | ORDiscovery 0.76 (0.62,0.93) ORReplication: 0.66 (0.56,0.79) |
4.80×10−6; 7.52×10−3 | 30697902 [77] |
| rs62081416* (L3MBTL4/ARHGAP28) | 854 Hispanic/Latino and 493 African American children with asthma | A | OR: 2.44 (1.63,3.65) | 1.57×10−5 | |||
|
| |||||||
| PGWAS (ICS) | rs3827907 (EDDM3B) | Patients with asthma. Discovery: 244 African Americans. Replication: African Americans (nR1=803 and nR2=563) and Latinos (nR3=1,461) |
Discovery: SNPxICS adherence on change in ACT score over 6 weeks of ICS treatment. Replication 1: SNPxICS adherence on time to ER/Hosp/OCS. Replication 2–3: SNPxICS use on ER/Hosp/OCS |
C | CoefDiscovery12.35 (NA) CoefR1: -0.07 (NA) CoefR2: 0.15 (NA) CoefR3: 0.96 (NA) |
7.79×10−8; 0.023; 0.029; 0.041 | 30367910 [78] |
|
| |||||||
| PGWAS (LABA) | rs1947048 (EPHA7) | 1,425 children and young adults with asthma (23% Hispanic/Latino, 10.4% African American, 32.5 Singaporean Chinese) | ER/Hosp/OCS despite LABA use | G | OR: 2.50 (1.69, 3.69) | 4.36×10−6 | 33706416 [79] |
| PGWAS (LABA) | rs6489992 (TBX3) | A | OR: 1.77 (1.40, 2.23) | 4.96×10−6 | |||
|
| |||||||
| PGWAS (ICS) | rs67026078 (CACNA2D3/WNT5A) | Children with asthma. Discovery: 2,681 Europeans. Replication 1: 538 Europeans. Replication 2: 854 Hispanic/Latinos, 493 African Americans, 426 Singaporean Chinese | ER/Hosp/OCS/SA despite ICS use | C | ORDiscovery: 1.50 (0.93, 2.43) ORR1: 1.83 (1.16, 2.90) |
4.22×10−6; R1; 0.01; R2: NS | 33303529 [80] |
|
| |||||||
| PGWAS (ICS) | rs1166980 (ROBO2) | Children with asthma. Discovery: 166 Europeans. Replication 1: 2,681 Europeans. Replication 2: 854 Hispanic/Latinos, 493 African Americans |
Discovery: ≥8% in FEV1 after 6 weeks of ICS treatment Replication: ER/Hosp/OCS/SA despite ICS use |
G | ORDiscovery: 7.01(3.29, 14.93) | 4.61×10−7, R1-R2: NS | 34442380 [81] |
| PGWAS (ICS) | rs72891545‡ (ROBO2) | Discovery: 2,681 Europeans | ER/Hosp/OCS/SA despite ICS use | A | OR: 4.79 (2.36, 9.73) | 1.44×10−5 | |
|
| |||||||
| PGWAS (ICS) | rs138717703 (RBMXP1/PTCHD4) | European adults with asthma (nDiscovery= 5,710; nReplication=1,141) | OCS despite ICS use | G | ORDiscovery: 1.73 (1.39, 2.16) ORReplication: 1.48 (0.75, 2.90)‡ |
7.91×10−7; 5.78×10−4 | 35501119 [82] |
| PGWAS (ICS) | rs77506063 (RBMXP1/PTCHD4) |
C | ORDiscovery: 1.73 (1.39, 2.16) ORReplication: 1.48 (0.75, 2.90)‡ |
7.91×10−7; 5.78×10−4 | |||
| PGWAS (ICS) | rs145325916 (RBMXP1/PTCHD4) | C | ORDiscovery: 1.74 (1.40, 2.16) ORReplication: 1.27 (0.66, 2.42)‡ |
6.18×10−7; 3.56×10−3 | |||
| PGWAS (ICS) | rs116023293 (HNRNPA3/P4 PTCHD4) |
G | ORDiscovery: 1.74 (1.40, 2.16) ORReplication: 1.27 (0.66, 2.42)‡ |
5.28×10−7; 3.56×10−3 | |||
|
| |||||||
| PGWIS (Age; ICS) | rs34631960 (THSD4) | 1,321 adult and child Europeans with asthma | SNPxAge use on ER/Hosp/OCS | C | ORDiscovery: 2.33 (1.61, 3.38) ORReplication: 1.82 (1.23, 2.7); |
7.08×10−6; 2.97×10−3 | 32119686 [83] |
| PGWIS (Age; ICS) | rs2328386 (HIVEP2) | T | ORDiscovery: 0.33(0.2, 0.55) ORReplication: 0.51(0.34, 0.77) |
1.86×10−5; 1.49×10−3 | |||
*
rs56151658 was not available in Hispanics/Latinos. The results for the most significant proxy in Latinos (r2=0.71) are shown (rs9275356).
†
Effect size from the largest replication cohort is shown.
‡
The genetic variant was identified using a candidate-gene approach using the GWAS summary statistics. Abbreviations: ACC: Acute asthma care; ACT: Asthma Control Test; Coef: Interaction coefficient estimate; CI: Confidence interval; EA: Effect allele; ER: Emergency room visits; FEV1: Forced expiratory volume in the first second; Hosp: Hospitalizations; GWAS: Genome-wide association study, ICS: Inhaled corticosteroids; LABA: Long-acting beta-agonists; OCS: Oral corticosteroids use; NA: Not available; NS: Non-significant; PGWAS: Pharmacogenomic GWAS (asthma treatment considered is shown within parenthesis); PGWIS: Pharmacogenomic genome-wide interaction study (tested environmental variable and asthma treatment considered are shown within parenthesis); Rn: Replication study (number n); SA: School absences; SE: Standard error of the beta coefficient; SNP: Single nucleotide polymorphism; P: P-value.