Table 3:
β2 adrenergic agonist studies: genetic associations
| Author, Year Country |
Study Type Age Group(s) Race/Ethnicity (n) |
Operational definition for Black subgroup |
Conditions(s) Drug(s) Studied |
PGx Marker | Findings | Outcome type and relative directionality of effect among Blacks |
|---|---|---|---|---|---|---|
| Mak 201831 USA, Puerto Rico SAGE II and GALA II studies (discovery cohort); GALA, SAGE, HPR, SAPPHIRE, AND CHOP studies (replication cohorts) |
Cross-sectional Children and adolescents (discovery cohort); children, adolescents, and adults (replication cohort) Discovery cohort: Black (475) Puerto Rican (483) Mexican (483) Replication cohorts: Black (1443) Puerto Rican (522) Mexican (202() |
Self-report; participant and all parents and grandparents self-identified as Black or African American (discovery cohort) | Asthma SABA (Albuterol) |
Whole genome sequencing | No significant associations identified in association with albuterol response in subgroup-specific analyses by race/ethnicity. Trans-ethnic meta-analysis identified 10 unique loci (represented by 27 SNPs) significantly associated with albuterol response. |
= Efficacy |
| Finkelstein 200929 USA |
Meta-analysis Children and adolescents Black (125) White (639) Hispanic (84) Other/not defined (112) |
NR | Asthma SABA (drug not specified) |
c.46A>G, p.Arg16Gly and/or c.79C>G, p. Gln27Glu mutations in the β2 adrenergic receptor (ADRB2); position 16 (arg/Arg, Arg/Gly, or Gly/Gly) and/or 27 alleles (Glu/Glu, Glu/Gln, Gln/Gln) | Beneficial effect of Arg/Arg at position 16 on response to treatment with a SABA was most pronounced in Black children treated with SABA (OR=3.54; 95% CI [1.37, 9.13]), as compared with other ethnicities. Arg allele somewhat more prevalent among Blacks as compared with Whites (Table 4). | ↑ Efficacy |
| Corvol 200912 USA, Mexico, Puerto Rico GALA and SAGE studies |
Cross-sectional Children, adolescents and adults Black (267) Mexican (301) Puerto Rican (399) |
Self-report (participant, both biological parents, and all four biological parents must report same ethnic background); 104 ancestry informative markers imputed into STRUCTURE 2.1 program for assessment of individual genetic ancestry estimates | Asthma SABA (Albuterol) |
Four interleukin 6 (IL6) SNPs and one IL6R SNP | No single SNP consistently associated with response to albuterol (as measured by change in FEV1) in all 3 populations. The C allele of IL6 promoter region variant c.−572C>G (rs1800796) associated with lower drug response (change in FEV1 12%) among Mexicans (p=0.02); no significant effect among Puerto Ricans or Blacks. The C allele is also 3 times more prevalent among Latinos vs. Blacks (Table 4). The A allele of c.486T>A, p.Asp162Glu (rs13306435) associated with reduced risk of lower drug response among Mexicans (p=0.002); allele frequency too low in the other two populations to allow testing. The A allele is 35 times more common in Latinos as compared with Blacks. No significant effect of remaining IL6 SNPs or the IL6R SNP in any of the populations. IL6 and IL6R gene-gene interaction was found to be associated with higher drug response to albuterol among Latinos, but lower drug response among Blacks. |
↓ Efficacy |
| Wechsler 200930 USA LARGE study |
RCT Adults Black (17) White (58) Asian (3) Hispanic (9) |
NR | Asthma LABA (Salmeterol + ICS + ipratropium bromide as needed) |
ADRB2 (β2 Adrenergic Receptor) c.46A>G, p.Arg16Gly genotype | Genotype specific outcome effects observed in the Black subgroup not observed in the overall study group. Blacks with genotype Gly/Gly treated with LABA + ICS had significant improvement in AM and PM PEF (29 L/min, p=0.013 and 45 L/min, p=0.0005) compared to placebo + ICS and when treated with LABA only had improved PEF measured at clinic visits during spirometry compared to placebo (39 L/min, p=0.0016) Blacks with genotype Arg/Arg treated with LABA + ICS showed a lack of improvement in AM and PM PEF (−12 L/min, p=0.57 and −2.2 L/min, p=0.92) compared to placebo + ICS and when treated with LABA only showed lack of improved PEF measured at clinic visits during spirometry compared to placebo (−4.8 L/min, p=0.73) As noted above, Arg allele is somewhat more common among Blacks vs. Gly allele as compared with Whites. |
↑ Efficacy |
Key: ↑ Efficacy=increased efficacy; ↑ Safety=increased safety; ↓ Efficacy=decreased efficacy; ↓ Safety=decreased safety; = Efficacy=equal efficacy; = Safety=equal safety; CI confidence interval; ICS inhaled corticosteroid; SABA short-acting β2 agonist; LABA long-acting β2 agonist; OR odds ratio; FEV forced expiratory volume; PEF peak expiratory flow; AM morning; PM afternoon/evening: ICS inhaled corticosteroid; SAGE Study of African Americans, Asthma, Genes, and Environments; GALA Genes-environments and Admixture in Latino Americans; HPR Hartford/Puerto Rico; CHOP Children’s Hospital of Philadelphia; SAPPHIRE Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity
Legend: This table summarizes data from included studies evaluating safety and effectiveness of beta-agonists in Blacks as compared with other groups, including directionality of effects reported in the literature focusing on the subset of studies that included analysis of genetic data.