A study provided evidence of a shared genetic architecture between gastroesophageal reflux disease and asthma.
In the study, published in Communications Biology, investigators analyzed data from 46,582 twins in three Swedish cohorts: the Study of Twin Adults Genes and Environment (STAGE, born 1959 to 1985, n = 25,387), TwinGene (born 1911 to 1958, n = 14,590), and Screening Across the Lifespan of Twins–Young (SALTY, born 1939 to 1958, n = 6,605). They hoped to better understand the genetic relationships between gastroesophageal reflux disease (GERD) and allergic diseases. GERD was defined as reporting heartburn more than once per week or pain behind the sternum more than once per week, relieved by antacid or acid-suppressing medicine.
Phenotypic data on GERD, asthma, allergic rhinitis, and eczema were collected through questionnaires and interviews. Genotype data were available for 26,895 twins. The study utilized both quantitative genetic and molecular genetic approaches to triangulate evidence.
The investigators found a modest genetic correlation between GERD and asthma of 0.18 using structural equation modeling on twin data. Polygenic risk score analyses revealed bidirectional associations between GERD and asthma, with odds ratios (OR) ranging from 1.09 to 1.14. Linkage disequilibrium score regression on genome-wide association study (GWAS) data showed a genetic correlation of 0.48 between GERD and asthma.
The study found little evidence for genetic overlap between GERD and allergic rhinitis or eczema, despite some weak associations.
Among the key findings were:
- Prevalence rates: GERD (12.0%), asthma (8.0%), allergic rhinitis (11.4%), and eczema (7.0%)
- Bivariate phenotypic associations: GERD and asthma (adjusted OR = 1.61, 95% confidence interval [CI] = 1.43–1.80), GERD and allergic rhinitis (adjusted OR = 1.14, 95% CI = 1.02–1.28), GERD and eczema (adjusted OR = 1.14, 95% CI = 1.00–1.30).
Twin correlations:
- GERD: rMZ = 0.33 (95% CI = 0.28–0.37), rDZ = 0.11 (95% CI = 0.07–0.15)
- Asthma: rMZ = 0.64 (95% CI = 0.61–0.68), rDZ = 0.29 (95% CI = 0.25–0.34)
- Allergic rhinitis: rMZ = 0.62 (95% CI = 0.59–0.65), rDZ = 0.30 (95% CI = 0.26–0.33)
- Eczema: rMZ = 0.43 (95% CI = 0.38–0.49), rDZ = 0.15 (95% CI = 0.10–0.20)
- Best-fitting twin models: ADE for GERD and eczema, AE for asthma and allergic rhinitis.
- Heritability estimates: GERD (32%), asthma (63%), allergic rhinitis (61%), and eczema (44%).
The genetic correlation between GERD and asthma was: rA = 0.18 (95% CI = 0.08–0.28). Cross-twin cross-trait correlations for GERD and asthma were: rMZ = 0.07 (95% CI = 0.02–0.12), rDZ = 0.04 (95% CI = 0.00–0.08). Further, there was a unique environmental correlation between GERD and asthma: rE = 0.11 (95% CI = 0.03–0.20).
Polygenic risk score analyses:
- GERD-PRS associated with asthma (adjusted OR = 1.14, 95% CI = 1.08–1.20 per standard deviation [SD] increase) and asthma-PRS associated with GERD (adjusted OR = 1.09, 95% CI = 1.05–1.14 per SD increase).
- Polygenic risk score prediction accuracy (are under the curve range): 0.60–0.66.
SNP-based heritability estimates:
- GERD: h2SNP = 0.13 (SE 0.01)
- Asthma: h2SNP = 0.08 (SE 0.004)
- Adult-onset asthma: h2SNP = 0.13 (SE 0.01)
- Childhood-onset asthma: h2SNP = 0.30 (SE 0.03)
- Allergic rhinitis: h2SNP = 0.12 (SE 0.02)
- Eczema: h2SNP = 0.08 (SE 0.02)
- Linkage disequilibrium score regression: Genetic correlations: GERD and asthma (rg = 0.48), GERD and eczema (rg = 0.20). No statistically significant correlation between GERD and allergic rhinitis.
Correlations were higher for adult-onset asthma with GERD compared with childhood-onset asthma (rg = 0.33, rg = 0.08, respectively).
Genomic structural equation modeling:
- Single latent factor model fit the genetic covariance structure (CFI = 0.93, SRMR = 0.09). Strongest loading: Eczema (β = 0.85, SE = 0.10, p = 1E-33). Lowest loading: GERD (β = 0.24, SE = 0.03, p = 2E-14).
After Mendelian randomization, the investigators noted that bidirectional causal effects between GERD and asthma were: (GERD to asthma: OR = 1.27, 95% CI = 1.12–1.43; asthma to GERD: OR = 1.09, 95% CI = 1.05–1.14). MR-Egger regression intercepts did not significantly deviate from zero. Leave-one-out and Q-heterogeneity analysis showed effect estimates were not overly influenced by any one variant.
Gene-based association analysis:
- Six pleiotropic genes identified (ERBB3, RBM6, HLA-B, SDK1, RERG, RAB5B) associated with both GERD and asthma. Asthma: 352 significantly associated genes, allergic rhinitis: 2, eczema: 65, GERD: 44.
Tissue enrichment analysis:
- GERD-associated genes enriched in brain tissues; asthma-associated genes in blood, spleen, lung, and small-intestine tissues; eczema-associated genes in spleen, blood, and small intestine tissues.
Shared gene set between GERD and asthma:
- GO_positive_regulation_of_gene_expression (pGERD = 0.002, pasthma = 0.0003 after Bonferroni correction).
The study's findings suggested potential biological mechanisms involving inflammatory pathways, with genes expressed differently in various tissues for GERD and asthma.
The study's strengths included its large sample size, use of multiple genetic analysis methods, and triangulation of evidence. Limitations included potential underestimation of allergic rhinitis prevalence as a result of reliance on self-reported physicians' diagnoses and the use of symptom-based GERD diagnosis without objective testing.
Ethics declarations can be found in the study.