520 - Genetic Variation in CRHR1 is Associated with Change in Respiratory Severity Score Following Corticosteroid Treatment in Extremely Premature Infants

Publication Number: 3501.520

Sarina R. Garcia, University of California, San Francisco, School of Medicine, San francisco, CA, United States; Melissa L. Spear, University of California, San Francisco, School of Medicine, Providence, RI, United States; Thaybeth I.. Malavé-Méndez, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Miguel A. Guardado, UCSF Benioff Children's Hospital San Francisco, San Francisco, CA, United States; Cheryl Chapin, UC San Francisco, SAN FRANCISCO, CA, United States; Erik Jensen, Stanford University School of Medicine, Palo Alto, CA, United States; Sherry E. Courtney, University of Arkansas for Medical Sciences College of Medicine, Little Rock, AR, United States; Jonathan L. Slaughter, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, United States; Matthew Kielt, Nationwide Children's Hospital, Columbus, OH, United States; Narayan Iyer, Children's Hospital Los Angeles, Los Angeles, CA, United States; Kim Gibson, Children's Mercy Hospital, Kansas City, MO, United States; Paul Toren, Children's Mercy Hospitals and Clinics, Kansas City, MO, United States; Cheri Gauldin, Children's Mercy Hospital, Kansas City, MO, United States; Philip L.. Ballard, University of California, San Francisco, School of Medicine, Bodega Bay, CA, United States; Ryan Hernandez, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; William Truog, Children's Mercy Hospitals and Clinics, Kansas City, MO, United States; Dara G. Torgerson, University of California, San Francisco, San Francisco, CA, United States; Tamorah Lewis, The Hospital for Sick Children, Toronto, ON, Canada

Background: Clinical response to postnatal corticosteroids varies among extremely premature infants, and identifying biomarkers of response to understand drivers of variability could improve therapeutic outcomes. A genetic variant in the intron of corticotropin-releasing hormone receptor 1 (CRHR1, rs7225082) has previously been associated with a change in respiratory severity score (RSS = MAP x Fi02) following treatment with systemic corticosteroids.

Objective: We aimed to validate this association in a larger prospective study of premature infants and identify potential causal variation in CRHR1.

Design/Methods: The DExamethasone for NeonAtal Lung Illness (DENALI) study included 101 infants from five U.S. NICUs (2016-2023). IRB approval was obtained at each site. Eligible infants were ≤32 weeks gestational age and 14-175 days postnatal age (PNA) at the start of DEX treatment. Infants were treated with a 7 day tapering course of DEX (cumulative dose 0.59 - 2.85 mg/kg). The primary outcome was assessed by RSS within 24 hours before the start of treatment (pre-RSS) and 7 days after (post-RSS), with clinical response defined as ΔRSS = post-RSS - pre-RSS. Genotyping of ~1.8M single nucleotide polymorphisms was performed followed by imputation using the TOPMed imputation server. Associations between CRHR1 variants and ΔRSS were tested using linear regression, adjusting for sex, pre-RSS, PNA, postmenstrual age, cumulative steroid dose by day 7, genetic relatedness, genetic population structure, and maternal race/ethnicity.

Results: The distribution of ΔRSS ranged from −12.56 to +4.18 with a mean of −3.47 (SD 3.11). No clinical or demographic characteristics were correlated with ΔRSS in single variate analyses. A total of 11 infants' RSS worsened after receiving DEX, 9 of whom carried at least one T allele at rs7225082. This allele was also associated with a smaller improvement in RSS overall (ΔRSS, β = −0.74, p = 0.04, frequency 61.4%), consistent with a reduced clinical response to corticosteroids as previously reported. Additional CRHR1 variants were in linkage disequilibrium with rs7225082, and were similarly associated with ΔRSS at p < 0.05 (min p-value=1.37x10-2). This included rs1040238305, which overlaps regulatory 5′ UTR regions, and rs4076452, an intronic variant previously linked to mediating hypothalamic-pituitary-adrenal axis stimulation.

Conclusion(s): We provide independent validation that rs7225082 is associated with clinical response to corticosteroids in premature infants, and identify additional CRHR1 variants as candidates for future biomarker and functional studies to elucidate causal roles.

Figure 1: Median ΔRSS by Genotypes at rs7225082 in CRHR1


Figure 2: LD Associations across CRHR1 Region (rs7225082) for ΔRSS
Figure 2. LocusZoom plot for the CRHR1 region flanking the lead SNP rs7225082 (purple diamond) on chromosome 17. The top panel displays association p-values (-log₁₀ scale) on the left vertical axis, with recombination rates on the right vertical axis. Chromosomal positions are displayed on the horizontal axis. The bottom panel shows nearby genes. Each SNP is represented by a dot, with the degree of linkage disequilibrium (r²) relative to the lead SNP indicated by color.