{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:10:33Z","timestamp":1787760633342,"version":"build-2784847793"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Circadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between <jats:italic>PER<\/jats:italic> and <jats:italic>CRY<\/jats:italic> polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 221 preterm infants of gestational age &amp;lt;34 weeks were included in this study (160 in the response group and 61 in the non-response group). The propensity score matching method was used to perform a 1:1 matching for all premature infants, and the general characteristics and clinical outcomes of the two groups were compared. The association between polymorphisms of the circadian transcription repressors <jats:italic>PER<\/jats:italic> and <jats:italic>CRY<\/jats:italic> and caffeine citrate treatment response in infants with apnea of prematurity was analyzed with co-dominant, dominant, recessive, and over-dominant models, as well as analysis of alleles. Generalized multifactor dimensionality reduction (GMDR) analysis was used to analyze the interaction between the <jats:italic>PER<\/jats:italic> and <jats:italic>CRY<\/jats:italic> genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After propensity score matching, 45 preterm infants were included in each of the response and non-response groups, and there were no statistically significant differences in general characteristics between the two groups (<jats:italic>P\u2009<\/jats:italic>&amp;gt;\u20090.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) (<jats:italic>P\u2009<\/jats:italic>=\u20090.043), retinopathy of prematurity (ROP) (<jats:italic>P\u2009<\/jats:italic>=\u20090.035), and invasive ventilation (<jats:italic>P\u2009<\/jats:italic>=\u20090.027), and their duration of oxygen use (<jats:italic>P\u2009<\/jats:italic>=\u20090.041) was longer. When corrected for false discovery rate, the <jats:italic>PER3<\/jats:italic> rs228669 recessive model (<jats:italic>P<\/jats:italic><jats:sub>FDR<\/jats:sub><jats:italic><jats:sub>\u2009<\/jats:sub><\/jats:italic>=\u20090.045) and the over-dominant model (<jats:italic>P<\/jats:italic><jats:sub>FDR<\/jats:sub>\u2009=\u20090.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR\u2009=\u20090.28, 95% CI\u2009=\u20090.12\u20130.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR\u2009=\u20094.18, 95% CI\u2009=\u20091.64\u201310.66). GMDR analysis revealed an interaction between the <jats:italic>PER<\/jats:italic> and <jats:italic>CRY<\/jats:italic> genes (<jats:italic>P\u2009<\/jats:italic>&amp;lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Circadian rhythms may play a role in the response of premature infants to caffeine citrate, and polymorphisms of the <jats:italic>PER<\/jats:italic> and <jats:italic>CRY<\/jats:italic> genes may influence the effectiveness of caffeine citrate treatment for apnea of prematurity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2024.1414185","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T04:56:02Z","timestamp":1721624162000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Association between PER and CRY gene polymorphisms and the response to caffeine citrate treatment in infants with apnea of prematurity"],"prefix":"10.3389","volume":"12","author":[{"given":"Jiang-Biao","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Ru","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Min","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Zhu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e20153757","DOI":"10.1542\/peds.2015-3757","article-title":"Apnea of prematurity","volume":"137","author":"Eichenwald","year":"2016","journal-title":"Pediatrics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s40272-020-00404-4","article-title":"Caffeine for the treatment of apnea in the neonatal intensive care unit: a systematic overview of meta-analyses","volume":"22","author":"Alhersh","year":"2020","journal-title":"Paediatr Drugs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e299","DOI":"10.1111\/j.1651-2227.2012.02664.x","article-title":"Genetic basis of apnoea of prematurity and caffeine treatment response: role of adenosine receptor polymorphisms: genetic basis of apnoea of prematurity","volume":"101","author":"Kumral","year":"2012","journal-title":"Acta Paediatr"},{"key":"B4","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s12325-020-01544-2","article-title":"Therapy for apnoea of prematurity: a retrospective study on effects of standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants","volume":"38","author":"He","year":"2021","journal-title":"Adv Ther"},{"key":"B5","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.epag.2018.09.001","article-title":"Association between adenosine receptor gene polymorphism and response to caffeine citrate treatment in apnea of prematurity; 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