The Role of Heme Oxygenase-1 Promoter Polymorphisms in Perinatal Disease.

Ruka Nakasone,Mariko Ashina,Kenji Tanimura,Shinya Abe,Kazumichi Fujioka,Hans Van Rostenberghe

doi:10.3390/ijerph18073520

Abstract

Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway, which degrades heme into equimolar amounts of carbon monoxide, free iron, and biliverdin. Its inducible isoform, HO-1, has multiple protective functions, including immune modulation and pregnancy maintenance, showing dynamic alteration during perinatal periods. As its contribution to the development of perinatal complications is speculated, two functional polymorphisms of the HMOX1 gene, (GT)n repeat polymorphism (rs3074372) and A(-413)T single nucleotide polymorphism (SNP) (rs2071746), were studied for their association with perinatal diseases. We systematically reviewed published evidence on HMOX1 polymorphisms in perinatal diseases and clarified their possible significant contribution to neonatal jaundice development, presumably due to their direct effect of inducing HO enzymatic activity in the bilirubin-producing pathway. However, the role of these polymorphisms seems limited for other perinatal complications such as bronchopulmonary dysplasia. We speculate that this is because the antioxidant or anti-inflammatory effect is not directly mediated by HO but by its byproducts, resulting in a milder effect. For better understanding, subtyping each morbidity by the level of exposure to causative environmental factors, simultaneous analysis of both polymorphisms, and the unified definition of short and long alleles in (GT)n repeats based on transcriptional capacity should be further investigated.

Highlights

Neonatal and perinatal complications have been recognized to occur in combination with genetic susceptibility and environmental factors such as maternal smoking, diabetes, or substance exposure
We collected the citations of the gathered articles, and 2 researchers (R.N. and K.F.) screened the related articles from 349 pieces of literature that matched with the single keyword, “Heme oxygenase-1 (HMOX1) polymorphism”
After excluding the UGT1A1 G71R polymorphism carriers, we found that carriers of the short allele (

Summary

Introduction

Neonatal and perinatal complications have been recognized to occur in combination with genetic susceptibility and environmental factors such as maternal smoking, diabetes, or substance exposure. Several studies have demonstrated the importance of oxidative and inflammatory stressors for their essential roles in the development of diseases during the perinatal period. Attempts to clarify the genetic components responsible for polymorphisms associated with the modulation of these stress cascades have been performed enthusiastically [1]. Among the three identified isoforms of HO, inducible HO-1, known as a stress-responsive protein, has been hypothesized to play a myriad of protective functions against several stressors, having antioxidant, antiinflammatory, anti-apoptotic, anti-coagulation, anti-proliferative, and vasodilative properties [3,4,5,6]. HO-1 is thought to play a role in maintaining immunologic

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