Phenotypic Associations With the HMOX1 GT(n) Repeat in European Populations

Abstract

Heme oxygenase 1 is a key enzyme in the management of heme in humans. A GT(n) repeat length in the heme oxygenase 1 gene (HMOX1) has been widely associated with a variety of phenotypes, including susceptibility to and outcomes in diabetes, cancer, infections, and neonatal jaundice. However, studies have generally been small and results inconsistent. In this study, we imputed the GT(n) repeat length in participants from 2 UK cohort studies (the UK Biobank study (n = 463,005; recruited in 2006-2010) and the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 937; recruited in 1990-1991)), with the reliability of imputation tested in other cohorts (1000 Genomes Project, Human Genome Diversity Project, and Personal Genome Project UK). Subsequently, we measured the relationship between repeat length and previously identified associations (diabetes, chronic obstructive pulmonary disease, pneumonia, and infection-related mortality in the UK Biobank; neonatal jaundice in ALSPAC) and performed a phenomewide association study in the UK Biobank. Despite high-quality imputation (correlation between true repeat length and imputed repeat length > 0.9 in test cohorts), clinical associations were not identified in either the phenomewide association study or specific association studies. These findings were robust to definitions of repeat length and sensitivity analyses. Despite multiple smaller studies identifying associations across a variety of clinical settings, we could not replicate or identify any relevant phenotypic associations with the HMOX1 GT(n) repeat.

Keywords: HMOX1; ALSPAC; Avon Longitudinal Study of Parents and Children; UK Biobank; heme oxygenase 1; phenomewide association studies.