of the proposed activity suitable for dissemination to the public (no proprietary/confidential information). It should be a self-contained description of the project and contain a statement of objectives and methods to be employed. It should be informative to other persons working in the same or related fields. DO NOT EXCEED THE SPACE PROVIDED. The goals of this study are to further understand the biology of effective methadone dose (MD) for long-term treatment of opioid addiction (OA) and to further enhance understanding of genetic variants that underlie risk of OA. Understanding the genetic variants contributing to variation in MD can tell us about both the biology underlying severity of addiction to opioids and potential biomarkers for clinicians to more-readily personalize treatment. There is substantial variability between individuals in effective MD, which we hypothesize is in part genetically driven, but no genetic variants have yet been consistently associated with MD. One genome-wide association study (GWAS) of MD, using self-reported ?usual? dose, reported a single genome-wide significant association among African Americans (AA), but not among European Americans (EA), with only modest confirming evidence in AA children, where this variant affected morphine dose required to treat post-surgical pain. We hypothesize that a well-powered GWAS of MD will identify replicable genetic variant associations with MD. Our GWAS will use strong measures of MD in a set of subjects in which EA, AA, and Latino Americans (LA) are all well represented. We will collect biospecimens from more than 500 people in methadone maintenance treatment, interview them, and get current and historical MDs from their treatment programs' medical records. Our interviews will include demographics, self-reported height and weight, and an extensive history of drug use. We will then generate genome-wide genotype data from the biospecimens and use biological pathway-based GWAS to identify functional pathways that may be associated with MD. We will assess these subjects as opioid addicts, pairing them with population controls to add to the parent project's GWAS of opioid addiction. The following aims summarize these goals: ? Supplement Aim 1: To establish a new initial cohort of methadone maintenance patients (N ? 500) for genetic studies. ? Supplement Aim 2: Conduct genome-wide association studies of methadone dose and opioid addiction. The proposed supplemental study is significant and innovative. It will use novel methods of characterizing MD, and a racially and ethnically diverse set of subjects, to contribute to knowledge of the biology of MD and of the severity of OA. It will also help clinicians determine individuals' optimal MD, which is critically valuable knowledge in light of the present opioid epidemic.
As the opioid epidemic continues, and the need for optimally effective treatment grows, a better understanding of the biology of variation in effective methadone dose (MD) among methadone maintenance patients is critical. In this study, we will initiate a new racially and ethnically diverse cohort of over 500 persons in methadone maintenance treatment and conduct genetic association studies to identify biological factors that may influence effective MD, adjusting for factors associated with MD that we recently identified. The project will construct a new biospecimen repository to lay a strong foundation for future investigations of effective MD, which is at the nexus between the severity of opioid addiction and its successful treatment.
