Returning Genetic Results on Arsenic Susceptibility to Bangladeshi Research Participants

Abstract: In recent years, returning genetic results to research participants has become a topic of debate, with a growing consensus that researchers should offer to return incidental findings and research results to participants. The research and debates surrounding return of results (ROR) have primarily taken place in high-income countries. Less attention has been paid to ROR in lower-resource countries. The investigators propose to examine the impact of ROR on behavioral changes related to arsenic exposure reduction within The Health Effects of Arsenic Longitudinal Study (HEALS) cohort (IRB18-1331). This cohort study is located in Araihazar, Bangladesh, a rural area of Bangladesh with substantial exposure to arsenic through naturally contaminated drinking water from local wells. In this cohort, the investigators have participant data on inherited genetic variation known to impact arsenic metabolism efficiency and risk for arsenic toxicities. These genetic data allow us to identify participants who are inefficient (vs. efficient) arsenic metabolizers. The investigators previously surveyed 200 HEALS participants regarding their attitudes towards receiving information about their genetic susceptibility to arsenic toxicity, and 100% of the participants indicated they wanted to receive this information. The investigators are proposing a study in which they enroll adults who have had consistently high urine arsenic levels (≥200 µg/g creatinine) based on 15-20 years of follow-up data. The 2 intervention groups (n=200) will be selected based on genotype (i.e. inefficient and efficient arsenic metabolizers, respectively), allowing for the selection of the groups to be quasi-random (based on inherited genotypes). The control group (n=100), will be selected at random within the HEALS participants who have had consistently high urine arsenic levels. The intervention will consist of three arms: 2 intervention groups (n=200) and 1 control group (n=100). The intervention arm will consist of two groups; intervention 1 and intervention 2. Participants in intervention 1 group will be selected based on being inefficient arsenic metabolizers, while participants in intervention 2 group will be selected based on being efficient arsenic metabolizers. The control group will consist of a random sample of HEALS participants. A standard informational intervention will be provided to both the intervention and controls groups, reminding them of the effects of arsenic exposure and strategies to reduce their exposure. The intervention groups will additionally be offered information on their arsenic metabolism efficiency (i.e., their genetic results indicating they are inefficient/efficient metabolizers and at increased/decreased risk for arsenic toxicities). Six months after the intervention, the urine arsenic levels of all groups will be measured. The investigators hypothesize that the intervention 1 group (inefficient arsenic metabolizers) will have a larger decrease in urine arsenic levels compared to the control group. The investigatorshypothesize that the intervention 2 group will have urine arsenic levels that differ from intervention 1 group

Specific Aims:

Aim 1. To enroll arsenic-exposed individuals to an intervention study to assess the impact of returning information on genetic susceptibility on arsenic exposure levels. To achieve this aim, The investigators will first recruit HEALS participants (residing in Araihazar, Bangladesh) with consistently high arsenic exposure (based on >15 years of exposure data). Using genetic information to perform quasi-randomization, the investigators will then assign low-efficiency metabolizers to the intervention 1 arm and high-efficiency metabolizers to the intervention 2 arm(return of genetic results + exposure reduction information) and the control arm (exposure reduction information only).

Aim 2. To assess the impact of the ROR intervention on arsenic exposure levels, the investigators will collect urine samples 6 months after the intervention and compare the arsenic levels to arsenic levels assessed in urine at baseline. The investigators will test the association between the intervention arms and the change in arsenic levels between baseline and follow-up.

Background Returning genetic results to research participants has become a topic of debate in recent years due in part to increasing availability of whole-genome genotyping and sequencing data and an improved understanding of genetic causes of disease. Whole genome sequencing data can contain information relevant to the health care of a research participant, although not necessarily relevant to the research questions; this has been termed "incidental findings." There is a growing consensus that researchers should offer to return such incidental findings to research participants. Groups such as the American College of Medical Genetics (ACMG) have provide recommendations regarding which genes and variants should be considered "medically relevant and offered to participants as part of the incidental findings. There is also a trend among researchers and funders to make research participants' genetic data freely available to them should participants want to access to it. These types of data could be specific research results (i.e., the specific genetic variants[s] under study in meeting a research project's aims) or genome-wide measures of genetic variation (potentially communicated as polygenic estimates of risk for specific disease or as an interpretation of participants' genetic ancestry). It has been suggested that providing participants their genetic results is one way by which researchers can demonstrate respect for participants and enhance participants' engagement in research.