DNA damaging substances (DDS) such as tobacco, alcohol, and chemotherapy increase risk of damage related disorders including cancer; however, predicting who will develop these disorders remains largely unsolved. Differences in DNA repair capacity and susceptibility to DDS may be caused by many genetic variants. Genetic variants in DNA repair pathway genes can predict cancer risk and have shown gene-environment interactions. However, much remains unknown and it is likely that additional associations are obscured by small effect sizes, interactions and rarity. The Fanconi Anemia pathway (FAP) repairs DNA interstrand crosslinks, a type of DNA damage induced by endogenous metabolites and exogenous DDS. FA is a rare, heterogenous, often recessive genetic disorder that typically causes bone marrow failure, early cancers and subfertility. Severity ranges from lethal in utero to milder cases diagnosed in adulthood, suggesting even milder subclinical cases exist. We aim to understand the relationships between DNA repair, aldehyde detoxification, and related pathways, DDS, and negative health outcomes. We seek to answer whether complex interactions between function-altering variants in FA and related pathways increase risk of health outcomes and whether sex or DDS modify the effect of these variants. Our objectives include 1) Assessing the co-existence of FA related outcomes (cancers, congenital abnormalities, bone marrow failure, chemotherapy and radiation therapy related adverse events, infertility, early menopause, frequent infections, hearing loss, etc.) to discover whether there exist patients who may have lower DNA repair capacity due to mutation burden in DNA repair pathways. 2) Devising multiple algorithms to estimate overall pathway pathogenicity. 3) Correlating the presence of variants in FAP genes with FA related outcomes, phenotypes, and disorders among patients not diagnosed with FA. 4) Examining this association with and without the presence of DDS and by sex.
