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(HRQOL): a Genome-Wide Study Approach cancers Article Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach Araba A. Adjei 1, Camden L. Lopez 2 , Daniel J. Schaid 2, Jeff A. Sloan 2, Jennifer G. Le-Rademacher 2 , Charles L. Loprinzi 1, Aaron D. Norman 2, Janet E. Olson 2, Fergus J. Couch 3, Andreas S. Beutler 1, Celine M. Vachon 2 and Kathryn J. Ruddy 1,* 1 Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; [email protected] (A.A.A.); [email protected] (C.L.L.); [email protected] (A.S.B.) 2 Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; [email protected] (C.L.L.); [email protected] (D.J.S.); [email protected] (J.A.S.); [email protected] (J.G.L.-R.); [email protected] (A.D.N.); [email protected] (J.E.O.); [email protected] (C.M.V.) 3 Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USA; [email protected] * Correspondence: [email protected] Simple Summary: Health-related quality of life (HRQOL) is associated with cancer prognosis as well as with age, sex, race, and lifestyle factors, including diet and physical activity. To investigate the hypothesis that HRQOL has genetic underpinnings in patients with cancer, we performed a genome-wide association study to evaluate genetic variants (single nucleotide polymorphisms, SNPs) associated with mental and physical QOL as measured by the PROMIS assessment tool in breast Citation: Adjei, A.A.; Lopez, C.L.; cancer survivors participating in a longitudinal cohort study, the Mayo Clinic Breast Disease Registry Schaid, D.J.; Sloan, J.A.; (MCBDR). Age and financial concerns were associated with worse physical and mental health, and Le-Rademacher, J.G.; Loprinzi, C.L.; previous receipt of chemotherapy was associated with worse mental health. SNPs in SCN10A, Norman, A.D.; Olson, J.E.; Couch, F.J.; LMX1B, SGCD, PARP12, and SEMA5A were associated with physical and mental QOL, but none at Beutler, A.S.; et al. Genetic Variations the genome-wide significance thresholds of p < 5 × 10−8. and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Abstract: Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome Approach. Cancers 2021, 13, 716. https://doi.org/10.3390/cancers in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS 13040716 to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental Academic Editors: Marieke J.H. health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Coenen and Daniel L. Hertz Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly Received: 31 December 2020 associated with global physical health (age: p = 1.6 × 10−23; financial concerns: p = 4.8 × 10−40) and Accepted: 4 February 2021 mental health (age: p = 3.5 × 10−7; financial concerns: p = 2.0 × 10−69). Chemotherapy was associated Published: 10 February 2021 with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global Publisher’s Note: MDPI stays neutral mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked with regard to jurisdictional claims in to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 published maps and institutional affil- and SEMA5A were also moderately associated with worse physical and mental health (p < 10−6). iations. These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL. Keywords: health-related quality of life; genome-wide association study; global physical and men- tal health Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Health-related quality of life (HRQOL) is a multifactorial concept of a person’s self- creativecommons.org/licenses/by/ perception of physical, psychological, and social functioning, often subdivided into sev- 4.0/). eral domains, including physical health, emotional health, cognitive functioning, fatigue, Cancers 2021, 13, 716. https://doi.org/10.3390/cancers13040716 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 716 2 of 15 and pain [1,2] HRQOL correlates with survival in patients with cancer, and is influenced by demographic characteristics, such as age, sex, and race. Lifestyle factors, including diet and physical activity, are also associated with HRQOL [3–6]. Quality of life in cancer patients is dynamic and is influenced not only by symptoms of the disease and adverse effects of the treatment but by psychological, social, and spiritual factors as well [7]. Additionally, cancer-related financial hardship has been associated with poor HRQOL [8,9]. Multiple biological pathways play a role in HRQOL [2], including via an impact of the dopaminergic pathway on emotional functioning and via an impact of the inflammation pathway on multiple domains of HRQOL. Specifically, links between the inflammatory pathway and both fatigue and pain are well-established [2–6,10]. Genetic variation may underlie individual differences in HRQOL, which are substan- tial even for patients receiving identical medical care for very similar health problems. There have been reports regarding the relationship between genetic polymorphisms and pain [11–14], and family and twin studies have identified 30–50% heritability for sub- jective well-being, depression, and anxiety, and 22–42% heritability for HRQOL [15–17]. Genetic underpinnings of inflammatory pathways may be important, with a number of single nucleotide polymorphisms (SNPs) in cytokine genes and the glutathione metabolic pathway found to be associated with QOL in different populations [2,18–20]. Although the exact mechanisms by which genetic variants in inflammatory genes contribute to individual variation in QOL are yet to be elucidated, inflammation may increase the severity of symp- toms experienced in diseases, such as cancer, impacting functional status and QOL [2,21]. Genetic variants in inflammatory, dopaminergic, serotonergic, and neurotrophic signaling, as well as neuroactive ligand-receptor interaction pathways, have been associated with overall HRQOL, and oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways appear to play a role in social functioning [1,2,15,18–20]. Candidate gene studies in lung cancer have reported that some SNPs in interleukin genes IL1b, IL1RN, and IL10 are associated with fatigue (a common driver of impaired HRQOL in patients with cancer) [2,18]. Other SNPs in inflammation pathway genes, such as PTGS2 and LTA, have also been associated with pain and QOL [22–25]. In addition, SNPs rs3858300, rs10741191, and rs3852507 in MGMT (a DNA repair pathway gene) have been associated with overall QOL in patients with lung cancer, and SNPs rs2756109 in ABCC2 and rs9524885 in ABCC4 (glutathione metabolic pathway) have been associated with pain [20]. An SNP in p38 MAPK signaling pathway gene, MEF2B rs2040562, has also been reported as a genetic determinant of HRQOL in patients with lung cancer [26]. Building on the findings of these candidate gene studies, a genome-wide study in 5142 Swedish women [17] did not find any SNPs significantly associated with QOL (Bonferroni- corrected significance threshold 2.86 × 10−7) but observed SNPs with moderate association, including rs17599095 in FSTL5 with social functioning and rs813299 in TRPM1 with global health/QOL. In this current study, we aimed to perform a comprehensive GWAS to explore the relationship between genetic variations and HRQOL domains in a large cohort of breast cancer survivors. 2. Results 2.1. Patient Characteristics The characteristics of the participants in this HRQOL study are shown in Table1. At the time of this study, 8317 patients had consented to the Mayo Clinic Breast Disease Registry (MCBDR), as depicted in Figure1. After exclusion of subjects without available genotyping data (n = 4901), those who did not return a follow-up questionnaire (n = 1129), and those who had prior cancer diagnosis (n = 352), a DCIS diagnosis (n = 329) or a metastatic disease diagnosis (n = 38), a total of 1568 patients remained. Nine had not responded to questions inquiring about financial concerns, and 117 had not completed the PROMIS-10 instrument, therefore, 126 additional patients were excluded from our analysis. Cancers 2021, 13, 716 3 of 15 Table 1. Patient characteristics (n = 1442). Demographic Factors n (%) Non-white, unknown, or undisclosed 56 (3.9%) Race White 1386 (96.1%) Mean (SD) 53.4 (11.5) Age at diagnosis in years Median (Q1, Q3) 51.5 (45.6, 62.4) Range 22.7–90.0 Mean (SD) 61.6 (12.8) Age at time of QOL assessment in years Median (Q1, Q3) 61.0 (52.5, 71.4) Range 26.2–95.5 Mean (SD) 8.2 (3.8) Years between cancer diagnosis and QOL Median (Q1, Q3) 8.3 (5.0, 10.9) assessment Range 0.9–16.7 Male 3 (0.2%) Gender Female 1439 (99.8%) Mean (SD) 2.1 (2.7) Financial concerns rating Median (Q1, Q3) 1.0 (0.0, 3.0) (patient-reported) Range 0.0–10.0 Cancers 2021, 13, x 4 of 15 Mastectomy 782 (54.2%)/660 (45.8%) Treatment received any time before QOL Axillary lymph node dissection (ALND) 530 (36.8%)/912 (63.2%) assessment Chemotherapy 608 (42.2%)/834 (57.8%) (Yes/No) of 0 (where 0 = no financial concern). Chemotherapy treatment was associated only with Radiation 689 (47.8%)/753 (52.2%) worse global mental health (p = 0.01), not global physical health.
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