Abstract
Background:
Crohn’s disease (CD) is an inflammatory condition that has deleterious effects on patients’ health-related quality of life (HRQoL). Demographic, clinical, and psychosocial factors contribute to variability in HRQoL; however, the influence of genetic variations related to altered inflammatory responses in individuals with CD is unknown. This exploratory study compared HRQoL scores across genotypes of functional genetic polymorphisms in cytokine candidate genes among individuals with CD.
Method:
This study used data and blood samples collected in a parent study in 39 patients with CD aged 15−30 years. Participant reports of HRQoL were collected using the Shortened Inflammatory Bowel Disease Questionnaire (SIBDQ). Genetic data were collected for 18 functional polymorphisms in eight cytokine candidate genes. SIBDQ scores were compared among genotypes using one-way, between-subjects analysis of variance.
Results:
SIBDQ scores differed across genotypes as follows: for IL-1R2 rs4141134 scores differed for total SIBDQ (p = .004) and systemic (p = .011), emotion (p = .038), and social domains (p = .025); for IL-10 rs1878672, scores differed for total SIBDQ (p = .031) and social domain (p = .008); for NFKB2 rs1056890, scores differed for social domain (p = .041); for TNF-α rs1800629, scores differed for total SIBDQ (p = .001) and bowel (p = .026), systemic (p = .014), and social domains (p = .045).
Conclusions:
Findings on differences in SIBDQ scores across functional genetic polymorphisms in cytokine genes suggest potential mechanisms that contribute to variability in HRQoL in adolescents and young adults with CD.
Keywords: genetics, health-related quality of life, Crohn’s disease
Crohn’s disease (CD) is an inflammatory chronic condition that has a profound impact on individuals’ health-related quality of life (HRQoL; Ganz, Sugarman, Wang, Hansen, & Hakan-Bloch, 2016; Woodward et al., 2016). HRQoL is a multidimensional concept that represents a person’s perception of their health and the effects of treatments (Alrubaiy, Rikaby, Dodds, Hutchings, & Williams, 2015). It is also an important patient-reported measure of health status and is modifiable with treatment (Jowett, Seal, Barton, & Welfare, 2001; van der Have et al., 2014). People with CD experience multiple co-occurring physical and mood-related symptoms and are required to manage complex treatment regimens (Conley & Redeker, 2016; Farrell, McCarthy, & Savage, 2016). In addition, worsening disease activity and increased symptoms of pain, fatigue, depression, and anxiety lead to less social satisfaction and impaired physical and mental functioning (IsHak et al., 2017; Kappelman et al., 2014; Ueno, Nakayama, Hagiwara, Kurimoto, & Hibi, 2017). Consequently, CD has negative effects on overall HRQoL.
Several factors contribute to variability in HRQoL across individuals with CD, including demographic, clinical, socioeconomic, and psychosocial characteristics (Moradkhani, Beckman, & Tabibian, 2013; van der Have et al., 2014). In a systematic review and meta-analysis that included 29 studies of adults with CD, authors identified increased disease activity, number of relapses, corticosteroid treatment, hospitalization, and work disability as risk factors for impaired HRQoL (van der Have et al., 2014). Additionally, being female, having higher perceived stress and lower perceived social support increase the risk for poor HRQoL (Moradkhani et al., 2013).
Burgeoning evidence links genetic characteristics to the interindividual variability in domains of HRQoL (e.g., pain, fatigue, emotional and social functioning) in other populations (Sprangers et al., 2010; Sprangers et al., 2014). Twin studies have demonstrated that 22−42% of the variance in quality of life is heritable (Bartels, 2015). The inflammatory pathway is thought to contribute to these differences in HRQoL. Inflammatory and immune responses affected by the dysregulation of cytokines can influence the development and intensity of symptoms of sickness behavior (e.g., pain, fatigue, difficulty sleeping, depressive symptoms), which can have deleterious effects on social functioning and, ultimately, HRQoL (Alexander et al., 2016; Sprangers et al., 2014). Cytokines are proteins, peptides, or glycoproteins that serve as important mediators or regulators of immune and inflammatory responses. Thus, pro-inflammatory genes encode or regulate cytokines that promote systemic inflammation, whereas anti-inflammatory genes encode proteins that suppress or inhibit inflammatory cytokines (Turner, Nedjai, Hurst, & Pennington, 2014). Studies of people with chronic conditions (e.g., cancer, Alexander et al., 2014; Alexander et al., 2016; Rausch et al., 2010, and asthma, Cortina et al., 2011) have demonstrated that polymorphisms in pro- and anti-inflammatory genes (e.g., IL-1RN, IL-6, IL-10, TNF-α) contribute to variability in HRQoL. The inflammatory pathway is of particular interest in patients with CD given the role of altered inflammatory processes in disease pathogenesis and severity; however, the genetic contributions to the variability in HRQoL in patients with CD is unknown.
The purpose of this exploratory study, therefore, was to compare HRQoL scores across genotypes of functional single-nucleotide polymorphisms (SNPs) in cytokine candidate genes among adolescents and young adults with CD. Comparing differences in HRQoL scores across genotypes can aid in identifying genetic markers that may contribute to the variability in HRQoL. This information has the potential to inform clinical decision-making through the identification of patients at high risk for poor HRQoL and potential new targets for tailored interventions to improve HRQoL in this population.
Method
Design and Participants
Participants in this exploratory cross-sectional, genetic ancillary study were recruited for a larger parent study characterizing sleep disturbances and fatigue in adolescents and young adults with CD and testing a two-phase behavioral and pharmacological intervention to improve these symptoms (Szigethy et al., 2016). Patients were included if they met the following criteria: biopsy-confirmed CD, between the ages of 15 and 30 years, scores of ≥7 on the Pittsburgh Sleep Quality Index and ≥45 on the Multidimensional Fatigue Inventory, and English-speaking. If patients were under 18 years of age, researchers obtained assent from the adolescent and consent from a parent. Patients were excluded if they had any psychiatric diagnosis based on the Structured Clinical Interview of the Diagnostic and Statistical Manual (DSM)-IV including substance dependence within the past 3 months; use of psychotropic medications, sleep agents, and/or opioids during the past month; a history of treatment with bupropion or contraindication as determined by the study physician; a current CD flare requiring hospitalization with intravenous steroid treatment; abdominal surgery within 1 month; an ostomy; medical conditions associated with severe fatigue; an acute medical condition or a history of chronic inflammatory condition other than CD; hemoglobin level <10 g/dL with age and gender adjustments; history of sleep apnea, restless legs syndrome, seizure disorder or head trauma resulting in loss of consciousness; acute infection within 7 days; or self-identified as pregnant or planning to become pregnant within 3 months. The University of Pittsburgh Intuitional Review Board approved this study.
Assessment of Health-Related Quality of Life
Investigators used the Shortened Inflammatory Bowel Disease Questionnaire (SIBDQ), a 10-item disease-specific tool for patients with IBD, to measure patient-reported HRQoL (Irvine, Zhou, & Thompson, 1996). In this instrument, patients respond to questions related to four HRQoL domains: bowel symptoms (i.e., urgency, pain, gas), systemic symptoms (i.e., fatigue, weight loss), emotional health (i.e., depression, stress, anger), and social function (i.e., canceling social engagements). Responses for each item are on a 7-point Likert-type scale. Total scores range from 10 (poor HRQoL) to 70 (optimal HRQoL). A total SIBDQ score ≤50 is considered to be indicative of poor HRQoL. In addition, each domain can be scored separately. The bowel symptoms and emotional status domains each consist of three questions, with domain scores ranging from 3 (poor) to 21 (optimal). The systemic symptoms and social impairment domains each consist of two questions, and these domain scores range from 2 (poor) to 14 (optimal). The validity and reliability of this instrument are well established (Irvine et al., 1996). We used the baseline SIBDQ scores collected for the parent study for the analyses for this ancillary study.
Other Data Collection
Demographic data collected included age, sex, race, and marital status. In addition, the Harvey Bradshaw Index (HBI) was used to collect disease activity data (Harvey & Bradshaw, 1980). HBI scores <5 are considered to be indicative of clinical remission, scores 5−7 of mild disease activity, scores 8−16 of moderate disease activity, and scores >16 of severe disease activity.
SNP Selection and Genotyping
We found 18 functional polymorphisms in eight pro- and anti-inflammatory candidate genes in the literature. For the purposes of this study, we defined functional polymorphisms as DNA variations that influence the structure, function, or level of a gene product (Albert, 2011). We included polymorphisms if they had a known functional consequence on the gene and/or had been previously associated with HRQoL in other chronic conditions (e.g., cancer, asthma). The polymorphisms in pro-inflammatory genes we included were rs4073 in interleukin 8 (IL-8); rs28362491 in nuclear factor kappa B subunit 1 (NFKB1); rs1056890 and rs12772374 in nuclear factor kappa B subunit 2 (NFKB2); and rs1800629, rs361525, rs1799964, and rs3093662 in tumor necrosis factor alpha (TNF-α). The polymorphisms in anti-inflammatory genes we included were rs4141134 in interleukin 1 receptor type 2 (IL-1R2) and rs1800871, rs1878672, rs3024493, and rs3021094 in interleukin 10 (IL-10). The polymorphisms in genes with both pro- and anti-inflammatory properties we included were rs2853550 in interleukin 1 beta (IL-1B) and rs1800795, rs1800796, rs2069835, and rs2069840 in interleukin 6 (IL-6).
We obtained genetic samples from whole blood collected at enrollment in the parent study. DNA was extracted using the protocol and reagents of the QiAMP MIDI DNA kit (QIAGEN, Germantown, MD). Genotypes were determined using either an iPLEX MassARRAY multiplex assay platform (Sequenom, San Diego, CA) or a TaqMan allele discrimination platform (Thermo Fisher Scientific Inc., Waltham, MA). Blind duplicates were included, with a 99.9% genotyping call rate. Two individuals separately verified genotypes.
Statistical Analysis
We used descriptive statistics and frequency distributions to describe sample demographic and clinical characteristics. To compare the differences in SIBDQ total and domain scores across genotypes, we used one-way, between-subjects analysis of variance (ANOVA). Participants were grouped based on genotype for each polymorphism: zero doses of minor allele (i.e., two copies of the common allele), one dose of minor allele (i.e., one copy of common allele, one copy of minor allele), and two doses of minor allele (i.e., two copies of minor allele). When the ANOVA was significant, we completed the Tukey post hoc test. Due to the exploratory nature of this study, we considered a p ≤ .05 significant. All data analyses were performed using SPSS Version 24 (IBM, Armonk, NY).
Results
Table 1 lists demographic and clinical characteristics, as well as HRQoL scores, of the sample. The 39 participants meeting inclusion criteria had a mean age of 24.5 years; the majority were female, Caucasian, and not married. Much of the sample (66%) had disease activity scores that indicated clinical remission. Overall, participants self-reported poor HRQoL (mean SIBDQ mean total score = 45.2). Of the functional SNPs tested, two in pro-inflammatory genes (Table 2), two in anti-inflammatory genes (Table 3), and none in genes with both pro- and anti-inflammatory properties (Table 4) were significantly associated with one or more domains of HRQoL.
Table 1.
Sample Characteristics and Health-Related Quality of life for Participating Adolescents and Young Adults With Crohn’s Disease.
| Characteristic | n (%) or Mean (SD) |
|---|---|
| Age (years), mean (SD) | 24.5 (3.7) |
| Sex (female), n (%) | 14 (61.5) |
| Race (Caucasian), n (%) | 35 (89.7) |
| Marital status (married), n (%) | 7 (17.9) |
| CD activity (HBI scores), n (%) | |
| <5 | 20 (66.7) |
| 5–7 | 11 (28.2) |
| 8–16 | 4 (10.3) |
| >16 | 1 (2.6) |
| SIBDQ domains (HRQoL), mean (SD) | |
| SIBDQ total | 45.2 (9.4) |
| Bowel domain | 14.6 (4.0) |
| Systemic domain | 7.7 (2.5) |
| Emotion domain | 13.1 (4.5) |
| Social domain | 9.9 (3.3) |
Note. N = 39. CD = Crohn’s disease; HBI = Harvey Bradshaw Index; SIBDQ = Shortened Inflammatory Bowel Disease Questionnaire; HRQoL = health-related quality of life.
Table 2.
Pro-Inflammatory Gene Polymorphisms and Differences in Health-Related Quality of Life (HRQoL) Scores in Adolescents and Young Adults With Crohn’s Disease.
| Pro-inflammatory Gene Polymorphism | SIBDQ Total | Bowel Domain | Systemic Domain | Emotion Domain | Social Domain | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | ID | Genotype | n | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p |
| IL-8 | rs4073 | AA | 8 | 45.5 (7.0) | .949 | 14.6 (2.9) | .401 | 7.0 (2.7) | .633 | 13.9 (1.6) | .498 | 10.0 (3.7) | .354 |
| AT | 26 | 45.5 (10.9) | 15.0 (4.6) | 7.9 (2.7) | 12.5 (3.9) | 10.2 (3.4) | |||||||
| TT | 8 | 44.3 (7.4) | 12.8 (3.6) | 7.2 (2.3) | 13.9 (3.6) | 8.3 (3.3) | |||||||
| NFKB1 | rs28362491 | ATTG/ATTG | 18 | 45.5 (9.5) | .650 | 13.9 (4.7) | .792 | 7.1 (2.5) | .311 | 12.5 (2.8) | .395 | 9.3 (3.3) | .856 |
| ATTG/DEL | 13 | 44.9 (9.8) | 15.0 (4.0) | 6.7 (2.2) | 13.8 (4.2) | 9.1 (3.5) | |||||||
| DEL/DEL | 2 | 50 (1.4) | 14.5 (0.7) | 9.5 (0.7) | 15.5 (0.7) | 10.5 (0.7) | |||||||
| NFKB2 | rs1056890 | GG | 19 | 41.7 (9.3) | .091 | 13.6 (4.6) | .379 | 7.0 (2.1) | .209 | 12.4 (3.6) | .228 | 8.3 (3.2) | .041* |
| GA | 12 | 48.8 (7.4) | 15.3 (2.9) | 7.8 (3.0) | 14.4 (3.0) | 11.3 (2.9) | |||||||
| AA | 7 | 47.6 (10.8) | 15.7 (4.3) | 9.0 (2.5) | 12.0 (3.9) | 10.9 (3.9) | |||||||
| rs12772374 | AA | 26 | 46.0 (9.4) | .384 | 14.4 (4.4) | .702 | 7.8 (2.7) | .779 | 13.2 (3.3) | .554 | 9.9 (3.6) | .386 | |
| GA | 10 | 45.4 (8.5) | 15.0 (3.7) | 7.1 (2.6) | 13.5 (3.3) | 9.8 (2.8) | |||||||
| GG | 3 | 38.0 (12.1) | 12.7 (3.2) | 7.3 (1.5) | 11.0 (6.2) | 7.0 (4.6) | |||||||
| TNF-α | rs1800629 | GG | 29 | 48.3 (7.6) | .001* | 15.3 (3.7) | .026* | 8.2 (2.4) | .014* | 13.7 (3.4) | .066 | 10.3 (3.1) | .045* |
| GA | 11 | 37.5 (9.1) | 12.1 (4.3) | 6.0 (2.4) | 11.5 (3.3) | 7.9 (3.8) | |||||||
| AA | 0 | — | — | — | — | — | |||||||
| rs361525 | GG | 34 | 45.2 (9.4) | .926 | 14.5 (3.9) | .878 | 7.8 (2.4) | .147 | 13.1 (3.4) | .958 | 9.7 (3.5) | .995 | |
| GA | 5 | 45.6 (10.0) | 14.2 (5.6) | 6.2 (3.3) | 13.0 (4.4) | 9.7 (3.7) | |||||||
| AA | 0 | — | — | — | — | — | |||||||
| rs1799964 | TT | 26 | 44.4 (9.8) | .591 | 14.3 (4.1) | .916 | 7.9 (2.1) | .256 | 12.8 (3.7) | .213 | 9.2 (3.5) | .319 | |
| TC | 13 | 46.4 (8.7) | 14.5 (4.5) | 7.2 (3.2) | 13.3 (2.7) | 10.2 (3.2) | |||||||
| CC | 1 | 53 | 16 | 4 | 19 | 14 | |||||||
| rs3093662 | AA | 32 | 45.6 (9.5) | .642 | 14.6 (3.9) | .553 | 7.7 (2.4) | .399 | 13.4 (3.2) | .311 | 9.7 (3.3) | .875 | |
| GA | 7 | 43.7 (9.4) | 13.6 (5.3) | 6.9 (3.1) | 11.9 (4.7) | 9.5 (4.1) | |||||||
| GG | 0 | — | — | — | — | — | |||||||
Note. N = 39. IL-8 = interleukin 8; NFKB1 = nuclear factor kappa B subunit 1; NFKB2 = nuclear factor kappa B subunit 2; SIBDQ = Shortened Inflammatory Bowel Disease Questionaire; SNP = single-nucleotide polymorphism; TNF-α = tumor necrosis factor alpha.
*Significance level reported from analysis of variance tests comparing differences in HRQoL scores across genotypes for each polymorphism. Significant at p < .05.
Table 3.
Anti-Inflammatory Gene Polymorphisms and Differences in Health-Related Quality of Life (HRQoL) Scores in Adolescents and Young Adults With Crohn’s Disease.
| Anti-Inflammatory Gene Polymorphism | SIBDQ Total | Bowel Domain | Systemic Domain | Emotion Domain | Social Domain | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | ID | Genotype | n | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p | Mean (SD) | p |
| IL-1R2 | rs4141134 | AA | 13 | 45.7 (7.6) | .004* | 13.9 (3.6) | .074 | 6.4 (2.9) | .011* | 13.5 (2.8) | .038* | 10.8 (3.0) | .025* |
| AG | 15 | 40.1 (8.6) | 13.1 (4.0) | 7.3 (2.0) | 11.4 (3.7) | 7.8 (3.5) | |||||||
| GG | 11 | 51.7 (8.6) | 16.7 (4.3) | 9.4 (1.9) | 14.8 (3.2) | 10.8 (3.0) | |||||||
| IL-10 | rs1800871 | GG | 22 | 45.6 (9.7) | .948 | 14.4 (4.3) | .975 | 7.5 (2.6) | .985 | 12.9 (3.4) | .946 | 10.2 (3.4) | .589 |
| GA | 14 | 45.1 (7.3) | 14.6 (3.6) | 7.6 (2.1) | 13.3 (4.0) | 9.1 (3.4) | |||||||
| AA | 3 | 43.7 (17.7) | 14.4 (6.6) | 7.7 (5.1) | 13.3 (2.3) | 8.7 (4.6) | |||||||
| rs1878672 | GG | 9 | 40.8 (11.1) | .031* | 13.4 (3.8) | .182 | 7.4 (3.1) | .519 | 12.1 (3.4) | .570 | 7.3 (3.4) | .008* | |
| GC | 21 | 48.8 (6.5) | 15.5 (3.8) | 8.0 (2.5) | 13.6 (3.8) | 11.1 (2.7) | |||||||
| CC | 9 | 41.33 (10.7) | 12.8 (4.8) | 6.8 (2.2) | 12.9 (2.8) | 8.9 (3.7) | |||||||
| rs3024493 | CC | 24 | 45.8 (10.7) | .641 | 14.7 (4.2) | .836 | 7.9 (2.8) | .333 | 13.2 (4.0) | .273 | 9.8 (3.5) | .804 | |
| CA | 13 | 43.5 (7.0) | 14.2 (4.4) | 6.8 (2.0) | 12.3 (2.2) | 9.3 (3.6) | |||||||
| AA | 2 | 49.5 (5.0) | 13.0 (1.4) | 9.0 (1.4) | 16.5 (0.7) | 11.0 (2.8) | |||||||
| rs3021094 | TT | 35 | 45.1 (8.9) | .779 | 14.5 (4.0) | .74 | 7.5 (2.3) | .446 | 12.9 (3.6) | .485 | 9.6 (3.5) | .846 | |
| GT | 4 | 46.5 (14.4) | 13.8 (5.6) | 8.5 (4.4) | 14.3 (2.1) | 10.0 (3.7) | |||||||
| GG | 0 | — | — | — | — | — | |||||||
Note. N = 39. IL-1R2 = interleukin 1 receptor type 2; IL-10 = interleukin 10; SIBDQ = Shortened Inflammatory Bowel Disease Questionnaire; SNP = single-nucleotide polymorphism.
*Significance level reported from analysis of variance tests comparing differences in HRQoL scores across genotypes for each polymorphism. Significant at p <.05.
Table 4.
Polymorphisms in Genes With Pro- and Anti-Inflammatory Properties and Differences in Health-Related Quality of Life (HRQoL) Scores in Adolescents and Young Adults With Crohn’s Disease.
| Gene Polymorphism | SIBDQ Total | Bowel Domain | Systemic Domain | Emotion Domain | Social Domain | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | ID | Genotype | n | Mean (SD) | p* | Mean (SD) | p * | Mean (SD) | p* | Mean (SD) | p* | Mean (SD) | p* |
| IL-1B | rs2853550 | GG | 32 | 45.7 (10.1) | 0.522 | 14.4 (4.3) | 0.911 | 7.6 (2.7) | 0.879 | 13.2 (3.7) | 0.675 | 9.9 (3.7) | 0.358 |
| AG | 7 | 43.1 (4.8) | 14.6 (3.8) | 7.4 (1.8) | 12.6 (2.2) | 8.6 (1.8) | |||||||
| AA | 0 | — | — | — | — | — | |||||||
| IL-6 | rs1800795 | GG | 16 | 46.7 (8.5) | 0.412 | 14.5 (4.2) | 0.874 | 7.9 (2.9) | 0.563 | 13.0 (3.3) | 0.714 | 9.7 (3.5) | 0.632 |
| GC | 15 | 42.8 (7.1) | 14.0 (3.4) | 7.0 (2.1) | 12.7 (2.3) | 9.1 (3.6) | |||||||
| CC | 9 | 47.2 (13.6) | 14.9 (5.4) | 7.9 (2.8) | 13.9 (5.3) | 10.6 (3.4) | |||||||
| rs1800796 | GG | 35 | 46.0 (9.4) | 0.117 | 14.8 (4.2) | 0.107 | 7.8 (2.5) | 0.135 | 13.1 (3.6) | 0.845 | 9.8 (3.5) | 0.480 | |
| GC | 4 | 38.3 (5.3) | 11.3 (2.1) | 5.8 (2.1) | 12.8 (2.8) | 8.5 (3.7) | |||||||
| CC | 0 | — | — | — | — | — | |||||||
| rs2069835 | TT | 34 | 45.6 (9.6) | 0.722 | 14.4 (4.1) | 0.243 | 7.6 (2.7) | 0.957 | 13.2 (3.7) | 0.507 | 9.9 (3.5) | 0.604 | |
| CT | 4 | 41.8 (8.7) | 13.3 (3.4) | 7.3 (2.1) | 13.3 (1.3) | 8.0 (3.6) | |||||||
| CC | 1 | 48 | 21 | 8 | 9 | 10 | |||||||
| rs2069840 | CC | 21 | 45.2 (10.0) | 0.931 | 14.7 (4.4) | 0.837 | 7.5 (2.4) | 0.957 | 13.2 (3.9) | 0.972 | 9.9 (3.1) | 0.810 | |
| GC | 13 | 44.7 (7.8) | 14.4 (3.1) | 7.8 (2.4) | 13.0 (3.2) | 9.2 (4.2) | |||||||
| GG | 5 | 45.2 (9.4) | 13.5 (5.5) | 7.5 (3.8) | 12.8 (2.6) | 10.0 (3.3) | |||||||
Notes. N = 39. IL-1B = interleukin 1 beta; IL-6 = interleukin 6; SIBDQ = Shortened Inflammatory Bowel Disease Questionnaire; SNP = single-nucleotide polymorphism.
*Significance level reported from analysis of variance tests comparing differences in HRQoL scores across genotypes for each polymorphism.
Significant Pro-Inflammatory Gene Polymorphisms
Genotype groups for NFKB2 rs1056890 had significant differences in social domain scores, F(2, 35) = 3.517, p = .041. Post hoc comparisons indicated that the mean score for those with zero doses of the minor allele (GG genotype) was significantly worse than the score for those with one dose of the minor allele (GA genotype; p = .05). Scores between participants with two doses of the minor allele (AA genotype) and those with other genotypes did not differ.
When compared to individuals with zero doses of the minor allele (GG genotype) for TNF-α rs1800629, those with one dose of the minor allele (GA genotype) had significantly worse scores for total SIBDQ (p = .001), bowel domain (p = .026), systemic domain (p = .014), and social domain (p = .045).
Significant Anti-Inflammatory Gene Polymorphisms
Genotype groups for IL-1R2 rs4141134 had significant differences in scores for total SIBDQ, F(2, 36) = 6.34, p = .004, systemic domain, F(2, 36) = 5.11, p = .011, emotion domain, F(2, 35) = 3.61, p = .038, and social domain, F(2, 37) = 4.10, p = .025. Post hoc analyses indicated those with one dose of the minor allele (AG genotype) had significantly worse scores for total SIBDQ compared to those with two doses of the minor allele (GG genotype; p = .003), for emotion domain scores compared to those with two doses of the minor allele (GG genotype; p = .033), and for social domain scores than those with zero doses of the minor allele (AA genotype; p = .025). Additionally, participants who had zero doses of the minor allele (AA genotype) had significantly lower systemic domain scores than those with two doses of the minor allele (GG genotype; p = .009).
Genotype groups for IL-10 rs1878672 had significant differences in total SIBDQ score, F(2, 36) = 3.83, p = .031. However, post hoc comparisons only indicated a trend toward significance where participants with zero or two doses of the minor allele (GG and CC genotypes, respectively) had lower scores than those with one dose of the minor allele (GC genotype; p = .067 and p = .067, respectively). Genotype groups for IL-10 rs1878672 also had significant differences in social domain scores, F(2, 37) = 5.55, p = .008. Post hoc comparisons indicated that the mean score for participants with zero doses of the minor allele (GG genotype) was significantly worse than the score for those with one dose of the minor allele (GC genotype; p = .007). Scores between participants with two doses of the minor allele (CC genotype) and those with the other genotypes did not differ.
Discussion
Our findings provide preliminary evidence that variations within cytokine genes can potentially serve as protective or risk factors for poor HRQoL in adolescent or young adult patients with CD. These findings are consistent with existing evidence linking a wide array of biological pathways, genetic polymorphisms, and other molecular markers to HRQoL domains in chronic conditions. In particular, there is evidence supporting the influence of the inflammatory pathway via cytokines on the domains of HRQoL (Ordonana et al., 2013; Sprangers et al., 2010; Sprangers et al., 2014).
In the present study, NFKB2 rs1056890 was significantly associated with social domain scores, with individuals having zero doses of the minor allele scoring worse in this domain than those with one dose of the minor allele (A). NFKB2, a pro-inflammatory gene, encodes the functional protein NFkB, a subunit of the transcription factor complex nuclear factor-kappa-B. NFkB plays a key role in the initiation of inflammatory processes through transcription activation and repression of several genes involved in inflammation and immune function (U.S. National Library of Medicine [NLM], 2018). Research has implicated increased activation of NFkB in the pathogenesis of CD (Han et al., 2017; Schreiber, Nikolaus, & Hampe, 1998). The rs1056890 polymorphism is in the 3′ untranslated region of the gene, which has been implicated in binding miRNAs and regulating protein translation (Ma, Becker Buscaglia, Barker, & Li, 2011; Tian et al., 2018). In other studies, this polymorphism has been associated with deleterious symptoms (e.g., pain, fatigue, sleep disturbance) that could directly influence a person’s overall quality of life and impair their social functioning (Aouizerat et al., 2015; Miaskowski et al., 2017). For example, in a sample of oncology patients who were undergoing radiation therapy, having the minor allele of rs1056890 was a significant risk factor for clusters of sickness behavior symptoms (i.e., pain, feeling drowsy, lack of energy, difficulty sleeping, sweats) and mood−cognitive symptoms (i.e., difficulty concentrating, feeling sad, worrying, itching, irritability; Miaskowski et al., 2017).
TNF-α rs1800629 was associated with scores for total HRQoL and all domains except the emotion domain in the present study. Specifically, individuals with a single dose of the A (minor) allele had lower total and domain scores when compared to those with the wild-type genotype of this polymorphism. TNF-α encodes a pro-inflammatory cytokine (i.e., TNF) that plays key roles in several biological processes, including cell proliferation, differentiation, and apoptosis, lipid metabolism, and coagulation (NLM, 2018; Online Mendelian Inheritance in Man®, 2018). The A allele in rs1800629, a variant in the promoter region of TNF-α, has been linked to higher levels of TNF expression (Wilson, Symons, McDowell, McDevitt, & Duff, 1997). Higher levels of TNF can dysregulate immune responses and are associated with systemic and intestinal inflammation (Komatsu et al., 2001). An exploratory study in children and adolescents with CD found that the A allele of rs1800629 was associated with significant increase in C-reactive protein levels and disease activity (Sykora et al., 2006). Furthermore, research has also linked the A allele with higher levels of pain severity (Reyes-Gibby et al., 2008), sleep disturbances, and fatigue (Aouizerat et al., 2009) in patients with cancer, all of which are consequential symptoms that can lead to reduced HRQoL. In patients with CD, drugs that block TNF activity (e.g., certolizumab, infliximab) help to maintain clinical remission (Behm & Bickston, 2008) and improve quality of life (Lichtenstein, Bala, Han, DeWoody, & Schaible, 2002).
IL-1R2 rs4141134 was associated with scores for total HRQoL and all domains except the bowel domain. Individuals with zero or one dose of the minor allele had worse HRQoL scores than those with two doses of the minor allele (GG). IL-1R2 is an anti-inflammatory gene that encodes an interleukin-1 cytokine receptor type 2 (IL-1R2) that is expressed on monocytes, neutrophils, and T and B lymphocytes (NLM, 2018; Vasilyev, Silkov, & Sennikov, 2015). IL-1R2 has anti-inflammatory properties and serves as an endogenous inhibitor of the pro-inflammatory interleukin 1 (IL-1) cytokine signaling (Peters, Joesting, & Freund, 2013). The minor allele in rs4141134, a variant in the promoter region of IL-1R2, has been associated with greater expression of IL-1R2 receptors in immune cells, likely leading to greater binding of inflammatory mediators in the IL-1 family and, ultimately, inhibition of inflammatory processes (Vasilyev et al., 2015). Our findings regarding rs4141134 are consistent with those of previous studies showing that the minor allele is protective against having low quality of life (Alexander et al., 2014) and fatigue (Aouizerat et al., 2015) in patients with cancer.
IL-10 rs1878672 was associated with scores for total HRQoL and social domain. IL-10 encodes for a cytokine (IL-10) produced by monocytes and lymphocytes that has anti-inflammatory signaling properties (NLM, 2018; Turner et al., 2014). The rs1878672 intronic polymorphism putatively affects the transcription level of the gene (Omoyinmi et al., 2012). In a study in patients with lung cancer, researchers reported that this polymorphism had an association with the quality-of-life subdomain of vitality, as measured by the Medical Outcomes Study Short-Form General Health Survey (SF-8); however, it is not clear of the direction of the relationship between the minor allele and vitality scores (Rausch et al., 2010).
These findings should be interpreted with consideration of some limitations. This study was cross sectional and exploratory and had a relatively small sample size. Given the exploratory nature of this study, we did not control for possible confounding factors (e.g., puberty, psychological stress, or self-reported race or ethnicity) or correct for multiple testing. Additionally, given the stringent inclusion criteria of the parent study and the requirement for individuals to have clinically meaningful poor sleep and fatigue, patients included in this study may not be representative of the larger population of individuals with CD. However, our findings do provide important preliminary evidence of associations between HRQoL and cytokine gene polymorphisms in this population. Future research with a larger sample size is necessary to replicate these findings and extend the understanding of the contributions of cytokine gene polymorphisms, in the context of other clinical, psychosocial, and environmental determinants, on the domains of HRQoL. Also needed are corroborating longitudinal studies that examine the temporal relationships among HRQoL, CD symptoms, inflammatory markers, and genetic variations or expression.
Conclusions
This exploratory study is, to our knowledge, the first of its kind in people with CD. Our findings provide preliminary evidence linking variations in cytokine genes with HRQoL in this population. These results also underscore the potential role of inflammatory and immune responses in variability of quality of life and add to the growing evidence base linking genetic polymorphisms to HRQoL domains in chronic conditions. Given that HRQoL can be modifiable, it is possible that, with further investigation, these polymorphisms could serve as stable biomarkers to aid in identifying individuals with CD who are at greater risk of poor HRQoL and as targets for personalized interventions.
Acknowledgments
The authors wish to express their gratitude to the patients, Sandra Deslouches, Kate Mcauliff, and Meredith Strassburger for their contributions in completing this research.
Footnotes
Author Contributions: Mitchell R. Knisely contributed to conception, design, acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Yvette P. Conley contributed to conception, design, acquisition, analysis, and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Eva Szigethy contributed to conception, design, acquisition, analysis, and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: National Institutes of Health (T32NR009759; Mitchell R. Knisely), International Society of Nurses in Genetics Research Grant (Mitchell R. Knisely), a Senior Investigator Grant from the Crohn’s and Colitis Foundation of America (Eva Szigethy), and the Sherman Prize from the Sherman Foundation (Eva Szigethy).
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