The authors have declared that no competing interests exist.
Analyzed the data: AL CJ HN NLP JL. Contributed reagents/materials/analysis tools: AL CJ HN NLP JL. Wrote the paper: AL CJ HN NLP JL. Design and conception of the study: AL CJ HN NLP JL. Collected the data: NLP.
Previous studies indicate an association between sleep problems and gastroesophageal reflux disease (GERD). Although both these conditions separately have moderate heritabilities, confounding by genetic factors has not previously been taken into account. This study aimed to reveal the association between sleep problems and GERD, while adjusting for heredity and other potential confounding factors.
This cross-sectional population-based study included all 8,014 same-sexed twins of at least 65 years of age and born in Sweden between 1886 and 1958, who participated in telephone interviews in 1998–2002. Three logistic regression models were used 1) external control analysis, 2) within-pair co-twin analysis with dizygotic (DZ) twin pairs discordant for GERD, and 3) within-pair co-twin analysis with monozygotic (MZ) twin pairs discordant for GERD. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and adjusted for established risk factors for GERD, i.e. sex, age, body mass index (BMI), tobacco smoking, and educational level.
A dose-response association was identified between increasing levels of sleep problems and GERD in the external control analysis. Individuals who often experienced sleep problems had a two-fold increased occurrence of GERD compared to those who seldom had sleep problems (OR 2.0, 95% CI 1.8–2.4). The corresponding association was of similar strength in the co-twin analysis including 356 DZ pairs (OR 2.2, 95% CI 1.6–3.4), and in the co-twin analysis including 210 MZ pairs (OR 1.5, 95% CI 0.9–2.7).
A dose-dependent association between sleep problems and GERD remains after taking heredity and other known risk factors for GERD into account.
Gastroesophageal reflux disease (GERD), defined as recurrent regurgitation of stomach contents into the esophagus which causes troublesome symptoms or complications
GERD; n (%) | Not GERD; n (%) | P-value |
||
|
1,327 (17) | 6,687 (83) | ||
|
Men | 544 (41) | 2,868 (43) | |
Women | 783 (59) | 3,819 (57) | 0.2023 | |
|
65–74 | 831 (63) | 4,014 (60) | |
≥75 | 496 (38) | 2,673 (40) | 0.0773 | |
|
≤9 | 923 (70) | 4,666 (70) | |
10–12 | 239 (18) | 1,168 (18) | ||
>12 | 159 (12) | 813 (12) | 0.2200 | |
Missing | 6 (0) | 40 (1) | ||
|
<25 (normal) | 572 (43) | 3,488 (52) | |
25–30 (overweight) | 563 (42) | 2316 (35) | ||
>30 (obese) | 130 (9) | 459 (7) | <.0001 | |
Missing | 62 (5) | 424 (6) | ||
|
Current smokers | 138 (10) | 764 (11) | |
Previous smokers | 473 (36) | 2,040 (31) | ||
Never smokers | 654 (49) | 3,594 (54) | 0.0007 | |
Missing | 62 (5) | 289 (4) |
Pearson’s chi-square test estimating the associations between GERD and sex, age, education, body mass index and tobacco smoking separately.
This nationwide population-based study was based on the Swedish Twin Registry, described in detail elsewhere
DZ pairs; n (%) | MZ pairs; n (%) | ||
|
51 (4) | 52 (6) | |
|
1004 (71) | 647 (71) | |
|
356 (25) | 210 (23) | |
|
Men | 137 (38) | 80 (38) |
Women | 231 (61) | 130 (62) | |
|
64–74 | 259 (73) | 149 (71) |
≥75 | 97 (27) | 61 (29) |
One twin has GERD, and the other not.
GERD was assessed by 10 validated questions
External analysis | ||||||
GERD |
Crude | Adjusted |
||||
|
n (%) | OR | 95% CI | OR | 95% CI | |
|
Seldom | 456 (35) | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 438 (34) | 1.5 | 1.3–1.7 | 1.5 | 1.3–1.7 | |
Often | 403 (31) | 2.1 | 1.8–2.4 | 2.0 | 1.8–2.4 | |
|
Seldom | 842 (65) | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 261 (20) | 1.5 | 1.3–1.8 | 1.5 | 1.3–1.8 | |
Often | 197 (15) | 1.8 | 1.5–2.1 | 1.7 | 1.5–2.1 | |
|
Seldom | 872(67) | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 269 (21) | 1.6 | 1.4–1.9 | 1.7 | 1.4–1.9 | |
Often | 162 (12) | 2.0 | 1.7–2.5 | 2.0 | 1.6–2.4 | |
|
Seldom | 709 (54) | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 357 (27) | 1.3 | 1.1–1.5 | 1.3 | 1.1–1.5 | |
Often | 240 (18) | 1.9 | 1.6–2.3 | 1.9 | 1.6–2.3 |
OR, odds ratio; CI, confidence interval.
The different numbers of GERD cases for the four sleep exposures are due to different numbers of missing observations in the sleep questions.
ORs adjusted for age, sex, educational level, body mass index, and tobacco smoking.
The insomnia index was constructed by combining the three different sleep problem questions and 0 points were given for “seldom”, 1 point for “sometimes” and 2 points for “often”. The highest scores, 4–6 points or if the participant had answered “often”, were then classified as “often having sleep problems”, 1–3 points as “sometimes having sleep problems” and 0 as ”seldom having sleep problems”.
Sleep problems were assessed in the SALT interview by the Karolinska Sleep Questionnaire
Co-twin within-pair analysis DZ twins | |||||
Crude | Adjusted |
||||
|
OR | 95% CI | OR | 95% CI | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.6 | 1.1–2.3 | 1.5 | 1.0–2.2 | |
Often | 2.2 | 1.5–3.4 | 2.2 | 1.5–3.4 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.6 | 1.0–2.3 | 1.5 | 1.0–2.3 | |
Often | 2.0 | 1.3–3.2 | 2.1 | 1.3–3.3 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.8 | 1.2–2.8 | 1.9 | 1.2–2.9 | |
Often | 1.8 | 1.1–2.9 | 1.7 | 1.0–2.8 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.2 | 0.8–1.8 | 1.1 | 0.7–1.6 | |
Often | 1.8 | 1.1–2.9 | 1.7 | 1.1–2.7 |
OR, Odds ratio; CI, confidence intervals.
Zygosity of the same-sexed pairs was assessed by asking each twin independently the question: “During childhood, were you and your twin partner as alike as ‘two peas in a pod’ or not more alike than siblings in general?” If both twins in the pair answered that they were “alike as two peas in a pod” they were classified as monozygotic (MZ), and if both answered that they “were not more alike than siblings” they were classified as dizygotic (DZ). If the twins answered differently they were categorized as “not determined”. This method of determining zygosity has been shown to be 98% accurate compared to DNA-testing
Co-twin within-pair analysis MZ twins | |||||
Crude | Adjusted |
||||
|
OR | 95% CI | OR | 95% CI | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.4 | 0.9–2.2 | 1.3 | 0.8–2.2 | |
Often | 1.6 | 0.9–2.8 | 1.5 | 0.9–2.7 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.6 | 0.9–2.7 | 1.6 | 0.9–2.8 | |
Often | 1.9 | 1.0–3.8 | 1.9 | 0.9–3.9 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.8 | 1.0–3.4 | 1.9 | 1.0–3.6 | |
Often | 1.5 | 0.7–3.2 | 1.4 | 0.7–3.1 | |
|
Seldom | 1.0 | (reference) | 1.0 | (reference) |
Sometimes | 1.5 | 0.9–2.3 | 1.5 | 0.9–2.4 | |
Often | 1.5 | 0.8–2.8 | 1.5 | 0.8–2.9 |
OR, odds ratio; CI, confidence intervals.
The potential confounding factors heredity, sex, age, educational level, body mass index (BMI), and tobacco smoking were predefined and selected as they are established risk factors for GERD
Dyzygotic pairs, N = 1 411 | Monozygotic pairs, N = 909 | |||
r |
ASE |
r |
ASE |
|
|
0.151 | 0.041 | 0.359 | 0.044 |
|
0.197 | 0.024 | 0.239 | 0.029 |
|
0.069 | 0.031 | 0.086 | 0.039 |
|
0.207 | 0.031 | 0.311 | 0.038 |
|
0.193 | 0.027 | 0.308 | 0.030 |
Polychoric correlation, tetrachoric for GERD as GERD only has two categories.
Asymptotic error of the polychoric/tetrachoric correlations.
The main analyses were performed in three steps. First, external control analyses using unconditional logistic regression were performed. As many twins had a co-twin in the cohort, correction for within-pair dependency was conducted with generalized estimated equations (GEE) to avoid underestimation of the variance. Crude odds ratios (ORs) and ORs adjusted for sex, age, educational level, BMI, and tobacco smoking were estimated. Second, within-pair co-twin analyses with DZ twin pairs were performed using conditional logistic regression. Only complete twin pairs were included in the analyses. Third, within-pair co-twin analyses with complete MZ twin pairs were performed using conditional logistic regression. Crude and adjusted ORs were also calculated for all within-pair analyses. In all three analyses, 95% confidence intervals (CIs) were estimated. By including only twin pairs discordant for GERD, i.e. where one twin had GERD and the other not, it was possible to adjust for genetic and early environmental factors in the within-pair analyses. This is due to the fact that MZ twins share 100% of their genes and DZ twins share on average 50% of their genes, and the large majority of twins share childhood environment. There can be variation in the genome for monozygotic twins too, due to epigenetic changes, and greater variations are found among older twins
Gastroesophageal Reflux Disease | ||||||
All pairs, N = 2 341 | Dyzygotic pairs, N = 1 411 | Monozygotic pairs, N = 909 | ||||
r |
ASE |
r |
ASE |
r |
ASE |
|
|
0.067 | 0.025 | 0.077 | 0.032 | 0.043 | 0.039 |
|
0.033 | 0.028 | 0.065 | 0.036 | −0.012 | 0.045 |
|
0.061 | 0.029 | 0.050 | 0.037 | 0.071 | 0.046 |
|
0.059 | 0.026 | 0.041 | 0.034 | 0.073 | 0.041 |
Polychoric correlation.
Asymptotic error of the polychoric correlations.
Nocturnal reflux symptoms |
Medication use to prevent pain |
||||||
yes | no | yes | no | ||||
|
n (%) | n (%) | p-value |
n (%) | n(%) | p-value |
|
|
Seldom | 105 (29) | 145 (36) | 122 (31) | 128 (35) | ||
Sometimes | 126 (35) | 127 (32) | 122 (32) | 125 (34) | |||
Often | 131 (36) | 127 (32) | 0.0964 | 139 (36) | 116 (31) | 0.3688 | |
|
Seldom | 215 (60) | 253 (63) | 226 (59) | 238 (65) | ||
Sometimes | 79 (22) | 80 (20) | 82 (21) | 73 (20) | |||
Often | 67 (19) | 67 (17) | 0.5781 | 76 (20) | 57 (15) | 0.2011 | |
|
Seldom | 216 (59) | 277 (70) | 242 (63) | 244 (65) | ||
Sometimes | 88 (24) | 80 (20) | 88 (23) | 79 (21) | |||
Often | 60 (16) | 44 (15) | 0.0134 | 53 (14) | 50 (13) | 0.7991 | |
|
Seldom | 176 (49) | 224 (56) | 208 (54) | 188 (51) | ||
Sometimes | 105 (29) | 103 (26) | 94 (24) | 110 (30) | |||
Often | 75 (23) | 75 (19) | 0.1279 | 82 (21) | 74 (20) | 0.2886 |
Nocturnal reflux symptoms was assessed by the question “Have you woken up during the night due to pain behind the breastbone or heartburn?”.
Use of reflux medications was assessed by the question “ Have you taken any of the following medications to prevent pain behind the breastbone or heartburn “, followed by a list of proton pump inhibitors used in Sweden at the time of the data collection.
Pearson’s chi-square test measuring the association between nocturnal reflux symptoms and sleep problems.
Pearson’s chi-square test measuring the association between use of reflux medications to prevent pain and sleep problems.
The insomnia index was constructed by combining the three different sleep problem questions and 0 points were given for “seldom”, 1 point for “sometimes” and 2 points for “often”. The highest scores, 4–6 points or if the participant had answered “often”, were then classified as “often having sleep problems”, 1–3 points as “sometimes having sleep problems” and 0 as “seldom having sleep problems”.
Among 8,951 twins eligible for inclusion in this study, 937 (10%) were excluded due to missing information on GERD. The remaining 8,014 twins, of whom 1,327 (17%) had GERD, were included in the descriptive analyses. After further exclusion of 157 (2%) twins with missing information on insomnia status, 7,857 remained in the main statistical analyses, while 786 individuals reporting heartburn or pain behind the breastbone were included in the sub analyses. The distribution of sex, age and education was similar between twins with and without GERD, whereas high BMI and tobacco smoking were overrepresented among those with GERD (
A dose-response association was observed between increasing sleep problems and occurrence of GERD in the external control analysis (
The sleep problem items were also analyzed separately and the association between “not rested when waking up” and GERD showed a similar dose-response association as the insomnia index, except in the within-pair model with MZ twins where the estimates were higher (
The intraclass correlations for GERD were 0.151 in DZ twin pairs and 0.359 in MZ twin pairs (
The cross-trait correlations for sleep problems and GERD were very weak, ranging from 0.033 (Not rested when waking up and GERD) to 0.067 (Insomnia index and GERD) in “all pairs”, 0.041 (Waking up too early and GERD) to 0.077 (Insomnia index and GERD) in DZ pairs and between −0.012 (Not rested when waking up and GERD) to 0.073 (Waking up too early and GERD in MZ twin pairs (
Finally, among those who reported waking up at night due to pain behind the breastbone or heartburn 16% “often” had disturbed sleep compared to 11% among those who did not and there was a significant association between nocturnal reflux symptoms and disturbed sleep (χ2 8.6; p-value 0.01) (
This twin study indicates a dose-response association between sleep problems and GERD, which remained after adjustment for genetic and familial environmental factors, as well as for sex, age, educational level, BMI and tobacco smoking.
When the results from the external analyses (including all twins) were compared with the results from the co-twin within-pair analyses for DZ and MZ twins (discordant for GERD), there were minor differences regarding “sometimes” having sleep problems, while the differences were slightly more pronounced for “often” having sleep problems. The association for “often” having sleep problems compared to “no” sleep problems was somewhat stronger among DZ twins compared to that of all twins, while the association was attenuated in the MZ twin analyses. Such a decrease in effect limited to MZ twins indicates genetic influence or limited statistical power, since the sample size for MZ twins was smaller than for the DZ twins. Measures of intrapair similarity (concordances and intraclass correlations) are greater for MZ than DZ pairs for GERD, supporting previous findings in this cohort that genetic factors are of moderate importance for GERD
In a previous population-based cross-sectional case-control study from our group, including 65,333 participants in the county of Nord-Trøndelag in Norway, a positive dose-response association between sleeplessness and GERD was found
A proposed mechanism for sleep problems causing GERD is that sleep deprivation leads to esophageal hyperalgesia, i.e. patients with GERD are more pain sensitive to their reflux symptoms when sleep deprived
Strengths of the present study include the population-based design, the extensive data collection based on structured telephone interviews, and the ability to, for the first time, adjust for genetic and early environmental factors in addition to other known risk factors for GERD and sleep problems. Other advantages include the validated assessment of GERD
In conclusion, this large population-based twin study indicates an association between sleep problems and GERD that remains after adjustment for heredity and familial environmental factors, as well as after other known risk factors for GERD and sleep problems.