Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings
HJ Kim,a,* H-S Lee,a,* SZ Kazmi,a,* HJ Hann,b T Kang,c J Cha,d S Choi,a H Swan,a H Kim,eYS Lee,f HS Ahna
aDepartment of Preventive Medicine, College of Medicine, Korea University, Seoul, KoreabMedical Research Institute, College of Medicine, Ewha Womans University, Seoul, KoreacHealth and Wellness College, Sungshin Women’s University, Seoul, KoreadDepartment of Public Health, Korea University, Seoul, KoreaeDepartment of Obstetrics and Gynaecology, Seoul National University Hospital, Seoul, Korea
fDepartment of Health Informatics and Management, College of Medicine, Chungbuk National University, Cheongju, Korea
Correspondence:HS Ahn, Department of Preventive Medicine, College of Medicine, Korea University, Inchon-ro 73, Seongbuk-gu, Seoul 02841, Korea. Email: [email protected] and YS Lee, Department of Health Informatics and Management, College of Medicine, Chungbuk National University, 411 Building E7-3, 1 Chungdae-ro, Seowon-gu, Cheongju 28644, Korea. Email: [email protected]
Accepted 10 April 2021.
ObjectiveTo quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI).
Design, setting and populationPopulation-based nationwide cohort study.
MethodsUsing data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale.
Main outcome measuresIRR of endometriosis among women with and without affected siblings.
ResultsFrom 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25–3.36),
and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19–11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43–7.55), 3.47 (95% CI 2.82–4.26) and 3.09 (95% CI 2.68–3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant.
ConclusionGenetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene– environment interaction exists between family history and smoking or early menarche.
Keywords Additive interaction, cohort study, endometriosis, environmental risk factors, familial risk, gene–environment interactions, genetic factors.
Tweetable abstractSignificant gene–environment interaction exists between family history of endometriosis and smoking or early menarche.
Please cite this paper as:Kim HJ, Lee H-S, Kazmi SZ, Hann HJ, Kang T, Cha J, Choi S, Swan H, Kim H, Lee YS, Ahn HS. Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings. BJOG 2021; https://doi.org/10.
1111/1471-0528.16769.
*These authors share joint first authorship.
Introduction
Endometriosis is an estrogen-dependent gynaecological dis- ease mostly affecting women of reproductive age.1 Among myriad suggested theories,2–4 genetic predisposition has been regarded as an important contributor to its pathogen- esis.5–8 Studies have shown a three- to nine-fold increased risk of endometriosis among first-degree relatives (FDR) of affected patients9–19 and two-fold higher disease concor- dance in monozygotic twins than dizygotic twins.20–22 Additionally, several genome-wide association studies23–25 have identified various specific genetic polymorphisms associated with the disease.
However, few studies exist on the familial aggregation of endometriosis, and even the magnitude of risk provided by them ranges widely, possibly as a result of heterogeneous study designs and sample sizes. Previous studies comprised mostly case–control studies that included up to a few hun- dred individuals, so quantifying incidence and risk ratios was not possible. Moreover, by including mainly hospital- based cases, their findings may not be representative of the general population. Therefore, precise quantification of endometriosis incidence and familial risk from population- level data are crucial.
In addition to genetic factors, a number of environmen- tal factors, including reproductive, lifestyle and behavioral factors have been linked to the aetiology of endometriosis;
however, the association with some of these factors remains inconclusive.26–28 Among these, smoking,29,30 early menar- che31 and low body mass index (BMI)32 have been more consistently associated with an increased risk and studies have shown a 1.4-fold to 3-fold elevated disease risk among women with these factors.
Accordingly, familial aggregation of endometriosis is influenced by both genetic and shared environmental fac- tors; however, the extent of their contribution to familial clustering remains unknown. Moreover, studies have sug- gested that these two factors may interact with each other, where the impact of environmental factors may differ on the risk of disease between persons with and without a genetic predisposition. Consequently, the combined effect of both factors may yield greater or lesser risk of outcome than the sum of their individual risks.33To our knowledge, interactions between family history and smoking, age at menarche or BMI has not been previously reported on a population-level. This warrants the need for large-scale studies that include information on family history and environmental risk factors to examine gene–environment interactions in endometriosis.
This nationwide population-based study extracted family relationship, healthcare utilisation, lifestyle habits and anthropometric data from the Korean National Health Insurance (NHI) and Screening Program (NHSP)
databases, to quantify familial risk of endometriosis in full siblings and controlled it for environmental factors to esti- mate their relative contributions to familial aggregation of the disease. Gene–environment interactions between famil- ial history and smoking, age at menarche or BMI were also examined.
Methods Data source
This study was conducted using the Korean NHI and NHSP linked databases. The NHI provides full population coverage and receives inpatient and outpatient hospital utilisation information sent by medical institutions for reimbursement purposes. Data submitted to NHI include primary diagnoses based on the International Classification of Disease 10th revision (ICD-10), prescriptions assigned and medical procedures or surgeries performed. The NHI database also retains kinship information of insured indi- viduals and their entitled dependents, which enabled us to identify blood-related FDR.
Data from the NHSP were used to analyse the influence of environmental risk factors. All insured citizens and their dependents are invited to participate in the NHSP biannual standardised health check-ups, which include question- naires on lifestyle habits such as smoking, alcohol con- sumption and physical activity as well as laboratory tests like chest radiograph, blood pressure, blood glucose, lipid parameters and anthropometric measurements such as BMI. During the study period, around 70% of all NHI enrollees received an NHSP check-up.
Assessment of family relationships
In Korea, under the mandatory NHI service, employed or self-employed individuals become beneficiaries by making monthly income-based payments. Spouses and children of beneficiaries are eligible to be enrolled in the NHI as dependents, following marriage registration or birth regis- tration. The presence of family relationship information between insured individuals and their dependents allowed us to identify family relationships such as full siblings and their biological parents. Though we do not have the break- down of monozygotic to dizygotic twins based on estima- tion for zygosity, twins were defined as full siblings with the same date of birth (7 days).
Study population: Inclusion and exclusion criteria
Inclusions: By using the NHI and NHSP databases, 831 227 women with full siblings sharing the same biological par- ents were included in this study. Only women who were eligible and participated in the NHSP were included.Exclu- sions: In order to identify blood-related FDR only and to minimise heterogeneity, we excluded single parents,individuals with step-parents, half-siblings and children not registered as dependent at birth. All persons not eligible for the NHSP, i.e. <20 years of age and who did not partici- pate in the screening program, were also excluded (Fig- ure S1 demonstrates study flow diagram). In all, 2 109 288 women shared the same biological parents, which included women with no sisters, so familial risk analyses were per- formed using 831 227 women who had at least one sister (Table S1).
Although our predefined study period was 2002–2018, endometriosis cases diagnosed before 2002 and those diag- nosed between 2002 and 2018 were included in the study, only if they were diagnosed as endometriosis in the NHI database. Participant entry and follow-up time are illus- trated in Figure S2. Sensitivity analyses were performed to estimate familial risks including and excluding cases diag- nosed before 2002, and we found that the results did not show any significant difference (Table S2).
Information of environmental risk factors
The NHSP database was used to acquire information on lifestyle and reproductive characteristics of each study par- ticipant, including age, height, weight, age at menarche, blood cholesterol, fasting blood glucose, systolic and dias- tolic blood pressures, smoking status, alcohol consumption and frequency of physical activity (see Appendix S1 for subgroup details). To assess the influence of environmental factors on disease development, we selected only the first NHSP results of patients (Appendix S2, Figure S3), as it was too complicated to include all biannual screening records of each risk factor for each study subject over a period of 16 years.
Identification of familial and non-familial cases
During the follow-up period, once a sibling was diagnosed with endometriosis, other siblings were considered exposed and identified as ‘with an affected sibling’ and also as the‘familial group’. In the event of a second sibling being diagnosed, she was defined as the first ‘familial case’ and remaining siblings were considered exposed to two familial cases and identified as ‘with more than one affected sib- ling’. In families with no endometriosis cases, all siblings were identified as ‘without an affected sibling’ and also as the ‘non-familial group’, and if during follow up any sib- ling(s) was diagnosed, she was defined as a ‘non-familial case’ (Figure S4).
Identification of endometriosis cases
We defined an endometriosis case as a woman who was admitted to a hospital with a principal diagnosis of endometriosis (ICD-10-code N80) and underwent laparo- scopic biopsy and pelvic ultrasound, and who also had more than three documented physician visits under the
principal diagnosis of endometriosis. Appendix S3 details the validation of identified cases.
Statistical analysis
Siblings who met the inclusion criteria were followed from 1 January 2002 up to a diagnosis of endometriosis, death, or end of follow up on 31 December 2018, whichever came first. Those born after 1 January 2002 were followed up from their date of birth.
The magnitude of familial aggregation was estimated as incidence rate ratios (IRRs) with 95% CI using Cox pro- portional hazard regression models by comparing the inci- dence of endometriosis in women with versus without affected full siblings. IRRs were also calculated according to relationships, i.e. with affected twin or non-twin or sib- lings. All Cox models were adjusted for familial clustering (Appendix S4).
The time-scale was in days where each participant was followed from their specific date of diagnosis with ICD-10 code for endometriosis as recorded in the NHI database till respective end of follow up. As each individual could have different length of follow up, we used person-time analyses, days were converted to years and person-years were calcu- lated.
To evaluate effect of age on familial risk, we conducted separate age-stratified familial analyses according to age groups, categorised with 10-year intervals from 0 to 50 years. Appendix S5 shows person-time analysis to demonstrate the age at which each female contributed to the study corresponding to her age.
To examine the association of environmental factors in endometriosis, Cox proportional hazards regression was used and hazard ratios were computed with a 95% CI.
Independent variables were the included environmental risk factors from the NHSP data, and the dependent variable was development of endometriosis. The proportional haz- ard assumption was tested using the Schoenfeld assumption and scaled Schoenfeld residuals. We also assessed the asso- ciation of environmental factors on the risk of endometrio- sis separately in familial and non-familial groups.
Standardised difference was used to compare the distribu- tion of baseline co-variates between familial and non- familial groups and a difference of 0.1 indicated negligible correlation between the group and a given risk factor.
To evaluate the contribution of environmental factors in familial aggregation, we analysed familial risk of endometrio- sis with and without adjustment of environmental risk fac- tors. Using a Cox model, familial risks without adjustments were first obtained, then age-adjusted familial risks were esti- mated. Subsequently, familial risks adjusted for environmen- tal risk factors were calculated. All Cox models were adjusted for clustering effect (Appendix S4). To account for temporal changes in endometriosis incidence, familial risk was
calculated by adding maternal year of birth as a covariate in the models as a surrogate for time periods (Table S3).
We assessed gene–environment interaction between familial risk of endometriosis and smoking, age at menar- che or BMI. We chose these environmental factors based on our risk factor analyses that demonstrated them to be significantly associated with the risk of disease and also from evidence present in the existing literature. Interac- tions were evaluated on an additive scale using risk differ- ence on the assumption that gene–environment are independent in the underlying population. Under the null hypothesis, the risk difference associated with one exposure (e.g. familial risk) is constant across levels of another expo- sure (e.g. smoking) and vice versa. We analysed whether the presence of both family history and a given environ- mental risk factor yielded greater or lesser risk than the sum of independent risks. This was conducted using cate- gorical variables, where each category was coded as a dichotomous variable and four disjoint categories were constructed for combinations of family history and envi- ronmental risk factors. We calculated IRRs with versus without family history and in women with versus without a given environmental risk factor. To calculate the com- bined effect of family history and environmental factor, we estimated IRRs in women with both family history and environmental factor compared with the reference group, defined as siblings with neither factor. Observed combined effects were compared with expected combined effects cal- culated as the sum of the individual effects minus 1. The presence of an interaction having both familial history and environmental risk factors would increase the risk for endometriosis more than expected.
For statistical interaction, the risk difference between family history and a given environmental risk factor was represented by Relative Excess Risk due to Interaction (RERI), Attributable Proportion (AP) and Synergy Index (SI)34 and their respective 95% CIs. In the presence of no interaction, RERI=0, AP= 0 and SI=1 (see Appendix S6 for detail).
All statistical analyses in this study were conducted with STATA/MP 13.1 (Stata Corp, College Station, TX, USA).
Patient and public involvement
We did not directly include patient and public involvement in the analysis of this study, but a committee in the NHI including patient representatives was involved in the study design and structure of our database.
Results
Cohort description
The cohort constructed for this study involved a total of 831 227 female full siblings. Through our familial analyses
we identified 19 195 women who had siblings affected by endometriosis and 2 090 093 women with no affected sib- lings. The demographics are summarised in Table 1. We observed no considerable difference in age, BMI, smoking status, age at menarche, alcohol consumption, physical activity, blood pressure, fasting blood glucose and blood cholesterol between the two groups.
Figure 1(A) shows the association between included environmental risk factors and endometriosis in the total study population, and smoking, early menarche and low BMI were significantly associated with disease development.
The hazard ratios for heavy smokers (≥20 pack-years), early menarche (<14 years) and low BMI (<18.5) were 1.57, 1.36 and 1.13 when non-smokers, delayed menarche (≥17–
25 years) and normal weight group were used as reference, respectively.
Familial risk analyses
Table 2 shows that among women with affected siblings, 1126 developed endometriosis and among those without affected siblings, 41 711 developed the disease with respec- tive incidences of 35.45/10 000 person-years and 11.85/
10 000 person-years. Correspondingly, the familial risk of endometriosis with versus without affected siblings was IRR 2.75 (95% CI 2.25–3.36). When adjusted for environmental risk factors, the slight reduction in risk to IRR 2.79 (95% CI 2.57–3.04) indicated that the attenuation of familial risk was not significant. IRRs for women with affected twins and for women with more than one affected sibling were 6.98 (95%
CI 4.19–11.62) and 8.10 (95% CI 4.59–14.29), respectively.
After adjusting for risk factors, the IRRs reduced to 6.70 (95% CI 4.02–11.17) and 7.87 (95% CI 4.45–13.93), though attenuation was not statistically significant.
Figure 1(B) shows that the familial risk increased with the degree of genetic relatedness and the cumulative inci- dence of endometriosis became more pronounced in women with a family history as time progressed.
There was no difference in familial risk when accounting for temporal changes in endometriosis incidence, which indicates minimal temporal biases over the years of our study (Table S3).
Age-specific familial risk
The familial risks were higher among younger age-groups and gradually declined as age increased (Figure S5). The risk was highest in the 10 to 19 year age-group with IRR 5.45 (95% CI 2.59–10.14). This pattern of age dependence in familial risks was also seen according to family relationships.
Interaction between family history and environmental risk factors
Figure 2 presents the separate and combined risks of family history and smoking, early menarche or low BMI.
Women with both positive family history and smoking, early menarche or low BMI had a significantly increased risk for endometriosis compared with the general popula- tion, with IRRs 4.28 (95% CI 2.43–7.55), 3.47 (95% CI 2.82–4.26) and 3.09 (95% CI 2.68–3.56), respectively.
For smoking and early menarche, the combined risk of family history and either environmental factor exceeded the sum of their individual risks (IRRs 4.28 versus 2.90) and (IRRs 3.47 versus 2.93), respectively. An RERI of 1.38 (95% CI 0.32–1.73) and 0.54 (95% CI 0.15–1.28), an SI of
Table 1.Study population demographics and association of environmental risk factors in endometriosis Demographics and
environmental risk factors
With affected siblings*
Without affected siblings*
Standardised difference
n(%) n(%)
Total number of women 19 195 2 090 093
Year of birth
~1971 1339 (8.15) 170 447 (6.98)
1972–1981 10 067 (39.20) 819 358 (52.45)
1982–1991 7276 (45.36) 948 031 (37.91)
1992–2001 513 (7.28) 152 239 (2.67)
2002–2017 0 (0) 18 (0.00)
Age of menarche (years)
<14 6908 (35.99) 688 995 (32.96)
14–16 6559 (34.17) 654 461 (31.31) 0.13074
≥17–25 486 (2.53) 50 715 (2.43)
Smoking (pack/year)
Non-smoker 16 965 (88.38) 1 812 523 (86.72)
0–9 1337 (6.97) 157 025 (7.51) 0.06014
10–19 86 (0.45) 8813 (0.42)
≥20 18 (0.08) 1674 (0.08)
Body mass index (kg/m2)
<18.5 3342 (17.41) 325 141 (15.56)
18.5–23 11 891 (61.95) 1 289 748 (61.71) 0.06485
23–25 1988 (10.36) 233 831 (11.19)
≥25 1974 (10.28) 241 373 (11.55)
Alcohol consumption
Non-drinker 9554 (49.77) 993 021 (47.51)
<4 servings once 5739 (29.90) 646 082 (30.91) 0.095
<1/week:≥4 servings once 2068 (10.77) 198 255 (9.49)
≥1/week:≥4 servings once 1062 (5.53) 144 343 (6.91)
Physical activity (per week)
≤2 times 16 559 (86.27) 1 764 034 (84.40) 0.06409
≥3 times 1901 (9.90) 220 899 (10.57)
Total blood cholesterol (mg/dl)
<200 14 774 (76.97) 1 580 628 (75.62)
200–239 3249 (16.93) 354 499 (16.96) 0.0863
≥240 681 (3.55) 69 505 (3.33)
Blood pressure (mmHg)
SBP<120 and DBP<80 13 045 (67.96) 1 421 252 (68.00)
SBP 120–130 and DBP<80 1802 (9.39) 200 521 (9.59) 0.01936
SBP 130–140 or DBP 80–90 3855 (20.08) 410 554 (19.64)
SBP 140–180 or DBP 90–120 481 (2.51) 56 711 (2.71)
Fasting blood glucose (mg/dl)
<100 18 607 (96.94) 2 027 734 (97.02)
100–125 428 (2.23) 44 860 (2.15) 0.01098
≥126 160 (0.83) 17 407 (0.83)
DBP, diastolic blood pressure; SBP, systolic blood pressure.
*Includes twin and non-twin female siblings.
1.73 (95% CI 0.44–3.02) and 1.28 (95% CI 0.88–1.67) and an AP greater than zero indicated significant statistical interaction (Table S4). Whereas for low BMI, the combined risk with family history was similar to the sum of individ- ual risks (IRRs 3.09 versus 2.98) with RERI, SI and AP showing a statistically non-interactive relationship.
Environmental risk factor analyses among familial and non-familial groups
Risk factor analyses were performed separately in familial and non-familial groups (Table S5). For smoking and early menarche, which showed a statistical interactive relation- ship with family history, the magnitude of estimated risk
Figure 1. (A) Forest plot demonstrating the association of potential environmental risk factors with the total study population. (B) Cumulative incidence of endometriosis among females with and without affected full siblings. Abbreviations: DBP, diastolic blood pressure; HR, hazard ratio; SBP, systolic blood pressure.
Table 2.Familial risk of endometriosis among full siblings
With affected siblings Without affected
siblings* (reference group)
Total* Non-twins Twins More than one*
Number of females at risk
19 195 17 713 188 168 2 048 382
Number of endometriosis patients
1126 1066 28 32 41 711
Person-years 317 604 310 964 3490 3150 35 208 910
Incidence/104 person-years (95% CI)
35.45 (33.44–37.59) 34.28 (32.28–36.40) 80.23 (55.40–116.20) 101.59 (71.84–143.65) 11.85 (11.73–11.96)
Crude IRRs (95% CI)
2.92 (2.39–3.56) 2.90 (2.67–3.17) 6.85 (4.14–11.34) 8.71 (4.95–15.30) 1.00 IRRs (95% CI)
adjusted for age and clustering
2.75 (2.25–3.36) 2.74 (2.52–2.99) 6.98 (4.19–11.62) 8.10 (4.59–14.29) 1.00
IRRs (95% CI) adjusted for environmental factors
2.79 (2.57–3.04)** 2.70 (2.48–2.94) 6.70 (4.02–11.17) 7.87 (4.45–13.93) 1.00
IRR, incidence risk ratio.
All Cox models have been adjusted for clustering effect.
*Includes twin and non-twin female siblings.
**Added twins as covariate.
on endometriosis was higher in the familial groups com- pared with the non-familial groups.
In the familial group, the hazard ratio for heavier smok- ers (≥20 pack-years) was 3.84 when non-smokers were used as the reference. Whereas in the non-familial group, the corresponding hazard ratio for heavy smokers was compar- atively lower, being 0.83.
Similarly, in the familial group, the hazard ratio for early menarche (<14 years) was 1.77 when delayed age of menarche (≥17–25 years) was the reference, and in the non-familial group, the corresponding hazard ratio for early menarche was comparatively lower, being 1.37.
On the other hand, we did not find significant differ- ences in the hazard ratios for low BMI when normal BMI was used as the reference between the familial and non- familial groups, the corresponding hazard ratios were 1.03 and 1.14.
We performed a stratified analysis on a subgroup of women who were non-smokers, with ordinary age at menarche and normal BMI with versus without affected siblings and found the IRR for family history was 2.71 (95% CI 2.33–3.15) (Table S6).
Discussion Main findings
This large-scale population based-cohort study used the Korean NHI database to follow 831 227 women with full siblings, and quantified a 2.75-fold elevated familial risk of endometriosis among women with versus without affected sisters. This study demonstrated that smoking, early menar- che and low BMI were significantly associated with the risk of developing endometriosis. Women with a positive family history as well as either of these environmental risk factors had a significantly high risk of the disease and can be con- sidered as a high-risk group. For smoking and early menar- che, their combined risks with family history were
markedly higher than the sum of their independent risks, showing statistically significant gene–environment interac- tion, though we did not observe this for low BMI.
Several case–control studies have investigated familial aggregation of endometriosis and reported risks of disease between five- and ten-fold, though these studies did not present risk ratios. Earlier in the 1980s, two US studies19,35 assessed 123 and 491 cases, respectively, and reported 6.9 and 4.9% of proband’s FDR had endometriosis compared with 0.9 and 2% for controls. Subsequent studies con- ducted in Norway10and the UK15comprising 522 and 250 endometriosis cases showed similar findings and reported a familial occurrence of 4.3 and 5.5% versus 0.6 and 0.8% in controls. An Icelandic study7 compared 750 women with matched controls and observed a 5.2-fold risk ratio for female siblings and a study from Japan13 assessing 339 affected females reported a 5.7 relative risk for sisters. In addition, a US study14 that included 485 cohort members showed nearly a ten-fold increased risk of endometriosis among FDR of affected women.
In our study, the familial risk for endometriosis was 2.75-fold, which is relatively lower than previous studies.
When comparing the results of studies, one should acknowledge the difference of study designs and method- ologies used. Previous studies mostly had case–control study designs and it is suggested that case–control studies may yield higher risk estimates even when cases and con- trols are similar in age or family size.36 Also, as previous studies were mostly based on specialised clinics or high- volume centres, they may have included more severe cases than the general population, in contrast our study selected patients from the entire Korean population.
Although previous studies mostly obtained information on kinship and endometriosis diagnoses from interviews or questionnaires that relied on selective recall, we used objective data from the NHI database so as to minimise recall errors.
Figure 2. Separate and joint effects of family history and environmental risk factors on the risk of developing endometriosis. Abbreviations: AP, attributable proportion of endometriosis risk due to interaction between two exposures; BMI, body mass index; IRR, incidence risk ratio; RERI, relative excess risk due to interaction between two exposures (family history and environmental factor); SI, synergy index to assess the type of interaction (synergistic or antagonistic) between two exposures.aEnvironmental risk factors=Smoking, early menarche, low BMI.bReference: Individuals without family history of endometriosis or environmental risk factors.cSeparate effect of a given environmental risk factor: IRR of endometriosis with versus without Smoking or early menarche or low BMI.dSeparate effect of Familial history: IRR of endometriosis with versus without a family history.
eCombined effect of familial history and a given environmental risk factor: IRR of endometriosis with both family history and smoking or early menarche or low BMI versus the reference (group).
Several lines of evidence have suggested that endometrio- sis is associated with a number of risk factors such as reproductive factors, including early menarche, and certain lifestyles and behaviours like alcohol use, BMI and smok- ing; however, the association with some of these risk fac- tors remains controversial.27,28,30,31,37,38
In our study, we found that smoking, early menarche and low BMI were sig- nificantly associated with endometriosis. Though both genetic and shared environmental factors influence the familial risk of a disease, our study suggests that genetic factors are the primary contributor in the familial aggrega- tion of endometriosis. First, we observed that after adjust- ing for risk factors, there was no significant attenuation in the familial risk (from 2.75- to 2.79-fold). Second, the risk increased with the degree of genetic relatedness, being sig- nificantly higher with affected twins compared with non- twins (IRRs 6.98 versus 2.74). We think the twins in this study are mainly monozygotic (≥80%), assuming they included all monozygotic and half of the dizygotic twins, given that the ratio of monozygotic to dizygotic twins in a general population is higher (Appendix S7).
Among the environmental factors analysed in our study, we found that women with both positive family history and smoking, early menarche, or low BMI had a markedly increased risk of endometriosis compared with the general population (Figure 2) and hence can be regarded as high- risk groups who should be considered for genetic risk counselling.
For smoking and early menarche, their combined risks with positive family history exceeded the sum of their indi- vidual risks, suggesting an interactive relationship that was statistically significant (Table S4), although this was not observed for low BMI. These findings implicate that genetic factors and smoking or early menarche potentiate each other’s effects rather than acting independently. In addi- tion, our risk factor analyses (Table S5) showed that the magnitude of association of these two environmental fac- tors was significantly higher in the familial group compared with the non-familial group, which further supports the notion that the impact of smoking and early menarche is selectively sensitive towards genetically predisposed women and that the risk of disease among women with a genetic tendency is exacerbated by the presence of these environ- mental factors. The above observations emphasise the importance of advising women with a familial tendency to avoid high-risk environmental exposures. They could be counselled that staying away from risk factors such as smoking may have an extra risk reduction effect on the prevention of endometriosis.
Interpretation
In women with earlier menarche, early and increased expo- sure to dysregulated inflammatory or angiogenic
mechanisms accompanied by retrograde menstruation2 is widely discussed as a cause of endometriosis.3Additionally, defective inflammation and immunity responses associated with tobacco smoking and altered fat metabolism have also been considered possible causative mechanisms.28,32 Our interaction analyses suggest that in genetically predisposed women, the mechanisms associated with the mentioned environmental factors are perhaps developed to a greater extent or individuals with a genetic susceptibility possibly have a low threshold for these mechanisms.
Limitations
Due to the administrative nature of the data, one may be concerned regarding the validation of endometriosis diagno- sis; however, to maximise diagnostic accuracy we developed case algorithms based on the number of hospital visits and selected a combination of algorithms with the highest speci- ficity and sensitivity. Though we examined the influence of risk factors such as age at menarche, BMI and smoking in estimating the familial risk of endometriosis, other non- genetic factors, such as number of sexual partners and pelvic inflammatory disease, were not investigated. So, there is a chance that familial endometriosis as being genetically inher- ited could have been over-estimated in our study. We did not calculate mother–daughter familial risk because we think a substantial number of cases above the age of 40 might have been missed, possibly because of the abrupt decline of endometriosis NHI utilisation among women>40 years even though they were diagnosed with endometriosis in the NHI.
Conclusion
Currently several genome-wide association studies (GWASs) have identified approximately 15 loci with single-nucleotide polymorphisms (SNP) associated with endometriosis.24,25,39 A meta-analysis of GWASs reported four genetic polymor- phisms associated with both reduced BMI and endometrio- sis40 and in another study a single SNP inMMP1gene has been shown to be related to both endometriosis and smok- ing.41,42 However, genetic studies investigating interactions between specific genes and early menarche, heavy smoking or low BMI are not available, though some research has been done between genes and chemical toxicants.43,44 Therefore, there is a need for further research to discover specific SNPs that interact with these risk factors.
This population-based study demonstrates that genetic factors are the main drivers in the familial aggregation of endometriosis. Although low BMI, smoking and early menarche were significantly associated with the disease, familial risk adjusted for environmental factors showed no significant attenuation, suggesting their limited contribu- tion to familial endometriosis. Significant statistical interac- tion was observed between family history and smoking or
early menarche, suggesting that genetic factors and these risk factors potentiate each other in the pathogenesis of endometriosis rather than acting independently.
Disclosure of interests
None declared. Completed disclosure of interests form available to view online as supporting information.
Contribution to authorship
HJK contributed to the conceptualisation, methodology, software, validation, formal analysis, investigation and visu- alisation; HSL contributed to the writing of the original draft and to formal analysis; SZK contributed to the formal analysis, writing the original draft, review and editing, inves- tigation, project administration, visualisation and supervi- sion; HJH contributed to the methodology, investigation, resources and supervision; TK contributed to the data cura- tion and formal analysis; JC and SC contributed to the investigation and visualisation; HS contributed to reviewing and editing; HK contributed to data curation, formal analysis and investigation; and YSL and HSA contributed to the conceptualisation, funding acquisition, method- ology, project administration, investigation, validation and supervision.
Details of ethics approval
All personal and medical data were protected and kept anonymous. This study was approved by the Korea Univer- sity institutional review board (Approval number – KUIRB-2020-0202-01; date of approval 11 August 2020.
Review type–expedited and exempted from review.
Funding
This study was supported by the research grant of Chung- buk National University in 2014.
Acknowledgements
None.Data availability
The data that support the findings of this study are avail- able from the Korean NHI Service, but restrictions apply to the availability of data, which was used with permission for the current study and therefore not publicly available.
Supporting Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Figure S1.Study flow diagram.
Figure S2. Inclusion of study participants and their fol- low up.
Figure S3. Acquiring risk factor information of study participants.
Figure S4.Time-line graph of the study.
Figure S5. Age-specific familial risks of endometriosis among full siblings.
Table S1. Number of sibships.
Table S2. Sensitivity analysis to assess familial risk of endometriosis including and excluding cases diagnosed before 2002.
Table S3. Familial risk analyses of endometriosis accounting for temporal changes.
Table S4. Joint effect of family history and environmen- tal risk factors on the risk of endometriosis and their statis- tical interaction.
Table S5. Environmental risk factor analyses on endometriosis in familial and non-familial groups.
Table S6. Familial risk of endometriosis among women who were non-smokers, with ordinary age at menarche and normal body mass index.
Appendix S1.Environmental risk factors subgroups.
Appendix S2.Acquiring risk factor information of study participants.
Appendix S3. Verification of identified endometriosis cases.
Appendix S4.Adjusting for clustering.
Appendix S5. Using person-time analysis to demonstrate the age at which each woman contributed to the study cor- responding to her age.
Appendix S6.Interaction analysis.
Appendix S7.Explanation of proportion of monozygotic:
dizygotic twins.&
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