All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Clinical Gastroenterology and Hepatology 2015;-:-–-
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Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease Q28
Louise Emilsson,*,‡ Cisca Wijmenga,§ Joseph A. Murray,k and Jonas F. Ludvigsson¶,# *Primary Care Research Unit, Vårdcentralen Värmlands Nysäter, Värmland County, Sweden; ‡Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; §Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; kDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; ¶Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; #Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
Q8
Q9
Q10 Q11 Q12
BACKGROUND & AIMS:
First-degree relatives of individuals with celiac disease are at increased risk for this disorder, but little is known about their risk for other autoimmune diseases. We assessed the risk of nonceliac autoimmune disease in first-degree relatives and spouses of people with celiac disease.
METHODS:
We identified individuals with celiac disease by searching computerized duodenal and jejunal biopsies, collected from 1969 through 2008, at 28 pathology departments in Sweden. Celiac disease was identified based on biopsy reports of villous atrophy (equal to Marsh grade 3; n [ 29,096). Individuals with celiac disease were matched with up to 5 controls (people without celiac disease) for sex, age, county, and calendar year (total, 144,522 controls). Through Swedish health care registries, we identified all first-degree relatives (fathers, mothers, siblings, and offspring) and spouses of individuals with celiac disease (n [ 84,648) and controls (n [ 430,942). We used Cox regression analysis to calculate hazard ratios (HRs) for nonceliac autoimmune disease (Crohn’s disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or ulcerative colitis) in these groups.
RESULTS:
During the follow-up period (median, 10.8 y), 3333 of the first-degree relatives of patients with celiac disease (3.9%) and 12,860 relatives of controls (3.0%) had an autoimmune disease other than celiac disease. First-degree relatives of people with celiac disease were at increased risk of nonceliac autoimmune disease, compared with controls (HR, 1.28; 95% confidence interval, 1.23–1.33), as were spouses (HR, 1.20; 95% confidence interval, 1.06–1.35). Risk estimates for nonceliac autoimmune disease did not differ between first-degree relatives and spouses of individuals with celiac disease (interaction test: P [ .11). HRs for celiac disease were highest in the first 2 years of follow-up evaluation.
CONCLUSIONS:
First-degree relatives and spouses of individuals with celiac disease are at increased risk of nonceliac autoimmune disease. In addition to genetic factors, environmental factors and ascertainment bias might contribute to the increased risk of autoimmunity in first-degree relatives of individuals with celiac disease.
Keywords: Population Study; Risk Factor; Genetics; Heredity; Celiac; Cohort; Shared Genetics; Autoimmune.
eliac disease (CD) is characterized by an immunemediated response to the intake of gluten, resulting in small intestinal villous atrophy.1 CD affects approximately 1% of the Western population.2 Earlier data suggested a concordance rate in monozygotic twins of approximately 75%, and development of CD is conditional on genetic background.3 CD also has been associated with several autoimmune diseases. Therefore, screening for CD is recommended in individuals with certain diseases, such as type I diabetes mellitus (T1DM) and autoimmune thyroid disease.4 In our recent
C
meta-analysis, approximately 6% of individuals with T1DM had CD, suggesting a more than 5-fold increased relative risk of CD in individuals with T1DM.5 The
Abbreviations used in this paper: CD, celiac disease; CI, confidence interval; FDR, first-degree relative; HR, hazard ratio; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1DM, type I diabetes mellitus; UC, ulcerative colitis. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.01.026
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
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Emilsson et al
Clinical Gastroenterology and Hepatology Vol.
association of CD and T1DM is explained partly by shared HLA genetics,6 and more than 60% of CD-associated loci outside the HLA region identified by genomewide association studies are shared with at least one other autoimmune disease.7 Loci within the HLA region also are shared with thyroid autoimmunity and systemic lupus erythematosus (SLE) and the risk loci outside of the HLA region have been shown to be shared primarily with T1DM, rheumatoid arthritis (RA), Crohn’s disease, and ulcerative colitis (UC).8 The prevalence of CD in first-degree relatives (FDRs) to individuals with CD is approximately 10%.9–11 Despite these findings, little is known about the risk of nonceliac autoimmune disease in FDRs to individuals with CD. One earlier study of 1272 FDRs showed an increased risk of T1DM but not thyroid autoimmunity or RA.12 Another smaller study showed that seemingly some autoimmune diseases were increased in 225 FDRs to CD children.13 However, the statistical power in both earlier studies was limited. Hence, we aimed to assess the risk of several autoimmune diseases in celiac FDRs compared with matched control FDRs (age, sex, county, and calendar year) in a nationwide population-based longitudinal cohort study. We hypothesized that celiac FDRs, in comparison with control FDRs, would have an excess risk of nonceliac autoimmune disease.
Methods Collection of Biopsy Data
Q14
Data regarding CD were collected in 2006 to 2008 through computerized duodenal/jejunal biopsies performed at all Swedish Pathology Departments between 1969 and 2008. CD was defined as having a biopsy specimen classified with villous atrophy equal to histopathology, stage Marsh III,14 with date of first pathologic biopsy as the date of diagnosis and study entry. In total, there were 29,096 celiac individuals identified. Taking small intestinal biopsy samples is the clinical routine in Sweden,15 and more than 95% of individuals with Marsh III changes have CD in a Swedish setting.15
Q15
No.
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First-Degree Relatives and Spouses Through the Swedish Multi-Generation Register18 we obtained data on all FDRs (father, mother, siblings, and offspring) to celiac individuals and controls; from the Total Population Register16 we obtained data on all registered spouses (defined through marriage) (Figure 1). Spouses should represent genetically different individuals sharing the same environment as the celiac/index individuals. Because we did not have access to dates of marriage or lengths of marriage, a person who was at some point married to a person with CD was classified as a spouse. All FDRs and spouses entered the study on the same date of the corresponding index individual’s study entry or at birth, whichever occurred latest (Figure 1). We defined exposure as being a celiac FDR or a celiac spouse. Celiac spouse was defined as a spouse to an individual with CD.
Outcome Measures Different autoimmune diseases, in which either the highest reported prevalence exceeding 50 or reported incidence exceeding 5 per 100,000 individuals in Western countries with a previously reported association to CD, were selected as outcome measures. Included diseases were defined according to relevant International Classification of Diseases codes (Supplementary Table 1). For Addison’s disease, the primary biliary cirrhosis, IgA deficiency, and chronic immune thrombocytopenia purpura prevalence figures were either approximately 15 to 25 per 100,000 individuals or unknown. We therefore calculated the incidence of these diseases in the Swedish Patient Register (containing inpatient and hospital-based outpatient data). Based on earlier data, the incidence in a control population of healthy individuals per 100,000 person-years was 7 for sarcoidosis,19 2 for IgA deficiency,20 1.5 for both Addison’s disease21 and chronic immune thrombocytopenia,22 and 0.3 for primary biliary cirrhosis.23 Given the high relative risk of sarcoidosis in
Reference Individuals: Controls By using the Swedish Total Population Register, all celiac individuals were matched with up to 5 reference individuals (controls) by the government agency Statistics Sweden.16 In all, there were 144,522 controls matched for sex, county, age, and calendar year of birth. All controls entered the study on the same date as their matched celiac individual (the date of positive biopsy). Patients with CD and their matched controls have been described in detail.17 Given the nationwide character of the study any individual selected as a control could have celiac FDRs. In this study about FDRs they were hence counted as control FDRs (with own CD).
-,
Figure 1. Linkage of registries.
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
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233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
Q16
2015
Autoimmunity in Celiac Relatives
CD (hazard ratio [HR], 4.03)19 and its higher incidence, this disease, but not the other 4 diseases, was included in our analysis of FDRs. Because research has shown no association with CD in a Swedish setting, we did not include multiple sclerosis24 and autoimmune hemolytic anemia25 among our outcomes. Furthermore, we did not include polymyalgia rheumatic and pernicious anemia because we found no studies indicating a relationship to CD (Supplementary Table).
Statistical Analyses
Q17
Q18
We used Cox regression to estimate HRs adjusted for sex, age group, calendar year, and own celiac diagnosis in the relative/spouse. Follow-up evaluation started at study entry of the FDRs/spouses and ended at outcome (registration of any autoimmune disease: Crohn’s disease, hypothyroidism, hyperthyroidism, T1DM, psoriasis, RA, sarcoidosis, SLE, or UC), death, emigration, or on December 31, 2009, whichever occurred first (Figure 1). We excluded individuals with any of the earlierdescribed autoimmune diagnoses before study entry. In our main analysis we examined the future risk of all the included nonceliac autoimmune diseases in celiac FDRs together, but we also analyzed the risk stratified by relative (father, mother, sibling, brother, sister, offspring, son, and daughter). In other analyses we examined the risk of each autoimmune disease separately as well as the absolute and excess risk of each of the diseases. Similar analyses were performed for spouses. In secondary analyses we restricted our outcome to those individuals with at least 2 records of autoimmune disease and to those in whom the autoimmune disease had been listed as the main diagnosis. We also analyzed the risk of any autoimmune disease, excluding FDRs who themselves had CD. Autoimmune disease in FDRs and spouses also was examined according to follow-up evaluation (time since the date of diagnosis of the index individual with CD until autoimmune outcome, 2 or >2 y). In an attempt to assess the impact of genetics we used an interaction test to perform an analysis comparing biological FDRs with spouses. Statistical significance was defined as 95% confidence intervals (CIs) for risk estimates not including 1.0. We used SPSS version 21.0 (SPSS, Inc, Chicago, IL) for all analyses.
Results Background Data We obtained data on 84,648 unique celiac FDRs and 430,942 control FDRs (Table 1). The majority of FDRs were male (61.1% in celiac FDRs vs 61.4% in control FDRs), which was expected because most CD patients are female. There were 3333 unique events of any nonceliac autoimmune disease in celiac FDRs compared with
3
Q1
Table 1. Characteristics of Celiac and Control FDRs Celiac FDR Control FDR P N, (%) N, (%) value Total, n Relation Father Mother Sibling Offspring Spouse Sexb Female Male Age group, yb 1939 and earlier 1940–1963 1964–1986 1987–2010 Calendar year at study entryb 1989 and earlier 1990–1999 2000–2010 Celiac disease in the relative Father (to celiac patient) Mother Sibling Offspring Spouse Sex, spouses Female Male Events (any nonceliac autoimmune disease) Father Mother Sibling Offspring Spouse Total unique events Follow-up time, y Median Range
84,648 (100)a 430,942 (100)a
Clinical Gastroenterology and Hepatology 2015;-:-–-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Autoimmune Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease Q28
Louise Emilsson,*,‡ Cisca Wijmenga,§ Joseph A. Murray,k and Jonas F. Ludvigsson¶,# *Primary Care Research Unit, Vårdcentralen Värmlands Nysäter, Värmland County, Sweden; ‡Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; §Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; kDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; ¶Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; #Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
Q8
Q9
Q10 Q11 Q12
BACKGROUND & AIMS:
First-degree relatives of individuals with celiac disease are at increased risk for this disorder, but little is known about their risk for other autoimmune diseases. We assessed the risk of nonceliac autoimmune disease in first-degree relatives and spouses of people with celiac disease.
METHODS:
We identified individuals with celiac disease by searching computerized duodenal and jejunal biopsies, collected from 1969 through 2008, at 28 pathology departments in Sweden. Celiac disease was identified based on biopsy reports of villous atrophy (equal to Marsh grade 3; n [ 29,096). Individuals with celiac disease were matched with up to 5 controls (people without celiac disease) for sex, age, county, and calendar year (total, 144,522 controls). Through Swedish health care registries, we identified all first-degree relatives (fathers, mothers, siblings, and offspring) and spouses of individuals with celiac disease (n [ 84,648) and controls (n [ 430,942). We used Cox regression analysis to calculate hazard ratios (HRs) for nonceliac autoimmune disease (Crohn’s disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or ulcerative colitis) in these groups.
RESULTS:
During the follow-up period (median, 10.8 y), 3333 of the first-degree relatives of patients with celiac disease (3.9%) and 12,860 relatives of controls (3.0%) had an autoimmune disease other than celiac disease. First-degree relatives of people with celiac disease were at increased risk of nonceliac autoimmune disease, compared with controls (HR, 1.28; 95% confidence interval, 1.23–1.33), as were spouses (HR, 1.20; 95% confidence interval, 1.06–1.35). Risk estimates for nonceliac autoimmune disease did not differ between first-degree relatives and spouses of individuals with celiac disease (interaction test: P [ .11). HRs for celiac disease were highest in the first 2 years of follow-up evaluation.
CONCLUSIONS:
First-degree relatives and spouses of individuals with celiac disease are at increased risk of nonceliac autoimmune disease. In addition to genetic factors, environmental factors and ascertainment bias might contribute to the increased risk of autoimmunity in first-degree relatives of individuals with celiac disease.
Keywords: Population Study; Risk Factor; Genetics; Heredity; Celiac; Cohort; Shared Genetics; Autoimmune.
eliac disease (CD) is characterized by an immunemediated response to the intake of gluten, resulting in small intestinal villous atrophy.1 CD affects approximately 1% of the Western population.2 Earlier data suggested a concordance rate in monozygotic twins of approximately 75%, and development of CD is conditional on genetic background.3 CD also has been associated with several autoimmune diseases. Therefore, screening for CD is recommended in individuals with certain diseases, such as type I diabetes mellitus (T1DM) and autoimmune thyroid disease.4 In our recent
C
meta-analysis, approximately 6% of individuals with T1DM had CD, suggesting a more than 5-fold increased relative risk of CD in individuals with T1DM.5 The
Abbreviations used in this paper: CD, celiac disease; CI, confidence interval; FDR, first-degree relative; HR, hazard ratio; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1DM, type I diabetes mellitus; UC, ulcerative colitis. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.01.026
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116
2
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
Q13
Emilsson et al
Clinical Gastroenterology and Hepatology Vol.
association of CD and T1DM is explained partly by shared HLA genetics,6 and more than 60% of CD-associated loci outside the HLA region identified by genomewide association studies are shared with at least one other autoimmune disease.7 Loci within the HLA region also are shared with thyroid autoimmunity and systemic lupus erythematosus (SLE) and the risk loci outside of the HLA region have been shown to be shared primarily with T1DM, rheumatoid arthritis (RA), Crohn’s disease, and ulcerative colitis (UC).8 The prevalence of CD in first-degree relatives (FDRs) to individuals with CD is approximately 10%.9–11 Despite these findings, little is known about the risk of nonceliac autoimmune disease in FDRs to individuals with CD. One earlier study of 1272 FDRs showed an increased risk of T1DM but not thyroid autoimmunity or RA.12 Another smaller study showed that seemingly some autoimmune diseases were increased in 225 FDRs to CD children.13 However, the statistical power in both earlier studies was limited. Hence, we aimed to assess the risk of several autoimmune diseases in celiac FDRs compared with matched control FDRs (age, sex, county, and calendar year) in a nationwide population-based longitudinal cohort study. We hypothesized that celiac FDRs, in comparison with control FDRs, would have an excess risk of nonceliac autoimmune disease.
Methods Collection of Biopsy Data
Q14
Data regarding CD were collected in 2006 to 2008 through computerized duodenal/jejunal biopsies performed at all Swedish Pathology Departments between 1969 and 2008. CD was defined as having a biopsy specimen classified with villous atrophy equal to histopathology, stage Marsh III,14 with date of first pathologic biopsy as the date of diagnosis and study entry. In total, there were 29,096 celiac individuals identified. Taking small intestinal biopsy samples is the clinical routine in Sweden,15 and more than 95% of individuals with Marsh III changes have CD in a Swedish setting.15
Q15
No.
-
First-Degree Relatives and Spouses Through the Swedish Multi-Generation Register18 we obtained data on all FDRs (father, mother, siblings, and offspring) to celiac individuals and controls; from the Total Population Register16 we obtained data on all registered spouses (defined through marriage) (Figure 1). Spouses should represent genetically different individuals sharing the same environment as the celiac/index individuals. Because we did not have access to dates of marriage or lengths of marriage, a person who was at some point married to a person with CD was classified as a spouse. All FDRs and spouses entered the study on the same date of the corresponding index individual’s study entry or at birth, whichever occurred latest (Figure 1). We defined exposure as being a celiac FDR or a celiac spouse. Celiac spouse was defined as a spouse to an individual with CD.
Outcome Measures Different autoimmune diseases, in which either the highest reported prevalence exceeding 50 or reported incidence exceeding 5 per 100,000 individuals in Western countries with a previously reported association to CD, were selected as outcome measures. Included diseases were defined according to relevant International Classification of Diseases codes (Supplementary Table 1). For Addison’s disease, the primary biliary cirrhosis, IgA deficiency, and chronic immune thrombocytopenia purpura prevalence figures were either approximately 15 to 25 per 100,000 individuals or unknown. We therefore calculated the incidence of these diseases in the Swedish Patient Register (containing inpatient and hospital-based outpatient data). Based on earlier data, the incidence in a control population of healthy individuals per 100,000 person-years was 7 for sarcoidosis,19 2 for IgA deficiency,20 1.5 for both Addison’s disease21 and chronic immune thrombocytopenia,22 and 0.3 for primary biliary cirrhosis.23 Given the high relative risk of sarcoidosis in
Reference Individuals: Controls By using the Swedish Total Population Register, all celiac individuals were matched with up to 5 reference individuals (controls) by the government agency Statistics Sweden.16 In all, there were 144,522 controls matched for sex, county, age, and calendar year of birth. All controls entered the study on the same date as their matched celiac individual (the date of positive biopsy). Patients with CD and their matched controls have been described in detail.17 Given the nationwide character of the study any individual selected as a control could have celiac FDRs. In this study about FDRs they were hence counted as control FDRs (with own CD).
-,
Figure 1. Linkage of registries.
FLA 5.2.0 DTD YJCGH54156_proof 20 March 2015 9:05 pm ce DVC
175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
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233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
Q16
2015
Autoimmunity in Celiac Relatives
CD (hazard ratio [HR], 4.03)19 and its higher incidence, this disease, but not the other 4 diseases, was included in our analysis of FDRs. Because research has shown no association with CD in a Swedish setting, we did not include multiple sclerosis24 and autoimmune hemolytic anemia25 among our outcomes. Furthermore, we did not include polymyalgia rheumatic and pernicious anemia because we found no studies indicating a relationship to CD (Supplementary Table).
Statistical Analyses
Q17
Q18
We used Cox regression to estimate HRs adjusted for sex, age group, calendar year, and own celiac diagnosis in the relative/spouse. Follow-up evaluation started at study entry of the FDRs/spouses and ended at outcome (registration of any autoimmune disease: Crohn’s disease, hypothyroidism, hyperthyroidism, T1DM, psoriasis, RA, sarcoidosis, SLE, or UC), death, emigration, or on December 31, 2009, whichever occurred first (Figure 1). We excluded individuals with any of the earlierdescribed autoimmune diagnoses before study entry. In our main analysis we examined the future risk of all the included nonceliac autoimmune diseases in celiac FDRs together, but we also analyzed the risk stratified by relative (father, mother, sibling, brother, sister, offspring, son, and daughter). In other analyses we examined the risk of each autoimmune disease separately as well as the absolute and excess risk of each of the diseases. Similar analyses were performed for spouses. In secondary analyses we restricted our outcome to those individuals with at least 2 records of autoimmune disease and to those in whom the autoimmune disease had been listed as the main diagnosis. We also analyzed the risk of any autoimmune disease, excluding FDRs who themselves had CD. Autoimmune disease in FDRs and spouses also was examined according to follow-up evaluation (time since the date of diagnosis of the index individual with CD until autoimmune outcome, 2 or >2 y). In an attempt to assess the impact of genetics we used an interaction test to perform an analysis comparing biological FDRs with spouses. Statistical significance was defined as 95% confidence intervals (CIs) for risk estimates not including 1.0. We used SPSS version 21.0 (SPSS, Inc, Chicago, IL) for all analyses.
Results Background Data We obtained data on 84,648 unique celiac FDRs and 430,942 control FDRs (Table 1). The majority of FDRs were male (61.1% in celiac FDRs vs 61.4% in control FDRs), which was expected because most CD patients are female. There were 3333 unique events of any nonceliac autoimmune disease in celiac FDRs compared with
3
Q1
Table 1. Characteristics of Celiac and Control FDRs Celiac FDR Control FDR P N, (%) N, (%) value Total, n Relation Father Mother Sibling Offspring Spouse Sexb Female Male Age group, yb 1939 and earlier 1940–1963 1964–1986 1987–2010 Calendar year at study entryb 1989 and earlier 1990–1999 2000–2010 Celiac disease in the relative Father (to celiac patient) Mother Sibling Offspring Spouse Sex, spouses Female Male Events (any nonceliac autoimmune disease) Father Mother Sibling Offspring Spouse Total unique events Follow-up time, y Median Range
84,648 (100)a 430,942 (100)a
