Familial Standardized Incidence Ratios Research Articles

Age- and Gender-Specific Familial Risks for Venous Thromboembolism

Background— This nationwide study sought to determine age- and gender-specific familial risks in siblings hospitalized for venous thromboembolism (VTE). Methods and Results— The Swedish Multigeneration Register on 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the years 1987–2007. Standardized incidence ratios were calculated for individuals whose siblings were hospitalized for VTE compared with those whose siblings were not affected. Among a total of 45 362 hospitalized cases with VTE, 2393 affected siblings were identified, with a familial standardized incidence ratio of 2.45 (95% confidence interval [CI], 1.66 to 3.61). Gender-specific differences in incidence rates were observed. The familial risks were significantly increased from the age of 10 to 69 years, with a familial standardized incidence ratio of 4.77 (95% CI, 1.96 to 10.83) at ages 10 to 19 years, which decreased to 2.08 (95% CI, 1.35 to 3.20) at ages 60 to 69 years, although the absolute risk increased with age. The familial standardized incidence ratios for siblings with 2 and ≥3 affected probands were 51.87 (95% CI, 31.47 to 85.00) and 53.69 (95% CI, 25.59 to 108.50), respectively. Spouses had low familial risks (standardized incidence ratio=1.07; 95% CI, 1.04 to 1.10; observed spouse cases=3900). Conclusions— Familial factors, although influenced by age and gender, are important risk factors for VTE. The present study shows that VTE is aggregated in families and suggests that uncovering the sources of familial aggregation (genetic and nongenetic) may be worthwhile. Moreover, in a small fraction of siblings, the familial risk was very high, suggesting segregation of rare but strong genetic risk factors.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Importance of Family History as a Risk Factor for Venous Thromboembolism

Venous thromboembolism (VTE) is a multifactorial disease with many known genetic and acquired risk factors.1 A positive family history is an independent risk factor for VTE that may reflect the presence of a hereditary thrombophilic disorder. However, the predictive value of a positive family history for detection of known heritable causes of VTE is low,2,3 suggesting that there are as-yet undiscovered genetic or environmental risk factors that account for the familial clustering of this disorder. Article see p 1012 In the current edition of Circulation , Zoller and colleagues4 present the results of their database linkage study that explored the role of family history as a risk factor for VTE. Using unique individual national identifiers to link data from the national Swedish Multigenerational Registry (a family data set that links second-generation Swedes born since 1932 with their siblings) with information from the Swedish Hospital Discharge Register (which contains complete data on all hospital discharge diagnoses since 1986), they identified 45 362 patients hospitalized for deep vein thrombosis, pulmonary embolism, thrombophlebitis (including superficial phlebitis), or thrombosis in unusual sites over a 21-year period. On the basis of results from other population-based epidemiological studies, the reported …

Is gastroschisis truly a sporadic defect? Familial cases of gastroschisis in Utah, 1997 to 2008

Gastroschisis remains an epidemiologic and pathogenetic dilemma, with genetics not thought to play a significant role in its etiology. The purpose of this study was to determine which gastroschisis cases in the Utah Birth Defect Network (UBDN) were related and the excess familial risk among multigenerational families. Gastroschisis cases born from 1997 through 2008 were identified from the statewide population-based UBDN and linked with the Utah Population Database (UPDB) to access multigenerational pedigrees. We analyzed these pedigrees using the familial standardized incidence ratio (FSIR). Of the 284 UBDN gastroschisis cases, one in 40 (n = 7; 2.5%) were reported to have another affected family member. Among these seven cases, three had affected sib pairs and four reported either a distant cousin, paternal uncle, maternal half-uncle, or paternal cousin with gastroschisis. UBDN-UPDB-linked cases resulted in many multigenerational pedigrees with the same affected descendents through marriage. We selected 30 pedigrees for repeated analysis based on two parameters: highest FSIRs with a p ≤ 0.01 and ≥2 cases. In these 30 pedigrees, FSIRs ranged from 3.7 to 93.5 (p < 0.009), each with two to eight distantly related cases (n = 64 distinct cases, representing 23% of the 284). We found a statistically significant excess risk for gastroschisis because of familial factors. Similar to many other birth defects, gastroschisis may fit a multifactorial model of inheritance. The UBDN-UPDB linkage provides a robust approach to investigating genetic factors. Genetic susceptibility should be further investigated because it may have a greater role in the etiology of gastroschisis than currently appreciated.

Familial Clustering of Hemangiomas

To assess the degree of relationship among individuals with hemangiomas and to evaluate the relative risk (RR) for family members of individuals with hemangiomas. Retrospective case-control study. Utah Population Database. Data sets of individuals of different ages with International Classification of Diseases, Ninth Revision (ICD-9) codes for hemangiomas were created from sources having medical records linked to the Utah Population Database. Controls were selected who matched cases for sex, birth year, and birthplace inside vs outside of Utah. Ten controls were selected per case, and sampling was performed without replacement. Kinship analysis tools were used to identify pedigrees having excess individuals with hemangiomas. Using conditional logistic regression analysis, RR for hemangiomas among several kinship classes was determined. Identified were 2514 distinct cases 12 years or younger with ICD-9 code 228.01, and the RR for sibs in this group was significantly increased (RR, 2.52; P<.001). Seventy-three founder families had 5 or more affected descendants with cluster P values≤.01; familial standardized incidence ratios ranged from 1.64 to 9.50. Family sizes ranged from 546 to 22291 descendants. Sibs have increased RR for infantile hemangiomas, suggesting a potential genetic contribution to this likely multifactorial disease. Identification of large families with distantly related individuals will be helpful for future shared segment identification analyses.

Parental history and venous thromboembolism: a nationwide study of age‐specific and sex‐specific familial risks in Sweden

The value of parental history as a risk indicator for venous thromboembolism (VTE) has not been determined in a nationwide setting. To perform the first nationwide study of age-specific and sex-specific familial VTE risks in offspring of parents hospitalized for VTE. The Swedish Multigeneration Register of 0-75-year-old subjects was linked to the Hospital Discharge Register for 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose parents were hospitalized for VTE as compared with those whose parents were unaffected. Among 45,362 hospitalized offspring cases with VTE, 4865 offspring of affected parents were identified with a familial SIR of 2.00 (95% confidence interval [CI] 1.94-2.05). Familial SIR was slightly higher for male offspring than for female offspring (2.08, 95% CI 2.00-2.16 vs. 1.91, 95% CI 1.84-1.99). The risk in offspring was further increased when both parents were affected (3.97, 95% CI 3.40-4.61), with high familial risks at ages 20-29 years (10.00, 95% CI 5.91-15.84). The familial risks for VTE among offspring were increased from the age of 10 years up to 75 years, with familial SIRs of 3.96 (95% CI 3.13-4.94) at age 10-19 years and 1.48 (95% CI 1.17-1.84) at ages 70-75 years. However, the absolute incidence rate increased with age. Parental history is potentially useful for risk assessments of VTE, although age needs to be considered. Our results support the use of an age-dependent multicausal model to estimate the risk of VTE.

Familial Risks in Cancer of Unknown Primary: Tracking the Primary Sites

Cancer of unknown primary (CUP) is diagnosed at the metastatic stage, and despite extensive diagnostic work-up, the primary tumor often remains unidentified. No data are available on familial clustering of CUP. We hypothesize that familial clustering of CUP with other cancers may be informative of the primary sites. A total of 35,168 patients with CUP were identified in the Swedish Family-Cancer Database, and risks between family members were calculated for concordant (CUP-CUP) and discordant (CUP-any other cancer) cancers using standardized incidence ratio (SIR). Familial cases of CUP accounted for 2.8% of all CUP cases in the offspring generation. Familial SIR for CUP was 1.69 when a sibling was diagnosed with CUP. As to discordant associations between siblings, CUP was associated with lung (SIR, 1.87), kidney (SIR, 1.82), liver (SIR, 1.67), ovarian (SIR, 1.45), colorectal (SIR, 1.26), and breast (SIR, 1.15) cancers and melanoma (SIR, 1.26). Upper aerodigestive tract, bladder, pancreatic, and prostate cancers were additionally associated with CUP. Notably, CUP was associated with families of kidney, lung, and colorectal cancers. The present data show that CUP is not a disease of random metastatic cancers but, instead, a disease of a defined set of cancers. The association of CUP with families of kidney, lung, and colorectal cancers suggests a marked genetic basis and shared metastatic mechanisms by many cancer types. Familial sites shared by CUP generally match those arising in tissue-of-origin determinations and, hence, suggest sites of origin for CUP. Mechanistic exploration of CUP may provide insight into defense against primary tumors and the metastatic process.

Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden

This is the first nationwide study to determine familial risks of unusual forms of venous thrombosis amongst offspring of affected parents and amongst siblings. The Swedish Multigeneration Register of 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the period 1987-2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for venous thromboembolism (VTE), as determined by the International Classification of Diseases, compared to those whose relatives were not affected by VTE. The total number of hospitalized patients with VTE was 45 362, of which 1824 (4.0%) were affected by a rare thrombotic condition. The familial SIRs in cases with a history of VTE in parents or siblings were significantly increased for migrating thrombophlebitis (1.81; 95% confidence interval (CI) 1.40-2.31), portal vein thrombosis (2.35; 95% CI 1.77-3.06), vena cava thrombosis (1.96; 95% CI 1.42-2.64) and cerebral venous thrombosis (1.74; 95% CI 1.30-2.28). Budd-Chiari syndrome (SIR, 0.92; 95% CI 0.24-2.38) and renal vein thrombosis (SIR, 1.72; 95% CI 0.62-3.77) were not significantly associated with parental or sibling history of VTE; however, these two conditions were very rare, and therefore, we cannot draw any definite conclusions from this finding. Family history is an important risk factor for most unusual forms of VTE. Moreover, even the paraneoplastic phenomenon, migrating thrombophlebitis (Trousseau's syndrome), is associated with a family history of VTE. Thus, our data suggest that most rare forms of VTE have a familial background.

Inflammatory bowel disease aggregation in Utah kindreds

The observed heritability of inflammatory bowel disease (IBD) is incompletely explained by known genetic risk factors. Kindred-specific genetic variants that cause IBD may be a source of "missing heritability." Given that they have been previously difficult to identify, we sought to identify high-risk IBD kindreds. We used a large population-based database--the Utah Population Database (UPDB)--which contains genealogical and healthcare data to characterize the risk of Crohn's disease (CD), ulcerative colitis (UC), and IBD in kindreds. We identified CD and UC cases using ICD-9 codes. We calculated the adjusted relative risk to relatives of affected individuals. We calculated the familial standardized incidence ratio (FSIR) to quantify the kindred-specific disease risk. In all, 3601 CD cases and 3976 UC cases met inclusion criteria. A total of 655 CD kindreds and 615 UC kindreds had a statistical excess of disease. Risk of disease varied among kindreds, with some kindreds demonstrating ≈ 20-fold elevated risk. For CD, UC, and IBD, relative risks were significantly elevated for first- and second-degree relatives and first cousins. The adjusted population attributable risks for familial CD, UC, and IBD were 0.20 (95% confidence interval [CI]: 0.17-0.23); 0.17 (0.14-0.21); and 0.19 (0.17-0.22), respectively. We identified multiple kindreds with a statistical excess of CD, UC, and IBD, and validated the UPDB as a resource for family studies in IBD. Given the need for novel genetic mapping strategies to explain the apparent missing heritability in IBD, further studies of these high-risk kindreds is justified.

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: A population‐based study

To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was approximately 8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99-3.41], P = 2.42 x 10(-15)) and second-degree relatives (1.48 [95% CI 1.34-2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44-11.83], P = 4.04 x 10(-9)) and second-degree relatives (2.39 [95% CI 1.21-4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04-2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18-1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06-1.35], P = 0.004). These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives.

The epidemiology of Graves' disease: Evidence of a genetic and an environmental contribution

Previous family and twin studies have indicated that Graves' disease has a heritable component. Family studies have also shown that some autoimmune disease cluster in families and genetic studies have been able to show shared susceptibility genes. In the present nation-wide study we describe familial risk for Graves' disease among parents and offspring, singleton siblings, twins and spouses with regard to age of onset, gender and number and type of affected family members. Additionally familial association of Graves' disease with any of 33 other autoimmune and related conditions was analyzed. The Swedish Multigeneration Register on 0–75-year-old subjects was linked to the Hospital Discharge Register from years 1987–2007. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized for Graves' disease compared to those whose relatives were unaffected. The total number of hospitalized Graves' patients was 15,743. Offspring with an affected family member constituted 3.6% of all patients among offspring. The familial SIR was 5.04 for individuals whose sibling was affected but it increased to 310 when two or more siblings were affected; the SIR in twins was 16.45. Familial risks were higher for males than for females. The SIR was increased to 6.22 or 30.20 when parental age was limited to 50 or 20 years, respectively. Graves' disease associated with 19 other autoimmune and related conditions, including Addison's disease, type 1 diabetes mellitus, Hashimoto/hypothyroidism, pernicious anemia, polymyositis/dermatomyositis, myasthenia gravis, discoid lupus erythematosus and localized scleroderma. Remarkably, there was a high disease concordance of 2.75 between spouses. The clustering between spouses suggests environmental effects on Graves' disease which may contribute to the observed gender effects. The demonstrated high risks should be considered in clinical counseling and in prevention plans.

Familial risks of psychotic disorders and schizophrenia among siblings based on hospitalizations in Sweden

Familial risks of psychotic disorders and schizophrenia have been assessed in previous studies. However, the degree of familial clustering in large population datasets remains to be established. We conducted a study on familial risks of psychotic disorders and schizophrenia by linking the Multigeneration Register to the nationwide Swedish Hospital Discharge Register. All patients younger than 72 years hospitalized for psychotic disorders or schizophrenia between 1987 and 2004 were included. Standardized incidence ratios (SIRs) were calculated for individuals with affected singleton siblings, twins or spouses compared with individuals whose siblings or spouses had no hospitalization for psychotic disorders or schizophrenia. A total of 40,228 hospitalized cases were identified of which 3006 were affected sibling pairs. The overall significant familial SIRs were 4.82 for psychotic disorders and 7.34 for schizophrenia. The highest SIRs were found in the younger ages. There were no significant gender differences. The significant SIR for psychotic disorders among twin pairs was 6.40 and the significant SIRs for psychotic disorders among spouses varied between 3.17 and 3.29. Age difference between siblings had no effect on the magnitude of the SIRs. The findings of the present large-scale study suggest that heritable factors have a stronger effect on psychotic disorders and schizophrenia than environmental factors. Future studies could coordinate epidemiological studies of large populations with molecular biology resources.

Familial risks for amyotrophic lateral sclerosis and autoimmune diseases

Population-level familial risks are not available for amyotrophic lateral sclerosis (ALS), and a few studies have analyzed familial association of ALS with other diseases. We used the Swedish Multigeneration Register to identify family members and link them to the Hospital Discharge Register to calculate standardized incidence ratios (SIRs) for familial association in ALS and 33 autoimmune diseases. Among 4,970 ALS patients, familial SIR for offspring of affected parents was 4.71, for singleton siblings, it was 29.83, and for members of multiplex families, it was 1,100; 1.1% of the offspring had an affected parent, and 2.2% an affected sibling. The high risks among siblings without affected parents may suggest recessive inheritance. The SIR for spouse correlation for ALS was 2.35 which may imply the influence of yet unknown environmental factors in ALS susceptibility. ALS associated with Behcet disease, multiple sclerosis, ulcerative colitis, and Wegener granulomatosis; however, chance associations cannot be excluded. In this first population level family study on ALS and 33 autoimmune and related conditions, we found high familial risks depending on the proband. These findings should guide future genomic studies. The high spouse correlation will be a challenge to environmental epidemiology of ALS.

Familial Risks for Hospitalization with Endocrine Diseases

Familial clustering of a disease is an indicator of a possible heritable cause. In the era of genome scans, the consideration of data on heritability should be important in the assessment of the likely success of the scans. The objective of the study was to carry out a family study on nonthyroid endocrine diseases to search familial clustering of these diseases beyond the known syndromes. The Swedish Multigeneration Register on 0- to 72-yr-old subjects was linked to the Hospital Discharge Register from years 1964 to 2004. Standardized incidence ratios were calculated for offspring of affected parents and siblings by comparing with those whose relatives had no hospitalization for nonthyroid endocrine diseases. A total of 11,948 hospitalized cases and 443 familial cases were identified. The familial standardized incidence ratios were increased for parathyroid, pituitary, and adrenal hyperfunctions and hypofunctions, some findings consistent with known syndromes, most clearly that for adrenal cortical hypofunction showing recessive inheritance described for autoimmune polyendocrine syndrome 1. The sibling risks were very high for many diseases, but some of these affecting young individual may be due to bias caused by selective hospitalization. A high sibling risk observed for anterior pituitary hypofunction may represent a yet-unknown recessive syndrome. To our knowledge this is a first population-based study on nonthyroid endocrine diseases. The results call for further studies to sort out the challengingly high sibling risk for many individual nonthyroid endocrine diseases, whether they are due to bias or possible recessive effects.

Familial risks for chronic obstructive pulmonary disease among siblings based on hospitalisations in Sweden

Background:Chronic obstructive pulmonary disease (COPD) is a progressive disabling condition, for which tobacco smoking, environmental pollution, inherited α-antitrypsin deficiency and their interactions are predisposing factors. We carried out a family...

Familial risks for depression among siblings based on hospitalizations in Sweden

Familial risks of depression have been assessed in small case-control studies, usually based on reported, but not medically verified depressions in family members; thus the degree of familial clustering for these diseases remains to be established. We conducted a nationwide study on familial risks of depression linking the Multigeneration Register of 0-72-year-old individuals to the Hospital Discharge Register for diagnosed depression patients in Sweden from 1987 to 2004. Standardized incidence ratios (SIRs) were calculated for affected singleton siblings, twins, and spouses by comparing those whose siblings or spouses had no recorded hospitalization for depression. A total of 60 477 hospitalized cases and 3849 affected siblings were identified with a familial SIR of 2.95, which was independent of sex, age at diagnosis, and age differences between siblings. When both siblings were diagnosed with manic, bipolar, or major depression, the SIRs were 5.87, 10.23, and 2.79, respectively. The SIR for twin pairs was 4.57. The SIR for spouses was 1.76. The significantly higher risk for siblings of depression patients than that for spouses suggests that heritable effects highlight familial susceptibility to this disease. To what extent it also contributes to familial depression remains to be established. The anticipated gene-environment interactions with sufficient sample sizes needs to be accommodated in future etiological studies on depression.

Quantification of the Familial Contribution to Müllerian Anomalies

To quantify the familial contribution to müllerian anomalies and determine a possible inheritance pattern. Cases of müllerian anomalies, identified by International Classification of Diseases and Current Procedural Terminology codes from January 1994 to March 2006, were collected from the largest hospital systems in the state of Utah. All records were subsequently matched to the Utah Population Database. Controls for this data set were randomly selected and matched based on birth year and gender. Highly specialized software "Kinship Analysis Tools (KAT)" was used for kinship analysis. A total of 1,397 cases qualified for the final analysis. The kinship analysis tool identified 27 family clusters. The mean familial standardized incidence ratio was 3.43(P<.01). Using the adjusted "Population Attributable Risk," approximately 10% of cases of müllerian anomalies appear to be attributable to a familial association. The relative risk for müllerian anomalies in each class of kinship was as follows: first-degree relatives 11.6 (95% confidence interval [CI] 5.42-24.82), parents/children 8.78 (95% CI 2.26-34.16), siblings 12.98 (95% CI 5.17-32.62), first cousins 1.44 (95% CI 0.76-2.76), and second cousins 1.30 (95% CI 0.96-1.77). Müllerian anomalies have a strong familial aggregation and follow a polygenic and multifactorial inheritance. II.

Age-specific familial risks of depression: A nation-wide epidemiological study from Sweden

Objective Familial risks of depression have been assessed in small case-control studies, usually based on reported, but not medically verified, depressions in family members; thus the degree of familial clustering of these diseases remains to be established. Methods The Multigeneration Register, in which all men and women born in Sweden from 1932 onward are registered together with their parents, was linked to hospital admission data. Standardized incidence ratios (SIRs) were calculated as the ratio of the observed to the expected number of cases in men and women with mothers or fathers affected by depression, compared with men and women whose mothers or fathers were not affected by depression. Results A total of respectively 60,477 and 79,969 depressions were recorded in offspring and parents. In 6.44% of all families, an offspring and a parent were affected, giving a population-attributable proportion of 4.04% and a familial SIR of 2.68. The parental transmission of depression was similar for both men and women (2.72 and 2.66). Conclusions This study has provided the first data on age-specific familial clustering of depressions, based on medically confirmed records. The risks were so high that hereditary factors were considered to be likely to contribute to depression, possibly modified by environmental factors. Age-specific risk tables would be helpful for clinical counseling.

Familial risks for asthma among twins and other siblings based on hospitalizations in Sweden

Asthma is a common disabling condition, with known environmental and familial risk factors and with their assumed interactions. We wanted to carry out a family study on asthma to address gene-environment interactions at a population level. We conducted a nation-wide study on familial risks for asthma. An asthma database was constructed by linking the Multigeneration Register on 0-72-year-old subjects to the Hospital Discharge Register for diagnosed asthma cases in Sweden from years 1987 to 2004. Standardized incidence ratios (SIRs) were calculated for affected singleton siblings, twins and spouses by comparing with those whose siblings or spouses had no asthma. A total of 67 370 hospitalized cases and 5638 affected siblings were identified with a familial SIR of 3.70, which was independent of sex, diagnostic age and age differences between the siblings. The SIR for different-sex twins was 5.17 and for same-sex twins it was 13.38. There was a low correlation between spouses for asthma. Asthma shows a higher familial risk than many common diseases. The higher difference in familial excess risk between singleton siblings and different-sex twins provides strong genetic epidemiological evidence for gene-environment interactions in asthma. The concept of gene-environment interactions needs to be accommodated in future aetiological studies on asthma. Data on environmental factors and family history are important for clinical risk estimation.

Familial risk for gastric carcinoma: an updated study from Sweden

Reliable data on familial risks are important for clinical counselling and cancer genetics. However, the estimates of familial risk of gastric cancer vary widely. We examined the risk of familial gastric cancer using the updated Swedish Family-Cancer Database with 5358 patients among offspring and 36 486 patients among parents. There were 133 families with one parent and one offspring diagnosed with gastric cancer, and 20 families with two affected offspring. Familial standardised incidence ratios (SIRs) were 1.63 and 2.93 when parents and siblings presented with gastric cancer, respectively. The high sibling risk was owing to cancer in the corpus (SIR 7.28). The SIR for cardia cancer was 1.54 when parents were diagnosed with any gastric cancer. Cardia cancer associated with oesophageal cancer, particularly with oesophageal adenocarcinoma. Among specific histologies, signet ring cancer showed an increase. A few associations were noted for discordant sites, including the urinary bladder and the endometrium. H. pylori infection, although not measured in the present study, is probably an important risk factor for the high sibling risk of corpus cancer. Familial clustering of cardia cancer is independent of H. pylori infection, and may have a genetic basis. The familial association of cardia cancer with oesophageal adenocarcinoma may provide aetiological clues.