Familial Standardized Incidence Ratios Research Articles

A Familial Analysis of Neurosarcoidosis Utilizing the Utah Population Database (P9-5.008)

<h3>Objective:</h3> To investigate for evidence of familial clustering within a large cohort of patients with Neurosarcoidosis utilizing the Utah Population Database. <h3>Background:</h3> Sarcoidosis is a multisystemic inflammatory disease that can affect the cardiac, integumentary, hepatic, renal, ocular, and neurologic systems. Neurologic manifestations include cranial neuropathies, meningitis, peripheral neuropathy, myelopathy, intraparenchymal mass lesions. Current evidence suggests familial clustering of sarcoidosis in Sweden as well as within the US Black population. Genes of interest include HLA-DP subregions, Annexin A11, Butyrophilinlike 2 gene, and Toll-like receptors. We investigated for evidence of shared genetics among our Intermountain West cohort of neurosarcoidosis patients. <h3>Design/Methods:</h3> We performed a retrospective review of all definite and probable neurosarcoidosis patients diagnosed and managed at our institution. Using the Utah Population Database (UPDB), a population-based genealogic resource containing medical and demographic information of over 11 million individuals, we identified high-risk pedigrees with excess familial aggregation of neurosarcoidosis using the Familial Standardized Incidence Ratio (FSIR). Unaffected subjects were identified and matched 10:1 to neurosarcoidosis patients by age, birth year, and pedigree structure in the UPDB. Familial risk analyses were performed to estimate the heritability of neurosarcoidosis FDRs, SDRs, and TDRs separately using multivariate logistic regression adjusting for sex, birth year, race, and ethnicity. <h3>Results:</h3> Out of the 54 patients in the cohort, the median age of patients was 63 years (SD 12 years), 36(66%) were female and 46 (85%) self-identified as Caucasian. A total of 12 (22%) had definite neurosarcoidosis and 42 (78%) had probable neurosarcoidosis. The initial symptom of sarcoidosis was neurologic in 34 (63%) of the patients. We studied the inter-relatedness of the patients with neurosarcoidosis. <h3>Conclusions:</h3> Neurosarcoidosis is a rare disease and thought to be a manifestation of a multisystem disease in which familial clustering and genetic analysis suggests that inherited factors play a role in the pathogenesis which requires further investigation. <b>Disclosure:</b> Dr. Crane has nothing to disclose. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon. Mr. Yu has nothing to disclose. Ms. Date has stock in Astrazeneca. Mr. Madsen has nothing to disclose. Ms. Fraser has nothing to disclose. Mr. Wong has nothing to disclose. Dr. Lord has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Clardy has received personal compensation for serving as an employee of Veterans Health Administration (VHA). Dr. Clardy has received personal compensation for serving as an employee of University of Utah Health. Dr. Clardy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology/AAN Publications. The institution of Dr. Clardy has received research support from Sumaira Foundation for NMO. The institution of Dr. Clardy has received research support from Western Institute for Veteran Research. The institution of Dr. Clardy has received research support from NIH/NINDS. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a AAN Summer Meeting CoDirector Travel and Lodging with AAN. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Grand Rounds Travel and Lodging with U of Iowa. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Barrow Neurological Institute. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Beaumont Health.

PD18-02 DESCRIBING PATTERNS OF FAMILIAL CANCER RISK IN SUBFERTILE MEN USING POPULATION PEDIGREE DATA

You have accessJournal of UrologyCME1 Apr 2023PD18-02 DESCRIBING PATTERNS OF FAMILIAL CANCER RISK IN SUBFERTILE MEN USING POPULATION PEDIGREE DATA Joemy Ramsay, Joshua Horns, Benjamin Emery, Kenneth Aston, and James Hotaling Joemy RamsayJoemy Ramsay More articles by this author , Joshua HornsJoshua Horns More articles by this author , Benjamin EmeryBenjamin Emery More articles by this author , Kenneth AstonKenneth Aston More articles by this author , and James HotalingJames Hotaling More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003273.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Subfertile men and their relatives show increased risk for certain cancers including testis, pediatric leukemia/lymphoma, thyroid, and prostate. We assessed risk for multiple cancers simultaneously to identify distinct familial multicancer patterns (FMPs) in azoospermic and oligozoospermic men. METHODS: We identified azoospermic (N=809) and oligozoospermic (N=669) men in the Subfertility, Health and Assisted Reproduction (SHARE) cohort and their family members out to third-degree relatives (azoo: N=27,148; oligo: N=23,626). Cancer cases were identified using the Utah Cancer Registry, a population-based SEER registry with statewide cancer records from 1966. Families with ≥10 individuals who lived in Utah for ≥1 year 1966-2017 were included in the analysis (azoo: N=426 families, 21,361 individuals; oligo: N=360 families, 18,818 individuals). The famcluster R package was used to cluster families on familial standardized incidence ratios (FSIRs). FSIRs were calculated across 34 cancer types and a weighted Gower distance with k-mediods clustering (k=2:20) was used to identify FMPs. k was selected using silhouette plots and consensus clusters with 1,000 bootstrap replicates. FMPs were assessed separately for azoospermia and oligospermia families. RESULTS: 13 FMPs were identified in azoospermia families and 12 FMPs in oligozoospermia families. Distinct overall patterns of familial cancer were observed between azoospermia and oligozoospermia families (Table 1). 12 out of 13 FMPs (36% of families) showed significantly increased risk for ≥1 cancer in azoospermia families and 11 out of 12 FMPs (40% of the families) showed significantly increased cancer risk in oligozoospermia families (Figure 1). CONCLUSIONS: This analysis described FMPs for subfertile men, with 36-40% of families showing elevated risk for ≥1 cancer. FMPs were unique between azoospermia and oligozoospermia families, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. Source of Funding: GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health NICHD: R01 HD106112 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e502 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joemy Ramsay More articles by this author Joshua Horns More articles by this author Benjamin Emery More articles by this author Kenneth Aston More articles by this author James Hotaling More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract 30: A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database

Abstract Introduction: Genetic risk variants are critical to risk prediction for invasive epithelial ovarian cancer (EOC), yet an estimated 50-55% of EOC heritability remains missing. Novel approaches to risk variant discovery are needed to detect variants that have not been uncovered by linkage analysis or genome-wide association studies (GWAS). We approach risk variant discovery using Shared Genomic Segment analysis (SGS), a novel statistical genetics method that enables risk variant discovery in extended high-risk pedigrees. Methods: The Utah Population Database (UPDB) is a population-based resource of over ten million individuals connected to the state of Utah, five million of whom are linked to a minimum of three generations of genealogy data. By linking this genealogy data with cancer data from the Utah Cancer Registry, we identified pedigrees with an excess risk of EOC. We generated germline genotyping data from cases (diagnosed 1983-2018) in a subset of these high-risk pedigrees, focusing on pedigrees well-suited for SGS (i.e., at least 3 cases separated by a total of at least 12 meioses). SGS identifies all runs of consecutive alleles that are shared identical-by-state by cases in a pedigree and determines which of these genomic segments are longer than would be expected by chance. These long segments are likely to be identical-by-descent, inherited from a common founder, and may harbor risk variants. Results: We successfully linked UPDB genealogy data to information from the Utah Cancer Registry to identify approximately 2,000 extended high-risk pedigrees with ≥5 ovarian cancer cases, an average of 7-10 meioses between pairs cases, and a statistically significant excess risk of ovarian cancer (α=0.05). We obtained biospecimens for 141 cases in 36 of the most promising pedigrees (i.e., high familial standardized incidence ratio, p-value&amp;lt;0.005, not attributable to known risk variants in BRCA1 or BRCA2 as observed in first-, second- or third-degree relatives of EOC cases). We genotyped 96 out of the 141 cases in these pedigrees (68%). SGS analyses to identify genomic regions that may harbor risk variants are currently underway. Conclusions: Using pedigrees identified in the UPBD, SGS has identified risk loci and novel risk variants for a number of diseases, including breast and hematologic cancers. We have identified a set of EOC high-risk pedigrees for SGS analysis and will leverage SGS to identify genomic regions that may harbor EOC risk variants. Citation Format: Mollie E. Barnard, Robert Sargent, G. Bryce Christensen, Bonita A. Mahaffey, James Albro, Elke A. Jarboe, Terence Rhodes, Nicola J. Camp, Jennifer A. Doherty. A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 30.

Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country.

Simple SummaryFamilial risk of cancer implies that two or more family members are diagnosed with the same cancer. This may be due to the genes or environmental factors that family members share. Familial risk for liver and gallbladder cancer is about 2.7 which means that when one family member is diagnosed with these cancers other family members have 2.7 times higher risk of being diagnosed with the same cancers compared to families were no member is yet diagnosed with these cancers. Risk between spouses is entirely due to shared environmental factors and for liver cancer there is a small risk. The most important way to prevent these cancers is to avoid their risk factors, alcohol, smoking and overweight, and to seek medical care for diabetes and liver infections.We used the Swedish Cancer Registry data to address familial risks for concordant (same) and discordant (different) hepatobiliary cancers, including their associations with any other cancers and with known risk factors. Risks were also assessed between spouses. The analysis covered Swedish families and their cancers between years 1958 and 2018. Adjusted familial risks were expressed as standardized incidence ratios (SIRs). Familial SIRs for concordant hepatocellular carcinoma (HCC) were 2.60, and for gallbladder cancer they were at the same level (2.76). Familial risk was also found for intrahepatic bile duct cancer and for female extrahepatic bile duct cancer. HCC was associated with lung and cervical cancers; extrahepatic bile duct and ampullary cancers were associated with colon and pancreatic cancers, suggesting Lynch syndrome. Among spouses, hepatobiliary cancer was associated with HCC, stomach, pancreatic, cervical and upper aerodigestive tract cancers. Among risk factors, family members diagnosed with alcohol-related disease showed association with HCC. The observed familial risks for hepatobiliary cancers were relatively high, and considering the poor prognosis of these cancers, prevention is of the utmost importance and should focus on moderation of alcohol consumption, vaccination/treatment of hepatitis viral infections and avoidance of overweight and other risk factors of type 2 diabetes.

Family History of Head and Neck Cancers.

Simple SummaryHead and neck cancers are cancers that arise between the mouth and larynx. Risk factors for these include smoking, alcohol, human papilloma virus (HPV) infection and family history. Because families can be identified for the whole Swedish population, we wanted to analyzed familial risks for HNC with same and different cancers among first-degree relatives. When a parent or sibling was diagnosed with HNC, other family members had a two-fold risk of being diagnosed with HNC, but the risk was higher when specific types of HNC, such as oral or nasopharyngeal cancers, were analyzed. Husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer which may be related to shared HPV infection. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination.Background: Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) infection, may contribute is not well established. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for HNC with same (concordant) and different (discordant) cancers among first-degree relatives using data from the Swedish Cancer Registry from 1958 to 2018. Results: Incidence for male and female oropharyngeal cancer increased close to four-fold in the past 39 years. Familial HNC was found in 3.4% of the study population, with an overall familial SIR of 1.78. Patients with concordant nasopharyngeal cancer showed a high risk of 23.97, followed by hypopharyngeal cancer (5.43). The husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer. Discussion/Conclusion: Nasopharyngeal cancers lacked associations with lifestyle or HPV associated cancers, suggesting a role for germline genetics, which was also true for the high-risk families of three HNC patients. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination.

RARE-24. IDENTIFYING INDIVIDUALS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS AT RISK FOR HEREDITARY CANCER SYNDROMES USING THE UTAH POPULATION DATABASE

BackgroundCNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. MethodsWe queried the UPDB for individuals ages 0–39 diagnosed with a primary CNS tumor (malignant and benign) between 1966–2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. ResultsWe identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P<0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3–6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n=2), von Hippel-Lindau (n=1), and rhabdoid tumor predisposition (n=1). ConclusionThe UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening.

Identifying individuals with primary central nervous system tumors at risk for hereditary cancer syndromes using the Utah Population Database.

10532 Background: CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. Early identification of HCSs results in improved cancer surveillance and outcomes, reducing the impact of CNS tumors in children. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. Methods: We queried the UPDB for individuals ages 0-39 diagnosed with a primary CNS tumor (malignant and benign) between 1966-2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. Results: We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P&lt; 0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3-6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n = 2), von Hippel-Lindau (n = 1), and rhabdoid tumor predisposition (n = 1). Conclusions: The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening and to always consider workup for associated HCSs.

1036 Familial aggregation of stillbirth

Stillbirth occurs in 1 out of every 168 pregnancies and accounts for 60% of perinatal deaths in the U.S. Prior studies assessed mother-daughter inherited predisposition to stillbirth and miscarriage but found little to no evidence of risk transmission. We conducted a retrospective cohort study to determine the familial aggregation and high-risk extended pedigrees of stillbirth. We utilized the Utah Population Database (UPDB), a population-based genealogy linked with state fetal death record database to identify mothers who suffered stillbirth between 1978 and 2018. The pedigrees of related family members were determined to identify the first-degree (father, mother and full-siblings), second-degree (grandparents, aunts/uncles, and nieces/nephews) and third-degree (first cousins) relatives of the affected mothers (probands). High-risk pedigrees with excess clustering of stillbirth were identified using the Familial Standardized Incidence Ratio (FSIR), which compares the incidence of stillbirth in a family to its expected incidence in the UPDB population. Mothers with stillbirth (N=7756) and their first-, second-, and third-degree relatives (n=391,797) were identified (Table 1 and Table 2). High-risk pedigrees (n=197) with excess clustering of stillbirth (FSIR ≥ 2; P-value < 0.05; Observed stillbirths ≥ 10) were identified for mothers (probands; n=1764 [22.7%]). Table 1 shows the top 10 high-risk pedigrees with statistically significant evidence for familial aggregation of stillbirth. Stillbirth persisted among 2nd degree relatives (0.34%) and 3rd degree relatives (0.38%) (Table 2). Familial aggregation of stillbirth occurs and is present in 22.7% of women with stillbirth. Stillbirth persisted in more distant relatives, which may further support a heritable or genetic contribution, as environmental exposures in distant relatives are expected to be randomly distributed compared with a proband’s exposures. Future studies should examine genetic variants in these high-risk families to identify de novo and inherited genes associated with stillbirth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort.

Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA. Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models. We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05). Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression.

Familial risks between giant cell arteritis and Takayasu arteritis and other autoimmune diseases in the population of Sweden

Giant cell arteritis (GCA, also called temporal arteritis) is a rare and Takayasu arteritis (TA) is an even rarer autoimmune disease (AID), both of which present with inflammatory vasculitis of large and medium size arteries. The risk factors are largely undefined but disease susceptibility has been associated with human leukocyte antigen locus. Population-level familial risk is not known. In the present nation-wide study we describe familial risk for GCA and for GCA and TA with any other AID based on the Swedish hospital diagnoses up to years 2012. Family relationships were obtained from the Multigeneration Register. Familial standardized incidence ratios (SIRs) were calculated for offspring whose parents or siblings were diagnosed with GCA, TA or any other AID. The number of GCA patients in the offspring generation was 4695, compared to 209 TA patients; for both, familial patients accounted for 1% of all patients. The familial risk for GCA was 2.14, 2.40 for women and non-significant for men. GCA was associated with 10 other AIDs and TA was associated with 6 other AIDs; both shared associations with polymyalgia rheumatica and rheumatoid arthritis. The results showed that family history is a risk factor for GCA. Significant familial associations of both GCA and TA with such a number of other AIDs provide evidence for polyautoimmunity among these diseases.

Familial associations between autoimmune hepatitis and primary biliary cholangitis and other autoimmune diseases.

Autoimmune hepatitis (AH) and primary biliary cirrhosis (PBC) are autoimmune diseases (AIDs) targeting cellular components of the liver. Being rare diseases, limited data are available about familial risks among these AIDs (concordant) or between them and other AIDs (discordant). We aimed to carry out an unbiased study on these AIDs based on medically diagnosed patients.We collected data on patients diagnosed in Swedish hospitals with AH, PBC and other AIDs and calculated familial standardized incidence ratios (SIRs) for concordant and discordant familial relative risks. The number of AH patients was 6,269, of whom 43.0% were male; patient numbers for PBC were 4,269, with 17.8% males. AH accounted for 0.8% and 0.6% of all hospitalized AIDs in Sweden. For AH only the familial risk between siblings was significant (3.83). For PBC the risks for offspring of parents (9.05) and siblings (10.88) were high, but only risk for females was significant. Spousal risks were very high, 5.91 and 6.07 for AH. Risk for AH was 2.21 in families of PBC, and it was 2.47 for PBC in families of AH patients. Among other AIDs, 14 showed a significant association with AH, compared to 16 AIDs with PBC. The surprising finding in this nation-wide family study on medically diagnosed patients was the high risk for AH (6.0) between spouses, which exceed the risk between siblings, suggesting the existence of strong environmental risk factors. AH and PBC were associated with multiple other AIDs. The results call attention to environmental factors in AID etiology which should also be in focus in taking anamnestic data from patients.

Familial associations for rheumatoid autoimmune diseases.

ObjectivePrevious studies have shown a familial component in RA and in some other rheumatic autoimmune diseases (RAIDs), but because of the different study designs the risk estimates for familial risks differ extensively. The objective of this study is to identify familial components for RAIDs.MethodsWe collected data on patients diagnosed in Swedish hospitals with RA, AS, PM/DM, SS, SLE and SSc (and scleroderma) and calculated familial standardized incidence ratios (SIRs) for each of these (concordant) and between them (discordant).ResultsThe combined number of RAID patients in the offspring population (for whom SIRs were calculated) was 71 544, and in the whole population the number was 152 714, accounting for 19.8% of all autoimmune diseases in Sweden. AS showed the highest concordant familial risk of 18.42, followed by SLE (14.04), SS (8.63), SSc (4.50), PM/DM (4.03) and RA (3.03). There was no sex difference in SIRs. Risks for AS and SLE were 80.28 and 19.53 for persons whose parents and siblings were affected. Discordant risks were far lower than concordant risks, but they were significant for RA with all the other five RAIDs, for SLE and SSc with four RAIDs, for AS and SS with three RAIDs and for PM/DM with two RAIDs, attesting to extensive polyautoimmunity between RAIDs.ConclusionThe derived familial risks in this nationwide family study on medically diagnosed RAID are compatible with emerging evidence on the polygenic background of these complex diseases. Novel genetic pathways offer new therapeutic targets that alleviate disease onset optimally in high-risk familial patients and others.

Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden

Genetic and family studies have indicated that Graves disease and Hashimoto thyroiditis have a heritable component which appears to be shared to some extend also with some other autoimmune diseases (AIDs). In the present nation-wide study we describe familial risk for Graves disease and Hashimoto thyroiditis identified from the Swedish Hospital Discharge Register (years 1964 through 2012) and the Outpatient Register (2001 through 2012). Family relationships were obtained from the Multigeneration Register and cancers from the Cancer Registry. Familial standardized incidence ratios (SIRs) were calculated for 29,005 offspring with Graves disease and for 25,607 offspring with Hashimoto thyroiditis depending on any of 43 AIDs in parents or siblings. The concordant familial risks for Graves disease and Hashimoto thyroiditis were 3.85 and 4.75, higher for men than for women. The familial risks were very high (11.35, Graves and 22.06, Hashimoto) when both a parent and a sibling were affected. Spousal familial risks were higher for Hashimoto thyroiditis (1.98/1.93) than for Graves disease (1.48/1.50). For Graves disease, 24 discordant AIDs showed a significant association; for Hashimoto thyroiditis, 20 discordant associations were significant. All significant discordant associations were positive for the two thyroid AIDs, with the exception of Hashimoto thyroiditis with Reiter disease. Overall 8 associations were significant only for Graves disease and 6 Hashimoto thyroiditis. The overall high concordant familial risks for Graves disease and Hashimoto thyroiditis suggest a strong genetic contribution to the familial risk. Significant familial associations among more than half of the 43 AIDs attest to the extensive polyautoimmunity among thyroid AIDs.

Familial risks in urolithiasis in the population of Sweden.

To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records. Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL. The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk. The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL.

Familial Clustering Identified in Periprosthetic Joint Infection Following Primary Total Joint Arthroplasty: A Population-Based Cohort Study.

It is estimated that the cost to treat periprosthetic joint infection in the United States will approach $1.62 billion by 2020. Thus, the need to better understand the pathogenesis of periprosthetic joint infection is evident. We performed a population-based, retrospective cohort study to determine if familial clustering of periprosthetic joint infection was observed. Analyses were conducted using software developed at the Utah Population Database (UPDB) in conjunction with the software package R. The cohort was obtained by querying the UPDB for all patients undergoing total joint arthroplasty and for those patients who had subsequent periprosthetic joint infection. The magnitude of familial risk was estimated by hazard ratios (HRs) from Cox regression models to assess the relative risk of periprosthetic joint infection in relatives and spouses. Using percentiles for age strata, we adjusted for sex, body mass index (BMI) of ≥30 kg/m, and a history of smoking, diabetes, and/or end-stage renal disease. Additionally, we identified families with excess clustering of periprosthetic joint infection above that expected in the population using the familial standardized incidence ratio. A total of 66,985 patients underwent total joint arthroplasty and 1,530 patients (2.3%) had a periprosthetic joint infection. The risk of periprosthetic joint infection following total joint arthroplasty was elevated in first-degree relatives (HR, 2.16 [95% confidence interval (CI), 1.29 to 3.59]) and combined first and second-degree relatives (HR, 1.79 [95% CI, 1.22 to 2.62]). Further, 116 high-risk pedigrees with a familial standardized incidence ratio of >2 and a p value of <0.05 were identified and 9 were selected for genotyping studies based on the observed periprosthetic joint infection/total joint arthroplasty ratio and visual inspection of the pedigrees for lack of excessive comorbidities. Although preliminary, these data may help to guide further genetic research associated with periprosthetic joint infections. An understanding of familial risks could lead to new discoveries in creating patient-centered pathways for infection prevention in patients at risk. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Parental influence on systemic sclerosis.

To examine parental influence on the development of systemic sclerosis (SSc; scleroderma). We designed 3 studies: mitochondrial inheritance, birth order (a possible surrogate marker for microchimerism), and paternal age at conception (a possible surrogate for telomere erosion) to examine their association with development of SSc. SSc was defined by International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 710.1 and ICD 10 M34.0, M34.1, and M34.9) and identified from statewide discharge data, University of Utah Health Science Center Enterprise Data Warehouse (UUHSC), and death certificates that were linked to the Utah Population Database (UPDB) for analysis. Mitochondrial inheritance was evaluated by conditional logistic regression and population attributable risk using familial standardized incidence ratio as the covariate. Chi-square test and logistic regression were used to evaluate birth order and maternal/paternal age at conception of the SSc proband. We found 1,947 unique SSc patients from UUHSC and UPDB. We selected 5 controls per case (n = 9,115), matched by birth year and sex. Mitochondrial inheritance analysis indicated no evidence to suggest SSc was associated with mitochondrial inheritance. Birth order and maternal/paternal age at conception analysis results show that they also do not significantly affect SSc development. Results suggest that although heritable risk of SSc is observed, mitochondrial inheritance, birth order, and parental age are not likely responsible for pathogenesis.

Family history as a predictor of hospitalization for hypertension in Sweden

Hypertension clusters in families. However, no nationwide study has investigated the family history as a predictor of hospitalization for hypertension, which was the purpose of this study. The study is a nationwide follow-up study. Swedish Multigeneration Register data for individuals aged 0-76 years were linked to Hospital Discharge Register data for 1964-2008. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were hospitalized with a main diagnosis of hypertension compared with those whose relatives were not. The total number of patients hospitalized with hypertension was 37,686. The familial SIR was 2.18 for individuals with one affected sibling, 44.83 for individuals with two affected siblings and 57.18 for individuals with three or more affected siblings. The SIR was 1.95 for parents with one affected child, 3.73 for parents with two affected children and 9.22 for parents with three or more affected children. The familial SIR among offspring was 1.84 for those with one affected parent and 3.62 for those with two affected parents. The familial risk for hospitalization with hypertension among offspring aged less than 30 years was 2.50 and 1.57 in those aged more than 60 years. Familial risks were similar for men and women. Spouses had low overall familial risks (SIR=1.2). Hospitalization for hypertension clusters in families. Very high risks were observed in families with multiple affected siblings, though the parent-offspring transmission was lower, suggesting the segregation of recessive or interacting susceptibility genes. The low familial risk in spouses suggests a minor nongenetic contribution.

Shared and Nonshared Familial Susceptibility to Surgically Treated Inguinal Hernia, Femoral Hernia, Incisional Hernia, Epigastric Hernia, and Umbilical Hernia

The familial risk of abdominal wall hernia (AWH) is largely unknown. In addition, it is unknown whether inguinal hernia (IH), femoral hernia (FH), incisional hernia (INH), epigastric hernia (EH), and umbilical hernia (UH) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant AWH (same disease in proband and exposed relative) and discordant AWH (different disease in proband and exposed relative). Data from the Swedish Multigeneration Register on individuals aged 0 to 78 years were linked to the Swedish hospital discharge register and the Swedish outpatient register for the period from 1964 to 2010. Standardized incidence ratios (SIRs) and 95% CIs for surgically treated IH (n = 209,814 cases), FH (n = 4,576), INH (n = 19,494), EH (n = 8,257), and UH (n = 22,761) were calculated for siblings of individuals with hernia compared with the siblings of unaffected individuals. The procedure was repeated for spouses. All concordant and most discordant familial sibling risks were increased. Familial concordant SIRs for siblings were IH = 1.97 (95% CI, 1.94-1.99), FH = 3.40 (95% CI, 2.44-4.62), INH = 2.24 (95% CI, 2.04-2.46), EH = 5.57 (95% CI, 4.64-6.64), and UH = 3.61 (95% CI, 3.33-3.91). Concordant familial risks were higher than discordant risks. For example, when the proband sibling had IH, the discordant SIRs were FH = 1.74 (95% CI, 1.61-1.88), INH = 1.22 (95% CI, 1.16-1.28), EH = 1.30 (95% CI, 1.20-1.40), and UH = 1.35 (95% CI, 1.29-1.41). Concordant SIRs for spouses were lower: IH = 1.23 (95% CI, 1.20-1.26), FH = 0.97 (95% CI, 0.64-1.36), INH = 1.56 (95% CI, 1.41-1.71), EH = 1.70 (95% CI, 1.09-2.45), and UH = 1.31 (95% CI, 1.09-1.56). Family history of surgically treated AWH is an important risk factor for surgical treatment of AWH. The 5 forms of AWH studied share familial susceptibility, but site-specific familial factors might exist. Several spouse risks were increased, suggesting the possibility of a nongenetic contribution to familial risks.

Family history and risk of hospital treatment for varicose veins in Sweden

Family history has been suggested as a risk factor for varicose veins, but recall bias may inflate the familial risks. The aim of this nationwide study was to determine familial risks for hospital treatment for varicose veins. Data from the Swedish Multi-Generation Register of people aged 0-76 years were linked to Hospital Discharge Register data for 1964-2008. Standardized incidence ratios (SIRs) were calculated for individuals whose relatives were treated in hospital for varicose veins and compared with those whose relatives were not. Only main diagnoses of varicose veins were considered. A total of 39 396 people had hospital treatment for varicose veins. The familial SIR among offspring with one affected parent was 2·39 (95 per cent confidence interval 2·32 to 2·46). The SIR for those with one affected sibling was 2·86 (2·76 to 2·97). SIRs were increased in both men and women. The SIR for individuals with two or more affected siblings or with two affected parents was 5·88 (5·28 to 6·53) and 5·52 (4·77 to 6·36) respectively. The SIR for the wives of men treated for varicose veins was 1·69 (1·59 to 1·80); that for the husbands of women treated for varicose veins was 1·68 (1·58 to 1·79). Using the Swedish Hospital Discharge Register, and thereby eliminating recall bias, family history of hospital treatment for varicose veins was associated with an increased risk of similar treatment among relatives. The increased spousal risk suggests a contribution from non-genetic factors.

A nationwide family study of pulmonary embolism: Identification of high risk families with increased risk of hospitalized and fatal pulmonary embolism

BackgroundFamily history is an important risk factor for deep venous thrombosis. However, few studies have determined the importance of family history of pulmonary embolism (PE). ObjectiveThis nationwide study aimed to determine the familial risks of fatal and hospitalized PE. MethodsThe Swedish Multi-Generation Register for subjects aged 0 to 76years old born since 1932 were linked to the Hospital Discharge Register and Cause of Death Register for the period 1964–2008. Standardized incidence ratios (SIRs) for first hospitalization or death (without previous hospitalization for PE) with a main diagnosis of PE were calculated for individuals whose parent or siblings were hospitalized with or died from PE, compared to those whose parent or siblings were not affected by PE. ResultsA total of 20,860 individuals were hospitalized for PE and 862 died due to primary fatal PE (without previous hospitalization for PE). The familial SIR for individuals with one sibling with hospitalized PE was 2.49 (95% CI 1.62-3.83). The familial SIR for siblings with two affected probands was 114.29 (95% CI 56.57–223.95). The familial SIRs for individuals with a parent or sibling hospitalized for PE were significantly increased for fatal PE (1.76; 95% CI 1.38-2.21) and hospitalized PE (2.13; 95% CI 2.04-2.23). Spouses had low overall familial risk for PE (1.09; 95% CI, 1.03-1.14). ConclusionThe high familial risk in multiplex sibling families suggests the existence of strong genetic risk factors for PE. Familial factors and possibly genetic factors are important risk factors for primary fatal pulmonary embolism.