Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment.

BACKGROUND: Chronic rhinosinusitis (CRS) is a highly prevalent inflammatory condition, with significant effects on morbidity and quality of life, yet little is known about its pathogenesis. Preliminary evidence suggests there is a heritable component to the multifactorial etiology of CRS; however, our understanding of this genetic susceptibility is limited. METHODS: Using an extensive genealogical database linked to medical records, the risk of CRS with nasal polyps (CRSwNP) and without polyps (CRSsNP) was calculated for relatives and spouses of adult probands (1638 CRSwNP and 24,200 CRSsNP patients diagnosed between 1996 and 2011) and were compared to random population controls matched 5:1 on sex and birth year from Cox regression models. RESULTS: First-degree relatives (1stDRs) of CRSwNP patients demonstrated a 4.1-fold increased risk (p < 10(-3) ) of carrying the same diagnosis, whereas second-degree relatives (2ndDRs) demonstrated a 3.3-fold increased risk (p < 0.004), compared to controls. In CRSsNP patients, 1stDRs were at 2.4-fold increased risk (p < 10(-15) ), whereas 2ndDRs were at 1.4-fold increased risk (p < 10(-15) ) of the same diagnosis. Third-degree relatives (3rdDRs) had a slight increased risk at 1.1-fold (p < 10(-7) ). Spouses of CRSsNP patients, who likely share environmental circumstances, exhibited a 2-fold increased risk (p < 10(-15) ). No increased risk was observed in spouses of CRSwNP patients. CONCLUSION: In the largest population study to date, a significant familial risk is confirmed in CRSwNP and CRSsNP, which may have a shared genetic and environmental component. Further understanding of the genetic basis of CRS and its interplay with environment factors could clarify disease etiology and lead to more effective targeted treatments.

Familial predisposition to developmental dysplasia of the hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common birth defect and is thought to have genetic contributions to the phenotype. It is likely that DDH is genetically heterogeneous with environmental modifiers. The Utah Population Database (UPDB) is a computerized integration of pedigrees, vital statistics, and medical records representing over 6 million individuals, and is a unique resource providing the ability to search for familial factors beyond the nuclear family, decreasing the effect of a shared environment. The purpose of this study is to assess the degree of relationship between individuals with DDH. METHODS: Datasets were created from UPDB statewide birth certificates and from the University of Utah Health Sciences Center enterprise data warehouse using records for DDH and linked to the UPDB. Controls for the dataset were selected that matched cases on birth year and sex and 10 controls were selected per case. Statistics computed for each family were the number of descendants, the observed number of affected, the expected number of affected, P value, familial standardize incidence ratio, relative risks (RRs), and standard error. A kinship analysis tool was used to find pedigrees with excess DDH. RESULTS: The combined data resulted in 1649 distinct individuals with DDH. RR was significantly increased in first-degree relatives (RR=12.1; P<0.000001), siblings (RR=11.9; P<0.000001) and first cousins (RR=1.7; P=0.04). A total of 468 families were identified with at least 5 affected individuals in a family. These results were then filtered to only contain families that had a P value of less than 0.01. This resulted in 141 founders with anywhere between 4 and 30 affected living descendants with a P value of less than 0.01 with family sizes ranging from 594 to 44,819 descendants. A total of 28 founders had a familial standardize incidence ratio of greater than 5.0. CONCLUSIONS: These data suggest a genetic contribution to DDH with a 12-fold increase in risk for first-degree relatives. Better phenotypic characterization and classification will be critical for future genetic analyses.

A population-based assessment of the familial component of acute kidney allograft rejection.

BACKGROUND: The genetic determinants of acute kidney transplant rejection (AR) are not well studied, and familial aggregation has never been demonstrated. The goal of this retrospective case-control study was to exploit the unique nature of the Utah Population Database (UPDB) to evaluate if AR or rejection-free survival aggregates in families. METHODS: We identified 891 recipients with genealogy data in the UPDB with at least one year of follow-up, of which 145 (16.1%) had AR and 77 recipients had biopsy-proven rejection graded >or=1A. We compared the genealogical index of familiality (GIF) in cases and controls (i.e. recipients with random assignment of rejection status). RESULTS: We did not find evidence for familial clustering of AR in the entire patient population or in the subgroup with early rejection (n = 52). When the subgroup of recipients with rejection grade >or=1A (n = 77) was analysed separately, we observed increased familial clustering (GIF = 3.02) compared to controls (GIF = 1.96), although the p-value did not reach the level of statistical significance (p = 0.17). Furthermore, we observed an increase in familial clustering in recipients who had a rejection-free course (GIF = 2.45) as compared to controls (GIF = 2.08, p = 0.04). When all recipients were compared to non-transplant controls, they demonstrated a much greater degree of familiality (GIF = 2.03 versus GIF 0.63, p < 0.001). CONCLUSIONS: There is a familial component to rejection-free transplant course and trend to familial aggregation in recipients with AR grade 1A or higher. If a genetic association study is performed, there are families in Utah identified in the current study that can be targeted to increase the power of the test.