Familial Incidence Research Articles

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.

Norovirus compared to other relevant etiologies of acute gastroenteritis among families from a semirural county in Chile

ObjectiveTo determine the dynamics of norovirus disease, a major cause of acute gastroenteritis (AGE), compared to other relevant etiologies, among families living in a lower middle income area. Study designFamilies with three or more members and with one or more healthy children <24 months of age were followed for 1–2 years to detect any AGE. Stool samples were tested for viral and bacterial pathogens and a questionnaire was completed for those with norovirus or rotavirus AGE. ResultsBetween April and June 2016, 110 families were enrolled, with 103 of them completing ≥12 months of follow-up. A total of 159 family AGE episodes were detected, mostly affecting one individual (92%). At least one pathogen was detected in 56% (94/169) of samples, of which 75/94 (80%) were sole infections. Norovirus was most common (n=26), followed closely by enteropathogenic Escherichia coli (EPEC) (n=25), rotavirus (n=24), and astrovirus (n=23). The annual incidence of family AGE was 0.77, and 0.12 for norovirus. Most norovirus AGE occurred in children <4 years old (96%). Only 13/159 (8%) index AGE cases resulted in a secondary case, of which four were associated with norovirus. The majority of norovirus strains were GII (85%), with a mild predominance of GII.4 (9/26; 35%); most norovirus isolates (69%) were recombinants. ConclusionsThe family incidence of AGE in this lower middle income community was nearly one episode per year, mostly caused by viruses, specifically norovirus closely followed by rotavirus and astrovirus. Norovirus infections primarily affected children <4 years old and secondary cases were uncommon.

Familial Risk for Moyamoya Disease Among First-Degree Relatives, Based on a Population-Based Aggregation Study in Korea

Genetic factors have been known to play a role in the etiology of moyamoya disease (MMD); however, population-level studies quantifying familial risk estimates are unavailable. We aimed to quantify familial incidence and risk for MMD in first-degree relatives (FDR) in the general population of Korea. By using the Korean National Health Insurance database which has complete population coverage and confirmed FDR information, we constructed a cohort of 21 940 795 study subjects constituting 12 million families with blood-related FDR and followed them for a familial occurrence of MMD from 2002 to 2017. Incidence risk ratios were calculated as MMD incidence in individuals with affected FDR compared with those without affected FDR, according to age, sex, and family relationships. Among total study subjects, there were 22 459 individuals with affected FDR, of whom 712 familial cases developed MMD with an incidence of 21.8/104 person-years. Overall, the familial risk for MMD was 132-fold higher in individuals with versus without affected FDR. Familial risk (incidence risk ratio; incidence/104 person-years) increased with the degree of genetic relatedness, being highest in individuals with an affected twin (1254.1; 230.0), followed by a sibling (212.4; 35.6), then mother (87.7; 14.4) and father (62.5; 10.4). Remarkably, there was no disease concordance between spouses. The risks were age-dependent and were particularly high in younger age groups. Familial risks were similar in males and females, and the risk of disease transmission was higher in same-sex parent-offspring and sibling pairs. Our study indicates that genetic predisposition is the predominant driver in MMD pathogenesis, with minimal contribution of environmental factors. These results could be utilized to direct future genetic studies and clinical risk counseling.

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.

Harnessing Population Pedigree Data and Machine Learning Methods to Identify Patterns of Familial Bladder Cancer Risk.

Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer. This study takes advantage of a unique population-level data resource, the Utah Population Database (UPDB), containing vast genealogy and statewide cancer data. Familial risk is measured using standardized incidence risk (SIR) ratios that account for sex, age, birth cohort, and person-years of the pedigree members. We identify 1,023 families with a significantly higher bladder cancer rate than population controls (familial bladder cancer). Familial SIRs are then calculated across 25 cancer types, and a weighted Gower distance with K-medoids clustering is used to identify familial multicancer configurations (FMC). We found five FMCs, each exhibiting a different pattern of cancer aggregation. Of the 25 cancer types studied, kidney and prostate cancers were most commonly enriched in the familial bladder cancer clusters. Laryngeal, lung, stomach, acute lymphocytic leukemia, Hodgkin disease, soft-tissue carcinoma, esophageal, breast, lung, uterine, thyroid, and melanoma cancers were the other cancer types with increased incidence in familial bladder cancer families. This study identified five familial bladder cancer FMCs showing unique risk patterns for cancers of other organs, suggesting phenotypic heterogeneity familial bladder cancer. FMC configurations could permit better definitions of cancer phenotypes (subtypes or multicancer) for gene discovery and environmental risk factor studies.

Inflammatory Bowel Disease Clusters Within Affected Sibships in Ashkenazi Jewish Multiplex Families

Inflammatory bowel disease (IBD) has a long-established familial incidence, 1 Kirsner J.B. et al. Ann Intern Med. 1963; 59: 133-144 Crossref PubMed Scopus (101) Google Scholar ,2 Hislop I.G. et al. Gut. 1969; 10: 994-995 Crossref PubMed Scopus (15) Google Scholar with an ever-increasing number of genetic risk alleles discovered, tolling more than 300 with current genome-wide association studies. 3 Liu J.Z. et al. Nat Genet. 2015; 47: 979-986 Crossref PubMed Scopus (1153) Google Scholar The Ashkenazi Jewish (AJ) population is enriched for mutations associated with rare Mendelian and common complex diseases 4 Kenny E.E. et al. PLoS Genet. 2012; 8e1002559 Crossref PubMed Scopus (104) Google Scholar and has an approximately 4-fold increased prevalence of IBD 5 Bernstein C.N. et al. Am J Gastroenterol. 2006; 101: 1559-1568 Crossref PubMed Scopus (442) Google Scholar and frequent familial aggregation. 6 Schiff E.R. et al. Dig Dis Sci. 2018; 63: 3049-3057 Crossref PubMed Scopus (6) Google Scholar However, familial aggregation does not necessarily imply an underlying, exclusively genetic etiology and has also been proposed to be caused by environmental factors. We aimed to determine the contribution of an underlying shared environment to familial aggregation by studying large AJ IBD sibships from a restricted geographic area. We hypothesized that, in a purely genetically inherited disease, affected siblings are expected to be randomly distributed within sibships. On the other hand, if there is an environmental contribution to the disease, it is expected that siblings in closer proximity due to birth order will share more environmental factors and will, thus, be more often concordant for disease than siblings substantially different in birth order.

Abstract ES3-1: Targeted approach to breast cancer surveillance in high risk women: update of the newest technologies and how to use them

Abstract In multiple prospective randomized trials, screening mammography alone has been demonstrated to reduce breast cancer mortality by approximately 30%. These studies did not account for differences in breast cancer risk. With increasing knowledge of factors that increase breast cancer risk including pathologic mutations, thoracic radiation at a young age, strong family history and incidence of some high-risk lesions, it has become clear that supplemental breast imaging might be necessary to improve early breast cancer detection and outcomes in women at increased risk. Additionally, it has become clear that different high-risk categories are associated with different types and presentations of breast cancer and that these differences might also translate into different imaging strategies. This presentation will address the standard breast cancer imaging tools such as Digital Mammography and Ultrasound and compare them with the newest imaging techniques in breast cancer imaging including Digital Breast Tomosynthesis, and physiologic imaging with a relatively new technology for screening: Contrast Enhanced Digital Mammography and Contrast Enhanced Breast MRI to include the most recent data on Abbreviated Breast MRI. There will be a discussion of fine-tuning the screening strategies based on the specific risk factors which will address the ideal frequency of screening, when screening should start and end and the utility of mammography and ultrasound in women undergoing breast MRI. Citation Format: M Jochelson. Targeted approach to breast cancer surveillance in high risk women: update of the newest technologies and how to use them [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES3-1.

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.

Situational Characteristics Uniquely Associated With Children's Exposure to Intimate Partner Violence.

Exposure to parental violence can have devastating consequences for children, including significant personal, social, and academic problems. The present study determined the situational factors that are associated with children's exposure to intimate partner violence (IPV) incidents. To examine whether these factors were unique to child witnesses' presence at IPV incidents, we also determined the factors that are associated with children's exposure to family violence (FV) and other family member witnesses' exposure to IPV incidents. Participants responded to an online panel survey investigating the role of alcohol and other drugs in family and domestic violence incidents in Australia. Nine hundred fifty-two respondents reported an IPV incident and 299 reported an FV incident; they provided details about their most recent incident. Results showed that child witnesses were more likely to be present during IPV incidents if the incident took place at home (odds ratio [OR] = 3.10), if a similar incident had occurred previously (OR = 1.66), if drugs were involved (OR = 1.60), and if a police report was made (OR = 2.61). There was some overlap with the other witness and violence combinations: The presence of a police report also predicted child witnesses' presence at FV incidents, and a home location also predicted other family member witnesses' presence at IPV incidents. These results enhance our understanding of the situations in which children might witness IPV incidents; future research is needed to determine whether these situational factors can be used to judge risk.

Family history of prostate cancer and the incidence of ERG- and phosphatase and tensin homolog-defined prostate cancer.

Family history is among the strongest known risk factors for prostate cancer (PCa). Emerging data suggest molecular subtypes of PCa, including two somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, phosphatase and tensin homolog (PTEN) loss. We examined associations between family history and incidence of these subtypes in 44,126 men from the prospective Health Professionals Follow-up Study. ERG and PTEN status were assessed by immunohistochemistry. Multivariable competing risks models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of PCa and molecular subtypes of disease. Thirteen percent of men had a positive family history of PCa at baseline. During a median follow-up of 18.5 years, 5,511 PCa cases were diagnosed. Among them, 888 were assayed for ERG status (47% ERG-positive) and 715 were assayed for PTEN loss (14% PTEN null). Family history was more strongly associated with risk of ERG-negative (HR: 2.15; 95% CI: 1.71-2.70) than ERG-positive (HR: 1.49; 95% CI: 1.13-1.95) disease (pheterogeneity : 0.04). The strongest difference was among men with an affected father (HRERG-negative : 2.09; 95% CI: 1.64-2.66; HRERG-positive : 1.30; 95% CI: 0.96-1.76; pheterogeneity : 0.01). Family history of PCa was positively associated with both PTEN null (HR: 2.10; 95% CI: 1.26-3.49) and PTEN intact (HR: 1.72; 95% CI: 1.39-2.13) PCa (pheterogeneity : 0.47). Our results indicate that PCa family history may be positively associated with PCa in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility in their development. It is possible that ERG-negative disease could be especially associated with positive family history.

Exploring the Concept of Food Insecurity and Family Hunger in Senegal, West Africa.

Using a previously validated instrument, surveys were conducted by researchers in a Senegalese village to elicit data on childhood food insecurity and health outcomes. Fifty-four participants were interviewed and completed the Community Childhood Hunger Identification Project (CCHIP) survey. More than half of the adults experienced hypertension or diabetes and also reported childhood food insecurity. The role of food coping strategies and social support were identified as factors that minimized the burden of food insecurity. Further testing with instruments that include analysis of cyclic food access patterns is warranted to best determine how to combat both food insecurity and noncommunicable chronic disease incidence in Senegalese families.

Analisis faktor yang Berhubungan dengan Kejadian Efek Samping pada Akseptor Putus Pakai IUD/Implant di Kabupaten Mamuju Tengah

In 1994 the International Conference on Population and Development (ICPD) has changed the paradigm in managing population problems, which was originally oriented to reducing fertility (humans as objects) to prioritizing individual reproductive health by respecting the reproductive rights of each individual (human being as the subject). The problem that occurs is the participation of couples of reproductive age in family planning programs is not yet complete. One problem that needs attention is that there are PUSs who drop out or no longer use contraception. The number of family planning dropouts in Indonesia has increased, from 11.46% in 2008 to 15.09% in 2012. The potential number of Indonesian population in 2015 reaches 300 million if the family planning movement or the number of family planning dropouts increases or does not run as expected. The results of the study (Maskanah, 2009) showed that the higher the incompatibility of contraceptive use (experiencing side effects), the higher the incidence of family planning contraception dropouts.This type of research is quantitative research with a cross sectional study design. Time of study in November 2018. The population is participants who dropped out of IUD/Implant KB in Central Mamuju Regency in 2018 with a population of 32. The study sample was taken using the Total Sampling method.The results showed that there was a relationship between maternal education level, quality of family planning services, and husband support with the incidence of side effects in drop-outs using IUD/Implant in Central Mamuju District. Efforts to increase PLKB coaching are needed for Participants in IUD and Implant KB, especially in the first month after installation. Improving the quality of family planning services, especially in signing informed consent and screening prospective acceptors before being served.Increased IEC to husbands about the importance of family planning that family-based affairs are not merely the matter of the wife.

Incidence of Socioeconomic, Family and School Variables in Low Literacy Levels

Diferentes politicas publicas llevadas a cabo en las ultimas decadas en Argentina han logrado mejorar significativamente los indices de permanencia de los ninos en las escuelas. Sin embargo, en contextos de pobreza, la permanencia escolar no ha estado siempre acompanada de niveles aceptables de aprendizaje. En el presente trabajo se propuso, entonces, analizar si existen variables socioeconomicas, familiares o escolares relacionadas con las dificultades que experimentan muchos ninos de barrios pobres para aprender a leer y escribir, a pesar de estar insertos en el sistema educativo. Con tal fin, en primer lugar, se conformaron dos grupos de ninos con base en los resultados de una prueba de escritura: uno con un muy bajo nivel de alfabetizacion y otro con un nivel de alfabetizacion similar al de la mayoria de sus pares. En segundo lugar, se realizaron entrevistas a las familias de los ninos de ambos grupos, para recabar datos sobre el nivel socioeconomico de la familia, las escuelas a las que asistian los ninos y el contexto alfabetizador hogareno. Las medidas obtenidas en la comparacion entre los grupos senalaron que no existieron diferencias entre si respecto de la medida de contexto alfabetizador hogareno pero si respecto del nivel socioeconomico. Asimismo, se observo que la escuela a la que asisten los ninos fue la variable que mejor predijo el desempeno en la escritura.

Genetic epidemiology of stuttering among school children in the state of Tamil Nadu, India

PurposeStuttering is a fluency disorder with a worldwide prevalence of 1%. Reports on the epidemiology of stuttering in India are limited. Our primary goal was to examine the prevalence of the disorder among school children. The study also aimed to examine risk factors associated with severity and the impact of parental consanguinity in stuttering. MethodChildren from 97 schools in the State of Tamil Nadu, India were screened. Extensive speech characterization, epidemiological details and three-generational pedigrees were collected for 180 probands. The genetic basis of stuttering was examined using the analysis of genealogical index of families (GIF), kinship group and sibling recurrence risk (SRR) measures. Regression analysis and chi-square tests were performed to test the association of risk factors with severity of the disorder. ResultsAmong the 74,544 school children screened, the prevalence of stuttering was found to be 0.46%. Pedigree analysis revealed a positive family history in 101 (56%) probands; overall familial incidence was 11%. We observed an overall male-favored sex ratio (4:1). Familial aggregation (GIF = 442.60, p-value <0.001) and sibling recurrence risk ratio (Ks = 0.197, SD = 0.041) was high among consanguineous families. Severity of stuttering was strongly associated with gender and moderately associated with age at onset. ConclusionThe prevalence of stuttering in Tamil Nadu is estimated for the first time in this study. High familial incidence, familial aggregation and sibling recurrence risk ratio point to the presence of a genetic basis. Familial aggregation was high among consanguineous families although consanguinity did not seem to play a role in severity.

Genetic background of Meniere’s disease

Meniere’s disease (MD) as an inner ear disorder including such symptoms as recurrent vertigo attacks, tinnitus, fluctuating or progressive sensorineural hearing loss. Its relatively frequent familial incidence implicates a genetic background. An autosomal dominant inheritance was commonly observed with a few exceptions. It was established that Meniere’s disease is not a monogenic disorder. Instead a group of genes of genomic and mitochondrial genes was established as determinants of hearing loss. Another group of genes was associated with inner ear (vestibulum, labyrinth, endolymph) alterations followed by dizziness and tinnitus. Altogether, many studies suggest a multigenic interaction to predispose to develop Meniere’s disease.

Abstract B024: Family history of prostate cancer and the incidence of ERG- and PTEN-defined prostate cancer

Abstract Introduction: Family history is among the strongest known risk factors for prostate cancer. Emerging data suggest unique molecular subtypes of disease, including common somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, PTEN loss. We examined associations between family history and incidence of these subtypes under the hypothesis that family history could be differentially associated with their occurrence. Methods: We studied 47,115 men in the prospective Health Professionals Follow-up Study from 1986 to 2009. ERG and PTEN status were assessed with immunohistochemistry. Multivariable competing risk models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of prostate cancer and disease defined by molecular subtypes. Results: During a median follow-up of 22.3 years, 5,606 prostate cancer cases were diagnosed. Among them, 889 and 711 were assayed for ERG status (48% ERG+) and PTEN loss (14% PTEN null), respectively. Prostate cancer family history was positively associated with both ERG+ (HR=1.85; 95% CI: 1.47-2.33) and ERG- (HR=2.20; 95% CI: 1.78-2.72) disease (P-heterogeneity=0.29). High-grade ERG+ disease suggested a pronounced association (HR=2.58; 95% CI: 1.85-3.61; P-heterogeneity versus high-grade ERG-: 0.08). Family history was also positively associated with PTEN null (HR=2.39; 95% CI: 1.53-3.71) and PTEN intact (HR=1.88; 95% CI: 1.54-2.28) prostate cancer (P-heterogeneity=0.34). Conclusion: Prostate cancer family history is positively associated with prostate cancer defined by ERG and PTEN, suggesting a similar role of genetic susceptibility for these subtypes. It is possible that high-grade ERG+ disease could be uniquely associated with positive family history. Citation Format: Dana Hashim, Amparo G. Gonzalez-Feliciano, Thomas U. Ahearn, Andreas Pettersson, Lauren Barber, Claire H. Pernar, Ericka M. Ebot, Stephen Finn, Edward L. Giovannucci, Rosina T. Lis, Massimo Loda, Giovanni Parmigiani, Kathryn L. Penney, Tamara Lotan, Philip W. Kantoff, Lorelei A. Mucci, Rebecca E. Graff. Family history of prostate cancer and the incidence of ERG- and PTEN-defined prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B024.

Tau Mutations Serve as a Novel Risk Factor for Cancer.

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731-9. ©2018 AACR.

Study of Family Clustering and PNPLA3 Gene Polymorphism in Pediatric Non Alcoholic Fatty Liver Disease

To find association of pediatric NAFLD with metabolic risk factors, and Patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene polymorphism. Cross-sectional study. Pediatric Hepatology unit of a tertiary care hospital. Overweight/obese children (<18 years) with (69 patients) or without (30 patients) NAFLD (ultrasonography based), and their parents. Metabolic screening, PNPLA3 gene polymorphism, and transient elastography. Association of pediatric NAFLD with parental metabolic risk factors and PNPLA3 gene polymorphism. In the NAFLD group, there was high parental incidence of metabolic diseases, fatty liver (80%) and low high-density lipoproteins levels (84%). Family history of NAFLD (in any parent), higher alanine aminotransferase levels and higher total cholesterol levels in the child independently predicted possibility of NAFLD, but similar results could not be replicated for PNPLA3 gene polymorphism. Controlled attenuation parameter measurement (by transient elastography) had high sensitivity and specificity to diagnose steatosis. There is high familial incidence of metabolic diseases in children with NAFLD. Controlled attenuation parameter can be useful as a non-invasive modality to screen fatty liver in children.

Relation between family performance indices and incidence risk of myocardial infarction

Relation between family performance indices and incidence risk of myocardial infarction

Loss of B cell Ezrin in lupus-prone Lyn-deficient mice downregulates B cell activation and autoimmune pathology

Abstract Systemic lupus erythematosus (SLE) is an aggressive autoimmune disorder that afflicts 1.5 million Americans. Human GWAS studies have reported a strong association between the Src family tyrosine kinase Lyn and incidence of SLE, and B cells from SLE patients exhibit decreased Lyn expression. Genetic deletion of Lyn in mice results in loss of peripheral B cell tolerance and development of human SLE-like autoimmunity, characterized by hyperactive B cell antigen receptor (BCR) signaling, autoantibody production and glomerulonephritis. However, the molecular regulators of B cell pathogenesis in Lyn-deficient mice have not been fully characterized. We have previously shown that the membrane-cytoskeleton linker protein ezrin regulates multiple aspects of B cell function through its dynamic switching between phosphorylated and dephosphorylated states. We observed that ezrin is hyperphosphorylated in Lyn-deficient B cells, suggesting that it may impact B cell activation in this context. To test this hypothesis, we generated conditional deletion of ezrin in the B cells of Lyn-deficient mice (hereafter referred to as DKO mice). Compared to Lyn-deficient mice, the DKO mice exhibited a significant decrease in splenomegaly and reduction in autoantibodies against a variety of autoantigens. Glomerulonephritis and deposition of IgG and complement factor C3 in the kidneys of DKO mice were also markedly reduced. The DKO B cells were hyporesponsive to BCR stimulation and displayed a calcium mobilization pattern reminiscent of that observed in anergic B cells. Our data demonstrate that ezrin regulates B cell hyperactivation and associated pathology in the absence of Lyn, and suggest that ezrin may be a novel molecular target in SLE.