Risk In First-degree Relatives Research Articles

Current State of Application of Formal Thought Disorder Screening Methods in First-Degree Relatives of Patients With Schizophrenia: A Narrative Review

Abstract: Historically, formal thought disorder (FTD) has been considered one of the distinctive key symptoms of schizophrenia and is still regarded as an important early warning sign and a marker of illness severity with solid predictive value. Recent studies are able to found that the presence of FTD is predictive of the subsequent diagnosis of schizophrenia and often precedes the frank clinical picture by several months. Much effort has been put into developing scales that can reliably detect FTD and can be readily applied in routine clinical practice. This narrative review investigated the use of FTD as a screening tool to assess risk in first-degree relatives of patients with schizophrenia. The results show that the use of these scales in firstdegree relatives of schizophrenic individuals during clinical contact and counseling is still an exception, despite their uniquely heightened vulnerability profile. To our knowledge, this is the first time that the application of FTD screening methods in first-degree relatives of schizophrenic individuals has been reviewed in a structured way.

Cardiovascular Disease Risk Profiling among First-Degree Relatives of Premature Coronary Artery Disease Patients

Background and Aims: First-degree relatives of patients with premature coronary artery disease are at heightened risk of cardiovascular events due to the synergy of genetic and environmental factors. The aim of this study was to assess the cardiovascular disease (CVD) risk factors and to estimate cardiovascular risk in first-degree relatives of patients with premature CAD. Methods: The study was conducted among first-degree relatives of patients with coronary artery disease in a tertiary care hospital in Kathmandu. A total of 144 first-degree relatives aged 18 years or older participated in this study. Age and gender matched subjects with no clinical evidence of CAD and no history of premature CAD in frst degree relatives were recruited as controls. The cardiovascular risk of study participants was assessed using the American Heart Association (AHA) Cardiovascular Risk Assessment Tool. Result: The study age group was between 18 to 59 years. The mean age of the subjects was 35.54 ± 10.57 years and 63.19% of subjects were men. A statistically significant number of first-degree relatives of premature CAD were found to be hypertensive and had metabolic syndrome. CVD risk factors like physical inactivity, smoking, diabetes, and dyslipidemia were found in 46.5%, 47.22%, 13.2%, and 52.01%, of the study participants, respectively. Conclusion: The study highlights the widespread presence of risk factors and underlying medical conditions among young study participants both with and without a family history of premature CAD. Appropriate direction based on opportunistic screening programs and risk stratifcation should be initiated which can play an important role in the primary prevention of early CAD.

Empowering Family Glaucoma Risk Communication Using QR-Code-Mediated Online Intervention

Attempts at engaging relatives of glaucoma patients in education and screening have had limited success. This study explores the feasibility of an electronic intervention to facilitate direct yet reliable glaucoma risk communication between open-angle glaucoma patients (probands) and their first-degree relatives (FDRs). Prospective survey and assessment of intervention. Fifty adult probands, engaging 140 FDRs. Phase I was an iterative process involving creating a customized website and Quick Response (QR)-code-based intervention designed with input from probands, FDRs of patients, community members, and researchers. In phase II, the intervention was deployed in a clinical setting; this involved recruiting probands who had a smartphone and were willing to use the QR-code to message their FDRs a standard message, including a website link about glaucoma risk in FDRs and the importance of getting examined. Follow-up interviews were conducted with probands 1 to 2 weeks after their clinic visit to assess the impact of the intervention. Demographic data, website analytics, and participant feedback were collected and analyzed. Increased awareness of glaucoma risk among FDRs and enhanced discussions. At the time of the first interview, probands reported that 70% of the FDRs were aware of the probands' glaucoma diagnosis, but only 26% had undergone glaucoma screening. Ninety percent of probands had no issues using the QR-codes. Website analytics recorded 73 visits from 51 distinct internet protocol addresses (IPs). After receiving the standard message, 95% of FDRs followed up with the probands, actively discussing glaucoma. Of the probands, 84% completed the follow-up interview 1 to 2 weeks after enrollment. Fifty-nine percent of the FDRs were reported to have scheduled screening appointments. The collected feedback revealed that 96% of probands found the intervention helpful, fostering glaucoma discussions with their FDRs and improving probands' comfort level in discussing health issues with FDRs from baseline (very comfortable: 88%, comfortable: 8%, neutral: 2%, and very uncomfortable: 2%) to the follow-up interview (very comfortable: 98% and comfortable: 2%). This innovative online method of communicating the risk of glaucoma to FDRs of probands prompted and increased the comfort level of familial discussions of glaucoma. More than half of FDRs reported making an appointment to get screened for glaucoma. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants

Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed. To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A. This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome-associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome-associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021. For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome-associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV. In total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77). In this case series, the presence of PGVs in 9 cancer syndrome-associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.

Predictors of perceived risk in first-degree relatives of patients with rheumatoid arthritis

ObjectivesTo define variables associated with perceived risk of developing rheumatoid arthritis (RA) in first-degree relatives (FDRs) of patients with RA.MethodsPatients with RA and their FDRs were invited to complete cross-sectional...

Abstract A033: Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants

Abstract Increased pancreatic cancer (PC) risk in first-degree relatives (FDRs) of PC patients with germline pathogenic/likely pathogenic variants (PLPV) is a motivator for cascade genetic testing. To date, unbiased FDR risk estimates for gene-specific risks of genetic cancer syndrome-associated cancers are unknown. These estimates would enhance genetic counseling of at-risk FDRs in families where the PC proband has been found to carry a PLPV. Study Aim: To objectively quantify gene-specific risks of six relevant cancers among FDRs of PC patients with germline PLPV in ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, and PMS2. Methods: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry PLPV among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios estimated risk by gene of six cancers among FDRs of PC patients carrying PLPV. Results: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). Conclusion: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs in PC families. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, and intervention. The gene-specific quantified cancer risks for FDRs of PC patients with syndrome-associated germline PLPV can inform counseling regarding extra-PC risks when considering cascade genetic testing. Citation Format: Xuan Chen, Kari Rabe, Margaret Meyer, Jennnifer Kemppainen, Masayasu Horibe, Shruti Chandra, Shounak Majumder, Gloria Petersen. Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A033.

Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death. To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups. A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively. The presence of DCM in a proband. Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative. The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]). In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives. ClinicalTrials.gov Identifier: NCT03037632.

Celiac Disease.

Celiac Disease.

Rare Germline Variant in NFATC4 Associated with Familial Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) has one of the highest familial risks of any cancer, with up to eightfold increased risk in first degree relatives of CLL patients. Genome-wide association studies (GWAS) have identified multiple common single nucleotide polymorphisms (SNPs) associated with risk, but these have modest effect. Similarly, identified germline variants associated with disease account for just a small minority of CLL patients, making familial CLL an attractive target for research, that could provide direct insight into pathobiology.We used whole exome sequencing (WES; Illumina) to search for rare germline variants (<1% Minor Allele Frequency) in 36 patients from 17 families with Mendelian-like CLL inheritance, where at least two affected family members were sequenced. Median age at diagnosis was 56.4 (range 41-72), 61% were male, 10/23 (43%) were IGHV -unmutated, and 5/24 (21%) had del17p and/or TP53 mutation. We found 3819 rare variants shared within all affected members of a given family. Of those, 71 non-synonymous variants were shared across at least 2 families, and 39 of these were predicted to be pathogenic by at least two commonly-used phenotype prediction tools. None of these variants are within known somatic CLL driver genes, nor were any found in genes near known CLL GWAS SNPs. In order to prioritize these variants, we assessed whether they were enriched among CLL cases (n = 646) as compared to ethnically matched normal population controls (n=8,920), a dataset we have recently reported (Tiao, Improgo et al, Leukemia). Using Fisher's exact test with Benjamini-Hochberg (BH) correction for multiple tests, we found that 27 of the 71 shared variants across multiple families were also enriched in unrelated CLL patients compared to controls. Among those, a rare variant of nuclear factor of activated T-cells 4 (NFATC4), rs200328372, was the most highly enriched in CLL (OR 20.8, Fisher-q-BH 0.026). This variant affects a splice acceptor site predicted to have a deleterious effect on the protein (FATHMM for non-coding variants). In a pathway analysis (MSigDB, DAVID) of genes carrying shared variants across families, NFATC4 together with SOS1 and PTPN7 were associated with the T-cell receptor, B-cell receptor, and MAP-kinase pathways, suggesting a possible role in CLL pathogenesis.The NFATC4 protein, also known as NFAT3, is part of a DNA-binding transcriptional complex that translocates to the nucleus after activation through dephosphorylation by calcineurin. This complex is involved in the inducible expression of cytokine genes in T cells, including interleukin (IL)-2 and IL-4. While NFATC1 has been implicated in CLL pathogenesis and was associated with more aggressive disease in a mouse model of CLL, the role of NFATC4 has not been elucidated. To further investigate this as well as its association with familial CLL, we compared gene expression profiling (GEP; Affymetrix U133 plus 2.0 array) data between familial and sporadic CLL patients and normal B-cells. While NFATC4 expression did not differ between normal B-cells (n=16) and CLL (n=143), it was significantly down-regulated in familial (n=47) as compared to sporadic (n=96) CLL cases (Mann-Whitney, p=0.005). In the 4 cases that harbor the shared risk variant, GEP results showed additional significant down-regulation of NFATC4 expression (Kruskal-Wallis, p=0.003 for all comparisons) (Figure 1).RNA sequencing (Illumina) demonstrated NFATC4 down-regulation in all CLL samples (not specifically in familial CLL as with GEP; n=100) versus normal B-cells (n=6; Mann-Whitney, p=-0.00024), suggesting a putative role for NFATC4 as a tumor suppressor. Since NFATC4 has over 30 alternatively spliced transcripts potentially affected by the rs200328372 variant, we used Cufflinks software to look at isoform-level RNA sequencing data, available on two relatives who carried this variant, compared to CLL cases and controls. Both relatives had reduced expression of all isoforms (Figure 2), suggesting that this mutation may reduce NFATC4 expression altogether. Studies of protein expression are ongoing.In conclusion, through rare germline variant analysis in familial CLL, we found a potentially deleterious variant of NFATC4 that is enriched in CLL. Subsequently, we used RNA sequencing data to show, for the first time, that NFATC4 expression is decreased in CLL versus normal B-cells, revealing a potential tumor suppressor mechanism in CLL. [Display omitted] DisclosuresBrown:Sun BioPharma: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy; Redx: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Janssen Oncology: Honoraria; AbbVie: Consultancy, Honoraria; Roche/Genentech: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Infinity Pharmaceuticals: Consultancy; Astellas Pharma: Consultancy.

Diabetes Risk Assessment with Blood Parameters of The First Degree Relatives of Patients with Type-2 Diabetes Mellitus

Objective: This study was conducted to evaluate the diabetes risk in first degree relatives of Type-2 diabetic patients who were not diagnosed with diabetes and test the validity of the Finnish Diabetes Risk Score (FINDRISK) in determining the risk of type-2 diabetes. Methods: First degree relatives of patients who were hospitalized in “İzmir Katip Çelebi University Atatürk Training and Research Hospital”, who were not diagnosed with diabetes before, were included in this cross-sectional study. The sample of the research consisted of 200 people determined by power analysis. Data were collected by “a structured question form” and the FINRISK scale. Participants’ height, weight, waist circumference were measured by the researcher, and venous fasting blood glucose (FBG) with Glycosylated Hemoglobin (HbA1c) were taken by the researcher. Results: The average age of the participants was 46.93 ± 14.83 (18-86). It was determined that the vast majority of the individuals participating in the study were female (65%), 63% were married, 50.5% received high school or higher education, and 59% worked in an income-generating job. The findings was indicated that 41.5% of the participants were in the ‘high-risk group’ for type-2 diabetes according to the FINDRISK score scale. Sensitivity of FINDRISK score to FBG was 100% and specificity was 60%. Conclusion: As a result of findings in this study indicate that It was determined that the risk of DM was high in the first degree relatives of the patients hospitalized with Type-2 DM and the FINDRISK score scale was a good scale in predicting new asymptomatic Type 2 diabetes.

Familial risk of Behçet's disease among first-degree relatives: a population-based aggregation study in Korea.

Previous studies have indicated that Behçet's disease (BD) has a genetic component, however population-level familial risk estimates are unavailable. We quantified the familial incidence and risk of BD in first-degree relatives (FDR) according to age, sex and type of family relationship. Using the Korean National Health Insurance database, which has full population coverage and confirmed FDR information, we constructed a cohort of 21940795 individuals comprising 12 million families, which were followed for a familial occurrence of BD from 2002 to 2017. Age- and sex-adjusted incidence risk ratios for BD were calculated in individuals with affected FDR compared with those without affected FDR. Among the total study population, 53687 individuals had affected FDR, of whom 284 familial cases developed BD with an incidence of 3.57/104 person-years. The familial risk (incidence) for BD was increased to 13.1-fold (2.71/104 person-years) in individuals with an affected father, 13.9-fold (3.11/104 person-years) with affected mother, 15.2-fold (4.9/104 person-years) with an affected sibling and the highest risk was 165-fold (46/104 person-years) with an affected twin. Familial risks showed age dependence, being higher in younger age groups. The sex-specific familial risk was similar in males and females. This study provides quantified estimates of familial incidence and risk in FDR of BD patients in an entire population. Familial risks were higher within generation (sibling-sibling) vs between generations (parent-offspring). This implicates complex interactions between genetic factors and shared childhood environmental exposures in the pathogenesis of BD.

Risk of schizophrenia in relatives of individuals affected by schizophrenia: A meta-analysis

A meta-analysis was conducted to estimate schizophrenia incidence in first-degree relatives (FDRs) of probands diagnosed with schizophrenia. The aim was to inform future schizophrenia research and improve accuracy of risk communication to patients. Schizophrenia risk in FDRs with 1 or 2 probands with schizophrenia was investigated by conducting a systematic review of cohort and case-control studies with the following criteria: published between 1977 and 2018; reported odds ratios (OR), relative risk (RR) or sufficient raw data to calculate OR or RR; used appropriate diagnostic criteria; and reported systematic proband recruitment and ascertainment of relatives. Studies were obtained via EMBASE and MEDLINE electronic database searches. From an initial 5755 articles, 19 met the inclusion criteria. Mean effect sizes across studies were estimated using random effects methods. Estimates for schizophrenia risk were OR = 7.69 (95% CI 5.11–11.56) for FDRs of one proband with schizophrenia compared to healthy control probands, increasing to OR = 11.11 (95% CI = 1.45–85.02) for FDRs with two probands with schizophrenia. These findings support the existing literature suggesting significant genetic liability for schizophrenia. The results can be used to educate individuals with a family history of schizophrenia about their risk.

Aortopathy and regurgitation in bicuspid valve patients increase the risk of aortopathy in relatives

BackgroundBicuspid aortic valve (BAV) is the most frequent cardiac congenital valvular disease. Although the BAV risk of first degree relatives (FDR) has been assessed (7–9%), there is little information as to the heritable risk for aortopathy. ObjectiveIdentify the specific risk for regional aortopathy in FDR with tricuspid aortic valve (TAV) of BAV patients according to their aortic phenotype and aortic regurgitation (AR). MethodsUsing an international consortium, BAV probands were assessed for aortopathy of the root, ascending aorta and for AR. Aortopathy was defined by the presence of segmental dilatation. The presence of segmental aortopathy and AR in BAV probands was evaluated as predictor for aortopathy in FDR with TAV. ResultsWe identified 74 FDR related to 49 probands with aortopathy and 66 FDR related to 31 probands without aortopathy. Demographic variables were similar between proband groups. Among FDR, 16 individuals had BAV (11.4%). TAV-FDR of probands with ascending aortopathy had higher incidence of root aortopathy (18.8% vs. 3.6% p < 0.05) while TAV-FDR of probands with root aortopathy had higher incidence of aortopathy at all aortic segments (55%vs25%, 55%vs21%, and 4%vs29% at annulus, root and ascending respectively, p < 0.05 for all). Independent predictors for root aortopathy in TAV-FDR were: ascending (OR = 6.23;95%CI:1.27–30.5) and root aortopathy (OR = 9.00;95%CI:1.58–51.1) in probands; and for ascending aortopathy: root aortopathy (OR = 4.04;95%CI:1.33–12.3) and AR in probands (OR = 4.84; 95%CI:1.75–13.4). ConclusionRoot and ascending aortopathy in BAV probands are strong predictors of aortopathy in their TAV-FDR. AR in BAV patients has an independent effect on the risk for ascending aortopathy in TAV-FDR.

Comparison of anthropometric, cardiovascular, autonomic, baroreflex sensitivity, aerobic fitness, inflammatory markers and oxidative stress parameters between first degree relatives of diabetes and controls

AimWe aimed at assessing cardiovascular risk of first degree relatives of diabetes (FDRD). MethodsA cross sectional study involving 90 apparently healthy normoglycemic volunteers aged between 15 and 50 years (45 FDRD and 45 FDRs of non-diabetics). We measured anthropometric parameters, baroreflex sensitivity, heart rate variability, cardiac autonomic function tests, and aerobic capacity, fasting blood glucose and insulin, lipid profile, inflammatory markers, nitric oxide and oxidative stress markers. ResultsFDRD had significantly higher hip circumference and BF%. Blood pressure, total peripheral resistance and cardiac output were comparable. FDRD had higher HR and rate pressure product. There were no significant differences in cardio-respiratory fitness (VO2max) and physical activity level. Time and Frequency domain parameters were comparable except for reduced NN50 and total power. Baroreflex sensitivity, 30:15 ratio and E: I ratio were significantly less in FDRD. Fasting glucose was comparable. Fasting Insulin, HOMA IR, HOMA %B and HOMA AD were higher while HOMA %S and QUICKI index were lower in FDRD. Lipid profile or lipid derived parameters were comparable except for higher non-HDLc in FDRD. Adiponectin was lower while Leptin and Leptin/apidonectin ratio was higher in FDRD. IL-6, hsCRP, TNF- alpha and MDA were significantly higher in FDRD, while TAS and nitric oxide were significantly lower in FDRD. ConclusionHigher body fat percentage, with insulin resistance, deranged cardiac autonomic function, higher oxidative stress and inflammation, lower adiponectin and nitric oxide levels places FDRD at higher cardiovascular risk and necessitates early lifestyle modification/intervention.

Facteurs de risque de maladie veineuse thromboembolique chez les jeunes femmes en contexte hormonal: Risque de survenue d’une maladie thromboembolique veineuse chez les membres de la famille au 1er degré de femmes ayant une maladie veineuse thromboembolique en contexte hormonal : étude « FIT – H »

To demonstrate an association between the risk of VTE in young women with hormonal exposure (pregnancy or oral contraceptive use) and the presence of a previous episode of VTE in their first-degree relatives, according to whether or not a detectable inherited thrombophilia was present. We will perform a multicenter case-control cross-sectional study. The main risk factor is defined by the presence of a symptomatic VTE in young women with hormonal exposure. The principle variable is the presence of an objectively diagnosed episode of VTE in first-degree relatives. We will need to include 2,200 family members in 440 cases. We expect to improve understanding of the thrombotic risk in first-degree relatives of patients in hormonal context with or without a past history of VTE.

Abstract 439: Elucidation of genetic susceptibility in nasopharyngeal carcinoma (NPC) by next-generation sequencing

Abstract Background: NPC has a striking geographical distribution. Hong Kong is one of the endemic regions in Southern China with incidence of 20 per 100,000 in males, 10 times higher than the rest of the world. NPC diagnosis usually occurs 20 years earlier than the other common cancers. Family clustering is often observed in both high- and low-risk regions. The relative risk in first degree relatives of NPC patients is increased from 6-10-fold compared to the general population, suggesting the important role of genetics in NPC development. Previously, we applied a whole-exome sequencing (WES) approach to characterize the germline variants in NPC and identified a novel genetic susceptibility gene MST1R associated with NPC cases having an early onset. This study also discovered several potential candidates involved in DNA repair, immune response, and epigenetic regulation. Aim: We aim to 1) validate MST1R as a genetic susceptibility gene and evaluate the clinical significance of its germline variants in association with survival and 2) to examine the association of the rare deleterious variants of fourteen candidate genes in a larger NPC case-control cohort. Methods: We examined the germline variants in 1224 cases (FH: 271 and sporadic 953) and 1256 age/gender matched Hong Kong (HK) controls by the targeted sequencing approach using Roche NimbleGen SeqCap EZ custom platform. Results: The MST1R rare deleterious variants were significantly associated with NPC, especially in the FH+ cases (OR=2.37, p=0.032). Combined analysis including both discovery (WES) and validation cohorts showed that the MST1R variants clustered at the Sema and tyrosine kinase (TK) domains were associated with NPC, respectively. The controls are intolerant to the rare deleterious variants in the TK domain, suggesting the more severe functional impact of those variants to its function. The sporadic cases with MST1R deleterious variants had disease progression (relapse or metastasis) much earlier than those without variants (n=756, HR=3.0, 95% CI 1.2-7.5, p=0.017). Among another fourteen candidates, multiple loss-of-function (LOF) germline mutations of a critical DNA repair gene, ATM, were identified in the FH+ cases, but not in any of sporadic cases and HK controls. Conclusions: This study confirmed MST1R as a genetic susceptibility gene in NPC. It encodes macrophage-stimulating 1 receptor, which has an important function in innate immunity for maintaining the macrophage hemostasis. The function of this gene and impact of its germline variants in NPC development and progression are under investigation. Our study also highlights the role of a DNA repair gene, ATM, in NPC susceptibility. Acknowledgements: NPC AoE funding was provided by the Hong Kong Research Grants Council (AoE/M-06/08) to MLL Citation Format: Wei Dai, Josephine Mun Yee Ko, Bianca Hoi Yan Ng, Hong Zheng, Maria Li Lung. Elucidation of genetic susceptibility in nasopharyngeal carcinoma (NPC) by next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 439.

Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis.

Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. (Hepatology 2018;68:166-171).

Reminders of cancer risk and pain catastrophizing: relationships with cancer worry and perceived risk in women with a first-degree relative with breast cancer.

First-degree relatives of women with breast cancer may experience increased worry or perceived risk when faced with reminders of their own cancer risk. Worry and risk reminders may include physical symptoms (e.g., persistent breast pain) and caregiving experiences. Women who engage in pain catastrophizing may be particularly likely to experience increased distress when risk reminders are present. We examined the degree to which persistent breast pain and experience as a cancer caregiver were related to cancer worry and perceived risk in first-degree relatives of women with breast cancer (N = 85) and how catastrophic thoughts about breast pain could impact these relationships. There was a significant interaction between persistent breast pain and pain catastrophizing in predicting cancer worry (p = .03); among women who engaged in pain catastrophizing, cancer worry remained high even in the absence of breast pain. Pain catastrophizing also moderated the relationships between caregiving involvement and cancer worry (p = .003) and perceived risk (p = .03). As the degree of caregiving responsibility increased, cancer worry and perceived risk increased for women who engaged in pain catastrophizing; levels of cancer worry and perceived risk remained low and stable for women who did not engage in pain catastrophizing regardless of caregiving experience. The results suggest that first-degree relatives of breast cancer survivors who engage in pain catastrophizing may experience greater cancer worry and perceived risk and may benefit from interventions aimed at reducing catastrophic thoughts about pain.

Identification of GAD65 AA 114-122 reactive 'memory-like' NK cells in newly diagnosed Type 1 diabetic patients by HLA-class I pentamers.

Type 1 diabetes is an autoimmune disease, in which pancreatic β cells are destroyed by autoreactive T cells in genetically predisposed individuals. Serum beta cell autoantibody specificities have represented the mainstay for classifying diabetes as autoimmune-mediated and for stratifying risk in first-degree relatives. In recent years, approaches were attempted to solve the difficult issue of detecting rare antigen-specific autoreactive T cells and their significance to etiopathogenesis such as the use of the MHC multimer technology. This tool allowed the specific detection of increased percentages of GAD65 autoreactive T cells by means of HLA A*02:01 GAD65 AA 114–122 pentamers in newly diagnosed diabetics. Here we provide evidence that GAD65 AA 114–122 pentamers can depict a GAD65 AA114-122 peptide expandable population of functionally and phenotypically skewed, preliminary characterized CD3-CD8dullCD56+ ‘memory-like’ NK cells in PBMC of newly diagnosed diabetics. Our data suggest that the NK cell subset could bind the HLA class I GAD65 AA 114–122 pentamer through ILT2 inhibitory receptor. CD107a expression revealed increased degranulation of CD3-CD8dullCD56+ NK cells in GAD65 AA 114–122 and FLU peptide expanded peripheral blood mononuclear cells of diabetics following GAD65 AA 114–122 peptide HLA A*02:01 presentation in respect to the unpulsed condition. CD107a expression was enriched in ILT2 positive NK cells. As opposite to basal conditions where similar percentages of CD3-CD56+ILT2+ cells were detected in diabetics and controls, CD3-CD56+CD107a+ and CD3-CD56+ILT2+CD107a+ cells were significantly increased in T1D PBMC either GAD65 AA 114–122 or FLU peptides stimulated after co-culture with GAD65 AA 114–122 pulsed APCs. As control, healthy donor NK cells showed similar degranulation against both GAD65 AA 114–122 pulsed and unpulsed APCs. The pathogenetic significance of the CD3-CD8dullCD56+ ‘memory-like NK cell subset’ with increased response upon secondary challenge in diabetics remains to be elucidated.

Rare germline variants in ATM are associated with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a highly heritable cancer, with a 7.5-fold increased risk in first-degree relatives.1 However, inherited predisposition to CLL remains largely unexplained by traditional linkage or genome-wide association studies. Here, we hypothesized that CLL heritability might arise from rare coding variants not analyzed in previous studies.