1st Degree Relatives Research Articles

Lipid Abnormalities in the Natural History of Diabetes

Objective: To explore lipid abnormalities in normoglycemic first-degree diabetic relatives (FDRs) and prediabetic and diabetic subjects in the natural history of diabetes.Research design and methods: Thirty six impaired fasting glucose (IFG), 61 isolated impaired glucose tolerance (I-IGT), 64 combined IFG-IGT, 73 diabetic, and 32 FDRs along with 57 normoglycemic healthy controls without family history of diabetes in 1st degree relatives, were selected purposively following 2003 ADA cut-off values and 2006 WHO/IDF grouping. Anthropometry and blood pressure of the subjects were taken. Fasting and 2-h plasma glucose and HbA1C were measured. Fasting plasma triglyceride, total cholesterol and HDL cholesterol were measured by enzymatic colorimetric method.Results: Serum triglyceride was higher in IFG, I-IGT, IFG-IGT, diabetic and FDRs compared to Control [145 (59- 307), 128 (66-584), 166 (68-764), 161 (69-750) and 130 (81-281) vs. 108 (47-219) mg/dl, P<0.01, P<0.01, P<0.001, P<0.001 and P<0.05]. Total cholesterol was raised in IFG-IGT and diabetes compared to Control [185 (105-310), 185 (123-326) vs. 171 (101-235) mg/dl, P<0.05] and FDRs. But HDL did not differ among the groups. Prevalence of metabolic syndrome was higher in IFG, I-IGT, IFG-IGT and diabetes and FDRs than Control [55%, 38%, 57%, 58% and 36% vs. 15%, P<0.001, P<0.01, P<0.001, P<0.001 and P<0.05] and also in IFGIGT and diabetic compared to I-IGT and FDRs (P<0.05).Conclusions: Higher prevalence of metabolic syndrome and raised serum triglyceride is seen among diabetic, prediabetic and 1st degree diabetic-relatives. Total cholesterol and non-HDL cholesterol is raised only in IFG-IGT and diabetes, the more decompensated glycemic states.J MEDICINE July 2015; 16 (2) : 83-88

Facial recognition deficits as a potential endophenotype in bipolar disorder

Bipolar disorder (BD) is considered a highly heritable and genetically complex disorder. Several cognitive functions, such as executive functions and verbal memory have been suggested as promising candidates for endophenotypes. Although there is evidence for deficits in facial emotion recognition in individuals with BD, studies investigating these functions as endophenotypes are rare. The current study investigates emotion recognition as a potential endophenotype in BD by comparing 36 BD participants, 24 of their 1st degree relatives and 40 healthy control participants in a computerised facial emotion recognition task. Group differences were evaluated using repeated measurement analysis of co-variance with age as a covariate. Results revealed slowed emotion recognition for both BD and their relatives. Furthermore, BD participants were less accurate than healthy controls in their recognition of emotion expressions. We found no evidence of emotion specific differences between groups. Our results provide evidence for facial recognition as a potential endophenotype in BD.

Screening of mentally handicapped Egyptian children for fragile X syndrome using clinical, cytogenetic and molecular approaches

Abstract . To screen children with idiopathic mental retardation (MR) using a clinical Ten-Item Checklist (TIC) and to analyzehigh-risk fragile X syndrome (FXS) cases by cytogenetic and molecular genetic techniques. This study was conducted on 192children with idiopathic MR enrolled from Pediatric clinics of University Hospitals and MR institutes of Alexandria, Mansouraand Benha Governorates, Nile Delta, Egypt (age range 2–14 years). Clinical scoring for patients was done using TIC according towhich patients were categorized either positive checklist withscore higher than 5 or negative with score less than 5. Positive casesunderwent cytogenetic analysis that provoke expression of fragile sites on chromosome X and molecular genetic analysis fordetection of permutation among cases or their 1st degree relatives. Analyzing all cases: IQ ranged from 30 to 80%, family historyof MR was found in 28.6% and consanguinity was positive in 26%. Positive checklist cases constituted 23.9% and remainder76.1% were negative checklist. The most frequent items in positive cases were large prominent ears, hyper-extensible fingerjoints, hyperactivity, and large narrow face with less common macro-orchidism. A positive linear association was found betweenlaboratory test positivity and TIC score being stronger with cytogenetic analysis compared to polymerase chain reaction (PCR)(P 0.001 and 0.02, respectively). Using TIC, 76.1% cases could be eliminated from the waiting list of genetics laboratories. Therelatively weaker association of TIC score to PCR compared to cytogenetic analysis together with areas under receiver operatingcharacteristic curve 0.743 and 0.814 respectively denote the higher accuracy and sensitivity of PCR analysis in final diagnosis ofFXS.Keywords: Fragile X syndrome, cytogenetics, molecular genetics, Egypt

Family history and ethnicity influencing clinical presentation of type 1 diabetes in childhood.

A different clinical presentation of type 1 diabetes (T1DM) could be supposed in children belonging to different ethnicities, with or without family history of autoimmunity. This study investigates the effect of ethnicity and family history of T1DM on clinical characteristics at presentation in a group of T1DM children. One hundred ninety-six T1DM children <18years, consecutively diagnosed during the years 2011-2014, were studied including 91% of Caucasians of Italian ancestry and 9% of non-Caucasian origin. Children with 1st or 2nd degree relatives affected by T1DM were younger at disease onset (p=0.005) and showed lower HbA1C levels (p=0.002), and higher IAA levels (p=0.01). Non-Caucasian children were younger at disease onset (p=0.029), and showed more severe hyperglycemia (p=0.008) and ketoacidosis (pH p<0.001). HbA1C levels were negatively related to positive family history of T1DM (p=0.01), fasting C-peptide levels (p=0.003), IAA levels (p=0.03), and IA-2 levels (p=0.003). The level of pH was positively influenced by fasting C-peptide (p=0.004), and negatively impacted by C-reactive protein (p=0.01) and non-Caucasian ethnicity (p=0.03). The milder metabolic decompensation in children with a positive family history of T1DM is probably explained by the awareness of the families in terms of early symptoms of T1DM, while the younger age at onset and the higher levels of autoantibodies may suggest a stronger genetic susceptibility, associated with a more aggressive autoimmune process. The younger age in non-Caucasian children is probably explained by the higher genetic susceptibility in subjects belonging to ethnic groups with a low T1DM incidence. Social aspects and poor living conditions probably predominate in determining the increased severity of metabolic decompensation at onset in children from non-Caucasian ethnicities.

Risk for death from prostate cancer predicted from complete family history of lethal prostate cancer (LPC).

175 Background: There are few published reports of relative risk (RR) for LPC based on family history of prostate cancer (PC) lethality. This study provides LPC RR using complete LPC family history data obtained from a statewide Cancer Registry linked to a genealogy database. Methods: The Utah Population Data Base (UPDB), which includes a statewide SEER cancer registry, includes 1,192,768 individuals with at least 12 of their 14 immediate ancestors. All males (probands) with specific LPC constellations were identified in the UPDB, and the observed number of LPC cases among these probands was compared to the expected number of LPC cases using internal cohort-specific rates from Utah death certificates including all deceased males with no 1st, 2nd, or 3rd degree relatives with LPC. LPC Family history was estimated for 1st degree to 3rd degree relatives for: number of LPC relatives affected, paternal versus maternal family history, and age at first PC diagnosis. Results: 3,921 individuals in UPDB were diagnosed with histologically confirmed PC, and had a Utah death certificate indicating PC as a cause of death and were designated LPC. The RR for LPC was significantly elevated with each additional first-degree relative (FDR) with LPC; even in the absence of FDR family history of LPC, significantly increased risk for LPC was observed in the presence of at least 1 LPC affected second degree relative (SDR). In the absence of positive FDR and SDR family history for LPC, there was still increased risk for LPC for males with 2 or more third degree relatives with LPC. Early age PC diagnosis in the LPC relative did not appear to affect LPC RR. Higher risks of LPC were associated with the maternal compared to the paternal lineages. Conclusions: Examination of lethal prostate cancer family history (in FDRs through TDRs) may be useful in identifying the cohort of men with prostate cancer most at risk for death from prostate cancer. Focused screening and treatment of this cohort holds potential to decrease the rates of undertreatment of lethal disease while avoiding over diagnosis and overtreatment in inconsequential disease.

Cross-sectional and Longitudinal Analyses of Factors Contributing to the Progressive Loss of the β-cell Function in Type 2 Diabetes.

Type 2 diabetes is a progressive disease characterized by insulin resistance and insulin secretory dysfunction. In this study, we assessed the factors contributing to an insulin secretory defect in type 2 diabetes patients. The subjects consisted of 382 patients with type 2 diabetes, aged 57±13 years. We estimated the β-cell function using 6-min post-glucagon increments in C-peptide (ΔCPR). A significant inverse correlation was observed between the time since the diagnosis of diabetes and ΔCPR. A simple liner regression analysis showed that ΔCPR decreases at a rate of 0.056 ng/mL/year. According to a multiple regression model, body mass index (BMI) and log (triglyceride) were positively correlated with ΔCPR. Time since the diagnosis of diabetes, diabetes in 1st degree relatives, the presence of diabetic retinopathy, and HbA1c were inversely correlated with ΔCPR. In 50 patients who underwent the glucagon stimulation test twice, the ΔCPR decreased from 2.27±1.47 to 1.72±1.08 ng/mL over a period of 6.5±0.9 years. A multiple regression analysis revealed the BMI and fasting plasma glucose level to be significant contributing factors to the decline in ΔCPR. The duration of diabetes, a low BMI, genetic factors, and the presence of microangiopathy may be associated with β-cell dysfunction in diabetic patients. The observations in this study suggest that obese subjects showed a rapid decline in the β-cell function despite an initial high CPR response. Environmental factors causing insulin resistance and glucotoxicity may therefore be involved in progressive β-cell failure.

Ultrasound and cytological diagnostics of thyroid - its proper application in case of coexisting disturbing clinical signs and symptoms, suggestive of active proliferative lesion

Ultrasound and cytological diagnostics of thyroid - its proper application in case of coexisting disturbing clinical signs and symptoms, suggestive of active proliferative lesion

The prevalence of Diabetes Mellitus, Dysglycaemia and factors that affect them in Public Employees of Kahramanmaras

Background: Our aim is to determine the prevalence of diabetes mellitus, hypertension, obesity, impaired fasting glucose and socio-demographic characteristics of employees in public institutions and organizations in Kahramanmaras province and to assess the effect of these variables in the development of diabetes mellitus. Methods: The work which was planned as a observational, cross-sectional and an analytical type study was conducted with 1201 male and female participants between 01/10/2013 and 01/12/2013 in the city of Kahramanmaras. Participants were grouped according to age, gender, body mass index (BMI), systolic and diastolic blood pressure, marital status and educational status. In order to determine whether there is correlation between the specified diabetes mellitus and impaired fasting glucose (IFG) groups and other parameters Pearson correlation analysis was performed. DM and a positive correlation between IFG and other parameters were evaluated. Results: DM detection rate in men: 10.0% in females: 9.9%. IFG ratio of male : 31.9 % of female: 27.8 % (P: 0.001). Single / widowed patients DM rate: 5.5 % , dysglycaemia rate : 22.7 %. Married patients with diabetes mellitus were: 10.7 % , with dysglycaemia: 31.7 % (P:0.006). DM ratio of patients that were graduated from primary school level of education: 15% ,dysglycaemia ratio: 27.9% (P = 0.005). High school graduates DM ratio : 11.6% dysglycaemia ratio : 29.8% (P = 0.06). Among university graduates DM ratio: 6.7% dysglycaemia ratio: 38.3% Incidence of DM was measured 15% in participants who had family history of DM , while in participants who had non-diabetic relatives it was 6.8% . Family history was questioned in the 1st degree relatives. The rate of IFG of patients with DM family story : 35.3%, while in patients with non DM family story : 28.2% (P

Profiling β Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme.

Mutation spectrum varies significantly in different parts and different ethnic groups of India. Social factors such as preference to marry within the community and among 1st degree relatives (consanguinity) play an important role in impeding the gene pool of the disease within the community and so in society by and large. The present paper discusses the role of consanguinity in profiling of beta thalassemia mutation, and thus the approach for prenatal screening and prevention based awareness programme. Clinically diagnosed 516 cases of beta thalassemia were screened at molecular level. A detailed clinical Proforma was recorded with the information of origin of the family, ethnicity, and consanguinity. The present study reports that subjects originating from Uttar Pradesh, Uttarakhand, Bihar, and Jharkhand have c.92+5G>C and c.124_127delTTCT mutation as the commonest mutation compared to the subjects hailing from Madhya Pradesh and Chhattisgarh and Nepal where sickle mutation was found more common. In 40 consanguineous unions more common and specific beta mutations with higher rate of homozygosity have been reported. This consanguinity-based data helps not only in deciding target oriented prenatal diagnostic strategies but also in objective based awareness programmes in prevention of thalassemia major birth.

Recommandations pour le diagnostic de prédisposition génétique au mélanome cutané et pour la prise en charge des personnes à risque

Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.

Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives.

Case reports have suggested an association between susceptibility to malignant hyperthermia (MH) and other muscle diseases in subjects with statin-induced muscle toxicity. The aim of the study was to further scrutinize this association in a population-based case-control study including 1st and 2nd degree relatives. Spontaneously reported cases with muscle disorders associated with statin therapy until September 2006 were identified in the Swedish Adverse Drug Reaction Registry at the Medical Products Agency. For each case, ten population-based controls, matched on year of birth and gender, were randomly selected from the National Registry of Swedish Citizens. First and 2nd degree relatives to cases and controls were identified in the Swedish Multi-Generation Registry. ICD codes that could be associated with susceptibility to MH or other muscle diseases were chosen, and subjects were followed until December 2007 with regard to occurrence of selected ICD codes in the Swedish Registries for Cause of Death and Hospital Discharge Diagnoses, respectively. The chosen ICD codes were significantly overrepresented in case families compared with control families (RR 1.56; 95 % CI 1.15-2.10). The strongest associations were identified for a diagnosis of drug-induced or specified or unspecified myopathy (RR 52; 95 % CI 22-123) or a diagnosis of unspecified hyperthermia in combination with drug-induced or specified or unspecified myopathy (RR 30; 95 % CI 6-148). In contrast, a diagnosis of unspecified hyperthermia in the absence of drug-induced or specified or unspecified myopathy was significantly underrepresented among case families (RR 0.42; 95 % CI 0.23-0.76). In a case-control study including 1st and 2nd degree relatives, statin-induced muscle toxicity was significantly associated with a diagnosis of drug-induced or specified or unspecified myopathy and with a diagnosis of unspecified hyperthermia in combination with a diagnosis of drug-induced or specified or unspecified myopathy.

Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia.

BackgroundFamilial hypercholesterolemia (FH) is an autosomal-dominant disease leading to markedly elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature myocardial infarction (MI). Mutation carriers display variable LDL cholesterol levels, which may obscure the diagnosis. We examined by whole-exome sequencing a family in which multiple myocardial infarctions occurred at a young age with unclear etiology.MethodsWhole-exome sequencing of three affected family members, validation of the identified variant with Sanger-sequencing, and subsequent co-segregation analysis in the family.ResultsThe index patient (LDL cholesterol 188 mg/dL) was referred for molecular-genetic investigations. He had coronary artery bypass graft (CABG) at the age of 59 years; 12 out of 15 1st, 2nd and 3rd degree relatives were affected with coronary artery disease (CAD) and/or premature myocardial infarction (MI). We sequenced the whole-exome of the patient and two cousins with premature MI. After filtering, we were left with a potentially disease causing variant in the LDL receptor (LDLR) gene, which we validated by Sanger-sequencing (nucleotide substitution in the acceptor splice-site of exon 10, c.1359-1G > A). Sequencing of all family members available for genetic analysis revealed co-segregation of the variant with CAD (LOD 3.0) and increased LDLC (>190 mg/dL), following correction for statin treatment (LOD 4.3). Interestingly, mutation carriers presented with highly variable corrected (183–354 mg/dL) and on-treatment LDL levels (116–274 mg/dL) such that the diagnosis of FH in this family was made only after the molecular-genetic analysis.ConclusionEven in families with unusual clustering of CAD FH remains to be underdiagnosed, which underscores the need for implementation of systematic screening programs. Whole-exome sequencing may facilitate identification of disease-causing variants in families with unclear etiology of MI and enable preventive treatment of mutation carriers in a more timely fashion.

Dupuytren’s disease and the risk of malignant neoplasms

The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren’s disease (DD) and in 2157 of their 1st degree relatives. In the first stage of the study, we evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in DD families along with the observed and expected frequencies of malignancies. In the second stage of the study, we examined the distribution of 20 common mutations/polymorphisms in 12 known cancer susceptibility genes among DD patients and 508 matched healthy controls. No such study has been published to date. Results. No significant differences were noted between malignancies diagnosed among members of DD families and the general population. Molecular examination of 20 mutations/polymorphisms in 12 cancer susceptibility genes in Dupuytren’s patients and controls showed a statistically significant association of one mutation with Dupuytren disease: D312M in XPD (OR = 1.75, p = 0.004). We observed a tendency toward changed frequencies of occurrence of central nervous system tumors, laryngeal cancer and non-melanoma skin cancers in DD families. The results of our study indicate a lack of a strong association between Dupuytren disease and familial cancer risk.

A67: Factors That Contribute to Classification of Children as Having Undifferentiated Juvenile Idiopathic Arthritis

Background/Purpose:According to the ILAR criteria, undifferentiated juvenile idiopathic arthritis (U‐JIA) includes children who fail to meet criteria for 1 of the other 6 categories or who meet criteria in more than 1 category. Classification requires category‐specific application of 5 exclusion criteria: 1. Psoriasis in the patient or a 1st degree relative; 2. Arthritis beginning after the 6th birthday in an HLA‐B27 + male; 3. HLAB27 associated disease in a 1st degree relative; 4. Rheumatoid factor positivity (RF+) on 2 occasions; and 5. The presence of systemic JIA (SoJIA).A pilot single‐centre study (n=21) revealed that psoriasis in a 1st degree relative was the most common reason for classifying patients as U‐JIA; disregarding this criterion would allow re‐classification of most U‐JIA patients and had no impact on the classification of JPsA patients (Chan et al., 2011). We aimed to determine the most frequent reasons for classifying children as U‐JIA from a large multicenter prospective cohort of children with JIA (n=1104).Methods:Two investigators reviewed data on patients diagnosed with UJIA extracted from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh‐Out) database. They identified by consensus the reasons for classifying patients as U‐JIA and the JIA category they would fall in if the following two changes were made: disregarding psoriasis in a 1st degree relative, considering patients as RF negative when only a single positive RF test was recorded.Results:84 patients (51 female), were classified as U‐JIA for the reasons shown in the . Exclusion criteria 1st degree relative with psoriasis (n=57) B27 male&gt;6 years + arthritis (n=4) RF+ on 2 occasions (n=1) RF+ on 1 occasion only (n=17) 1st degree relative with B27 related disease (n=4) SoJIA (n=0) Fulfills criteria for 2 categories (n=2) Revised category if exclusion criteria disregarded Oligo 25 9 2 Poly RF− 13 2 Poly RF+ 5 (1 RF+x2, 4 RF+x1) ERA 12 5 Systemic 2 1 JPsA 4 1 U‐JIA 1 1 2 (JPsA + ERA)If the criterion of having a 1st degree relative with psoriasis was disregarded, 25 patients would be classified as oligo JIA, 13 poly RF−, 5 poly RF+, 12 ERA and 2 SoJIA. If a single positive RF test was considered to be insufficient to meet the ILAR criterion of RF positivity, 9 patients would be re‐classified as oligo JIA, 5 ERA, 1 SoJIA, 1 JPsA and 1 would remain U‐JIA.Conclusion:Psoriasis in a 1st degree relative is the most common factor contributing to the classification of a child as having U‐JIA and removing it from the existing criteria should be considered. The presence of a single positive test for RF was the second most common reason resulting in a classification of U‐JIA. Definitive RF testing (two tests) should be maintained to satisfy the criterion of “RF positivity”.

Screening for celiac disease in 1st degree relatives: a 10-year follow-up study

BackgroundAlthough it is known that first degree relatives of celiac patients have an increased risk for celiac disease few studies are available on its incidence. We investigated the incidence of serologic conversion and of new cases of celiac disease among first degree relatives with negative results at a first screening.MethodsFrom a total of 634 first degree relatives of 186 biopsy-proven celiac disease patients diagnosed between October 2000 and October 2010, 450 subjects agreed to participate in the study (Group I), and underwent serologic screening. Between January 2010 and October 2012, out of the initial group of 450, 205 previously sero-negative subjects consented to participate in a second stage of the study and undergo new serologic testing (Group II). All serologically positive individuals of both groups (I and II) were genotyped for celiac disease-predisposing alleles (HLA-DQ2/DQ8).Results19 subjects (4.2%) out of the 450 subjects of Group I disclosed positive serologic results, presence of DQ2 and/or DQ8 alleles and celiac disease-compatible mucosal abnormalities. The 205 previously negative first degree relatives from Group II that underwent new serologic testing disclosed eight sero-converted subjects. Mucosal abnormalities in five of these patients confirmed the diagnosis of celiac disease. During the 10-year period of the study the incidence of sero-conversion was 8/205 and the incidence of biopsy-proven celiac disease cases was 5/205.ConclusionsOur data are coincident with other works on this subject and confirm once again that relatives of celiac patients, especially first degree relatives are at high risk of developing celiac disease. In view of the relatively low incidence further studies are needed to try to establish a useful and cost-effective algorithm for follow-up of relatives of celiac patients.

Completeness of pedigree and family cancer history for ovarian cancer patients.

ObjectiveTo investigate the completeness of pedigree and of number of pedigree analysis to know the acceptable familial history in Korean women with ovarian cancer.MethodsInterview was conducted in 50 ovarian cancer patients for obtaining familial history three times over the 6 weeks. The completeness of pedigree is estimated in terms of familial history of disease (cancer), health status (health living, disease and death), and onset age of disease and death.ResultsThe completion of pedigree was 79.3, 85.1, and 85.6% at the 1st, 2nd, and 3rd time of interview and the time for pedigree analysis was 34.3, 10.8, and 3.1 minutes, respectively. The factors limiting pedigree analysis were as follows: out of contact with their relatives (38%), no living ancestors who know the family history (34%), dispersed family member because of the Korean War (16%), unknown cause of death (12%), reluctance to ask medical history of relatives (10%), and concealing their ovarian cancer (10%). The percentage of cancers revealed in 1st (2%) and 2nd degree (8%) relatives were increasing through surveys, especially colorectal cancer related with Lynch syndrome (4%).ConclusionAnalysis of pedigree at least two times is acceptable in Korean woman with ovarian cancer from the first study. The completion of pedigree is increasing, while time to take family history is decreasing during three time survey.

Abstract P5-13-03: Factors associated with prophylactic mastectomy among BRCA-positive patients with no personal history of breast cancer

Abstract Background: The rate of prophylactic mastectomy (PM) has recently increased1. A deleterious mutation in the BRCA1 or BRCA 2 genes is among the major reasons why patients pursue PM 2, 3. Women with BRCA1 or BRCA2 gene mutations have up to an 87% risk to develop an invasive breast cancer (BC), and up to 45% risk for ovarian cancer (OC)2, 3. Most studies evaluating predictors of PM in BRCA mutation carriers are performed among women with breast cancer; however, accurate predictors for PM among unaffected BRCA mutation carriers are less defined. In a single institution study we aimed to evaluate predictors of PM among BRCA carriers with no personal history of breast cancer. Method: One hundred seventy seven women with no personal history of BC, who tested positive for a BRCA1 or BRCA 2 germline mutation, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database under an IRB approved protocol at UT MD Anderson Cancer Center. Univariate analyses using chi-square and logistic regression analysis were used to determine predictive factors associated with PM. The patient characteristics examined included age, martial and educational status, bilateral salphingo-oophorectomy (BSO), family history of 1st and 2nd degree relatives with breast (BC) and ovarian cancer (OC), race, and BRCA genetic test result. Results: Out of the 177 BRCA1 and BRCA 2 positive patients, 51 (29%) elected for PM. The average age for the cohort was 44 years (range 23-91). The majority were Caucasian (81%), and married (72%) with a college degree (64%). One hundred sixty-four (92%) patients had 1st and 2nd degree relatives with BC, 93 (53%) had 1st and 2nd degree relatives with OC, and 85 (48%) had undergone BSO. A logistic regression model was run to identify factors associated with undergoing PM, including family history of OC, family history of BC, BSO and age. Patients with a family history of OC were 2.5 times more likely than those without to have had a PM (p = 0.0125), and patients who had a BSO were 0.137 times less likely to have had a PM (p &amp;lt;.0001). Only 12 patients did not have a family history of BC and none of those patients had a PM, so an Odds Ratio could not be calculated. However, it was determined through the Fisher's exact test that patients with a family history of BC were more likely to undergo a PM (p = 0.0198). Conclusion: The rate of PM in our cohort was slightly lower than expected. Factors associated with PM included a family history of BC and OC. Interestingly, having had a BSO was associated with lower likelihood of undergoing PM (menopausal status will be further evaluated); possibly due to the knowledge that BSO reduces breast cancer risk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-03.

Abstract 351: The Family Study: Assessment of the Risk for Sudden Cardiac Arrest in Family Members of Cardiac Arrest Patients

Background: Sudden cardiac arrest (SCA) is devastating for the patient’s family, friends, and community. There is limited information on its identifiable familial predisposition. Objectives: To evaluate the familial risk pattern for SCA in family members of cases compared to age-and-sex matched control groups. Incidence of prior symptoms and SCA triggers were also compared. Methods: We used a prospectively collected, population-based registry of all out-of-hospital cardiac arrests (OHCAs) in the Greater Toronto Area, to identify cases from 2010-2012. Cases were defined as SCA patients aged 18-65 who arrested from a cardiac cause and were treated by Emergency Medical Services. Two relatives per patient were interviewed regarding symptoms prior to the arrest, cardiac history and family history of SCA. Control patients with known coronary heart disease (CHD) and healthy participants were recruited from PCI procedures and the Family Practice Units at St. Michael’s Hospital. Results: Complete family and medical history was obtained for 66 SCA cases, 56 heart disease patients and 27 healthy controls. Underlying diseases were CHD in 77%, non-CHD structural heart disease in 9%, primary arrhythmic in 3% and presumed cardiac of unknown etiology in 11%. A higher proportion of SCA individuals had a family history of SCA in 1st degree relatives (19/66; 28.8%) than 1st degree relatives of healthy controls (2/27; 7%; p=0.006) and 1st degree relatives of patients with heart disease (14/56; 25%) (Table 1). Among families with SCA, 3/66 (4.5%) had a history of &gt;1 relative with SCA, vs. none in either control group. Most SCA patients experienced one or more warning symptoms in the hour preceding an arrest (40/66; 61%); 24/66 (36%) experienced a cardiac arrest during or following exercise. Conclusion: Family members of SCA patients have a higher SCA prevalence than family members of healthy controls. A high proportion of SCA patients experienced symptoms in the hour preceding their arrest.

Chromogranin A is a T cell antigen in human type 1 diabetes

Chromogranin A (ChgA) is a beta cell secretory granule protein and a peptide of ChgA, WE14, was recently identified as a ligand for diabetogenic CD4 T cell clones derived from the NOD mouse. In this study we compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. T cell responders to antigens were detected in PBMCs from study subjects by an indirect CD4 ELISPOT assay for IFN-γ. T1D patients (n = 27) were recent onset patients within one year of diagnosis, typed for HLA-DQ8. Controls (n = 31) were either 1st degree relatives with no antibodies or from the HLA-matched general population cohort of DAISY/TEDDY. A second cohort of patients (n = 11) and control subjects (n = 11) was tested at lower peptide concentrations. We found that WE14 is recognized by T cells from diabetic subjects vs. controls in a dose dependent manner. Treatment of WE14 with transglutaminase increased reactivity to the peptide in some patients. This work suggests that ChgA is an important target antigen in human T1D subjects and that post-translational modification may play a role in its reactivity and relationship to disease.

Disease severity in familial cases of IBD

BackgroundPhenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. AimTo know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. Methods5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. ResultsIn UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33years [IQR 25–44] vs 37years [IQR 27–49]; p<0.0001); (CD: 27years [IQR 21–35] vs 29years [IQR 22–40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. ConclusionWhen a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.