First-degree Relatives Of Probands Research Articles

Familial clustering of nonalcoholic fatty liver disease in first-degree relatives of adults with lean nonalcoholic fatty liver disease.

The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD. This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.

Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test. Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Relationship Between a Vitamin D Genetic Risk Score and Autoantibodies Among First-Degree Relatives of Probands With Rheumatoid Arthritis and Systemic Lupus Erythematosus.

ObjectiveHigher 25-hydroxyvitamin D (25(OH)D) levels have been associated with reduced risk for autoimmune diseases and are influenced by vitamin D metabolism genes. We estimated genetically-determined vitamin D levels by calculating a genetic risk score (GRS) and investigated whether the vitamin D GRS was associated with the presence of autoantibodies related to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in those at increased risk for developing RA and SLE, respectively.MethodsIn this cross-sectional study, we selected autoantibody positive (aAb+) and autoantibody negative (aAb-) individuals from the Studies of the Etiologies of Rheumatoid Arthritis (SERA), a cohort study of first-degree relatives (FDRs) of individuals with RA (189 RA aAb+, 181 RA aAb-), and the Lupus Family Registry and Repository (LFRR), a cohort study of FDRs of individuals with SLE (157 SLE aAb+, 185 SLE aAb-). Five SNPs known to be associated with serum 25(OH)D levels were analyzed individually as well as in a GRS: rs4588 (GC), rs12785878 (NADSYN1), rs10741657 (CYP2R1), rs6538691 (AMDHD1), and rs8018720 (SEC23A).ResultsBoth cohorts had similar demographic characteristics, with significantly older and a higher proportion of males in the aAb+ FDRs. The vitamin D GRS was inversely associated with RA aAb+ (OR = 0.85, 95% CI = 0.74-0.99), suggesting a possible protective factor for RA aAb positivity in FDRs of RA probands. The vitamin D GRS was not associated with SLE aAb+ in the LFRR (OR = 1.09, 95% CI = 0.94-1.27). The SEC23A SNP was associated with RA aAb+ in SERA (OR = 0.65, 95% CI = 0.43-0.99); this SNP was not associated with SLE aAb+ in LFRR (OR = 1.41, 95% CI = 0.90 – 2.19).ConclusionGenes associated with vitamin D levels may play a protective role in the development of RA aAbs in FDRs of RA probands, perhaps through affecting lifelong vitamin D status. The GRS and the SEC23A SNP may be of interest for future investigation in pre-clinical RA. In contrast, these results do not support a similar association in SLE FDRs, suggesting other mechanisms involved in the relationship between vitamin D and SLE aAbs not assessed in this study.

Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years

ObjectiveFactors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands’ HLA-B27 and radiographic sacroiliitis...

Predictive Testing for Tumor Predisposition Syndromes in Pediatric Relatives: An Asian Experience.

Approximately 10% of pediatric cancer patients possess germline pathogenic/likely pathogenic variants (PV/LPV) in known tumor predisposition genes. Predictive testing is the optimal approach to identify asymptomatic at-risk relatives to guide gene-directed surveillance for early cancer detection and/or risk-reducing strategies. However, the uptake rate for predictive testing remains low in Asian countries. We aim to evaluate the uptake rate of predictive testing in a pediatric population (aged under 21-years-old) in a multi-ethnic Asian cancer center. Our retrospective analysis included families with PV/LPVs identified in genes associated with pediatric tumor predisposition. Of the 83 pediatric first-degree relatives (FDRs) from 49 unrelated families, 20 FDRs (24.1%) originating from 13 families (26.6%) underwent predictive testing. Genes tested in pediatric FDRs were APC, RB1, SBDS, SDHA, SDHB, SDHD, and TP53. All pediatric FDRs of probands with PV/LPVs in RB1 and biallelic PVs in SBDS underwent predictive testing, while <45% of pediatric FDRs had predictive testing for familial PV/LPVs identified in the APC, SDHA, SDHB, SDHD, and TP53 genes. Amongst the 13 families who underwent pre-test counseling, 80% of pediatric FDRs in these families proceeded with predictive testing. Malay pediatric FDRs and siblings of probands were more likely to undergo predictive testing. We conclude that the predictive testing rate in pediatric FDRs is higher than that of adult FDRs in Asia, but still below the global average. We postulate factors that may influence predictive testing uptake in pediatric FDRs includes a lack of genetics awareness, concerns regarding insurance, and genetic discrimination.

1269The SADS heart of the matter: a review of the sudden arrhythmic death syndrome (SADS) biobank - the cornerstone of a national strategy

Abstract Background Sudden cardiac death (SCD) in the young (age 1-35) is commonly attributed to structural and arrhythmogenic syndromes, for which there is often an underlying genetic basis. Expert recommendation emphasises the importance of genetic testing in such cases, however to date this remains the first and only national programme in Europe to facilitate this. Aim To review detection rates of genetic variants in samples tested via the SADS BioBank and possibly demonstrate the merits of this novel resource for primary prevention for family members. Methods Family screening and consent for genetic testing was carried out in the Family Heart Screening Clinic. Result analysis of samples sent for molecular autopsy via the BioBank from its induction in January 2015 was performed. Genetic analysis was conducted via the same internationally accredited next generation sequencing lab. Results From January 2015 to July 2019, 161 samples had been stored in the SADS BioBank following confirmed SADS death on autopsy; 33% female and 67% male. Of these, 24 (14.9%) samples were sent for genetic testing: 21 for a 380 gene molecular autopsy and 3 for a targeted hypertrophic cardiomyopathy panel (173 genes). Of 24 samples tested, 10 (42%) yielded positive genetic variants: 4 American College of Medical Genetics (ACMG) Class IV or V mutations considered pathogenic, and 6 ACMG class III variants of uncertain significance (VUS). Familial cascade screening following confirmed pathogenic mutations resulted in detection of 3 (33.3%) positive genotypes in 9 first-degree relatives. Screening of relatives of Class III positive probands resulted in diagnosis of an Inherited Cardiac Condition (ICC) in 25% of first-degree relatives. 8.2% of first-degree relatives of probands with negative gene testing were given an ICC diagnosis following clinical screening. Conclusions This short study demonstrates the unique potential the SADS BioBank has to offer in terms of identifying those most at risk and optimising prevention strategies for relatives, thus highlighting the role for such a resource in terms of preventative screening in the future. Pathogenic Variant (ACMG Class IV &amp; V) Variant of Uncertain Significance(ACMG Class III) No Gene Variant Identified Number Detected (n = 24) 4 6 14 1st Degree Relatives Screened (n = 86) 17 20 49 2nd Degree Relatives Screened (n = 46) 4 23 19 Genotype Detected (n = 4) 3 1 0 Phenotype Detected (n = 10) 1 5 4 Breakdown of clinical and genetic results of family screening by ACMG class. Abstract Figure.

Analysis of the incidence in malignant neoplasms in firstdegree relatives of probands with glial brain tumors

The article presents a simplified analytical method of evaluating the cancer incidence in first-degree relatives with glial brain tumors. The method is based on the use of population cancer incidence rates in the Belarus population and the estimated numbers of first-degree relatives in the time interval corresponding to the average life span in the Belarus population. This method was employed to analyze the cancer incidence in the patients of first-degree relatives who were treated at the N.N. Alexandrov National Cancer Centre. Their diagnosis was the glial brain tumor. The number of the investigated first-degree relatives was 1012, of them 502 were males and 510 – females. As of December 31, 2015, this group had 63 cases of malignant neoplasms. According to the findings of the analysis performed, the first-degree relatives are at an increased risk for brain, rectum, thyroid and corpus uteri cancers. However, the statistically significant risk was found only for brain cancer incidence. The standardized incidence rate in first-degree relatives was 3.39 for this site (95 % CI 1.10–7.92), which is consistent with the data obtained by specialists of other countries (USA, Sweden and others).The agreement of the standardized incidence values suggests that the simplified analytical method provides an adequate account of the incidence among the patients of first-degree relatives with an established diagnosis of malignant neoplasm.

Abstract 1239: Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type

Abstract Background: Pancreatic cancer (PC) ranks among the top causes of cancer mortality. Risk stratification is an important step toward prevention and early detection. Prior work has shown that ABO blood type (non-O) and first-degree family history of PC are associated with increased PC risk. Individuals with first-degree family history of PC have a 2- to 3-fold increased risk, but it is unclear if ABO blood type plays a role in the familial aggregation of PC. We investigated PC risk among first-degree relatives (FDRs) of PC probands based on the probands' serologic blood type (O vs non-O). Methods: A total of 702 probands sequentially enrolled in the Mayo Clinic Pancreas Research Registry from 2000-2016 with serologic ABO blood type provided information on family history of cancer for 5,178 FDRs. FDRs were grouped based on their related probands' blood type as type O (n=242; 1,768 FDRs) vs non-O (n=460; 3,410 FDRs). Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the number of PC cases observed among FDRs to those expected using data from the Surveillance, Epidemiology and End Results (SEER) Program as the reference population. SIRs for PC risk were calculated separately for FDRs of probands with type O vs FDRs of probands with non-O blood, and stratified by sex of FDRs and relationship to proband (parent, sibling, or offspring). Results: Compared to the SEER reference, PC risk was nearly 2-fold higher among FDRs of PC probands (SIR=1.76; 95%CI: 1.35-2.26). When stratified by probands' ABO type, risk for PC was higher among FDRs of probands with non-O blood (SIR=1.94; 95%CI: 1.41-2.60), compared to FDRs of probands with O blood (SIR=1.42; 95%CI: 0.83-2.28). Parents of probands with non-O blood had increased PC risk (SIR=3.28; 95%CI: 2.18-4.74, n=920), but not parents of probands with O blood (SIR=1.75; 95%CI: 0.75-3.45, n=484), p-value for between-group difference=0.10. Among FDRs of probands with O blood, female FDRs had increased PC risk (SIR=2.12; 95%CI: 1.06-3.79), but male FDRs did not (SIR=0.86; 95%CI: 0.31-1.88). Higher PC risk was observed among female FDRs of probands with non-O blood (SIR=2.28; 95%CI: 1.44-3.41) than male FDRs of probands with non-O blood (SIR=1.62; 95%CI: 1.00-2.48). Mothers of probands with O blood had increased PC risk (SIR=2.89; 95%CI: 1.05-6.28) compared to fathers (SIR=0.79; 95%CI: 0.09-2.84). Both mothers (SIR=3.60; 95%CI: 1.96-6.03) and fathers (SIR=2.95; 95%CI: 1.61-4.95) of probands with non-O blood had increased PC risk. No major findings were observed among probands' siblings or offspring. Conclusions: PC risk is greater among FDRs of PC probands with non-O blood than among FDRs of probands with type O. PC risk is higher among parents of probands with non-O blood, and female FDRs and mothers of probands with non-O blood. Possible clustering of non-O blood type in families may contribute to increased PC risk. Citation Format: Aarti Kolluri, Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, Brendan T. Broderick, William R. Bamlet, Ann L. Oberg, Robert R. McWilliams, Gloria M. Petersen. Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type [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 1239.

A comparative meta-analysis of neurocognition in first-degree relatives of patients with schizophrenia and bipolar disorder

ObjectiveCognitive impairment is a familial and heritable aspect of major psychoses and might be a shared vulnerability marker for schizophrenia and BP. However, it is not clear whether some aspects of cognitive deficits are uniquely associated with risk for specific diagnoses. MethodsA novel meta-analysis of cognitive functions in first-degree relatives of probands with bipolar disorder (BP-Rel) and schizophrenia (Sch-Rel) was conducted. Current meta-analysis included 20 studies and compared cognitive functions of 1341 Sch-Rel, 939 BP-Rel and 1427 healthy controls. ResultsSch-Rel was associated with cognitive deficits in all domains (d=0.20–0.58) and BP-Rel underperformed healthy controls in processing speed, verbal fluency and speed based executive function tests (d=0.33–0.41). Sch-Rel underperformed BP-Rel in general intellectual ability, working memory, verbal memory, planning, processing speed and fluency (d=0.24–0.42). ConclusionsInefficiency in processing information and impaired processing speed might be common vulnerability factors for major psychoses. On the other hand, low performance in accuracy based tasks and deficits in general intellectual ability, verbal learning, planning and working memory might be more specifically associated with risk for schizophrenia.

Advanced Colorectal Neoplasm Screening in First-Degree Relatives is Better Understanding as Cruciform Screening

Aim: Colonoscopy screening of colorectal neoplasm in first-degree relatives is reported frequently, and is recommended in guidelines. However, data from China is limited. This observation study is to evaluate the current situation in Dongguan, China. Methods: All first-degree relatives were recommended to perform colonoscopy screening when a proband is found in a family. They were divided into 3 groups, the down, up and crossing screening group (children, parents and siblings of proband). Control group rolled in healthy people who underwent colonoscopy while medical examination in our hospital. All subjects ranged from 30-80 (not included) years old. Advanced colorectal neoplasm is defined as: high-grade adenoma, villioustublar adenoma, adenoma with diameter ≧ 1 cm and colorectal cancer. Colonoscopy findings of lesions, site and size of the ACNs and polyp, pathology results of all subjects were recorded. Statistical analysis was run with SPSS 19.0. Results: In 52 subjects of the Down screening group, 6 were found to be CANs, 9 were adenoma, the overall morbidity in the group is 28.8%. 8 out of 43 subjects in up screening group were found CANs, 7 were adenoma, making the overall morbidity is 34.9% of the group. There were 3 subjects in crossing screening group out of 28 found to be CANs, 5 subjects were adenoma, overall morbidity of the group is 28.6%. Comparing to the control group, there were 176 subjects involved, 15 of them were found to be CANs, 9 were found adenoma, overall morbidity is 13.6% in control group. Statistical analysis indicates that there were significant statistical differences when comparing the down, up and crossing screening group to control group (all p<0.05). Conclusion: First-degree relatives of proband in Dongguan have a high incidence of colorectal neoplasm, it is recommended to run colonoscopy screening. And it is better understanding as ‘Cruciform screening’ while screening of first-degree relatives.

Familial Aggregation of Insomnia.

There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first-degree relatives (Mage = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (Mage = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia.

Familial aggregation of Parkinson disease in Utah: A population-based analysis using death certificates.

Objective:To describe clustering of death from Parkinson disease (PD) in relatives in a large US study.Methods:We analyzed the Utah Population Database resource, which includes genealogy data of more than 2.7 million individuals linked to 519,061 individuals with a Utah death certificate (DC). We identified individuals whose DC included PD as a cause of death using ICD coding. In those individuals whose Utah DC listed PD as a cause of death, the relative risk (RR) of death with PD was determined among close and distant relatives using sex-, birth year–, and birthplace-specific rates.Results:We identified 4,031 individuals whose DC indicated PD. Among 18,127 first-degree relatives of probands with a Utah DC, the RR of death with PD was significantly increased (RR = 1.82, 95% confidence interval [CI] 1.61–2.04). The RR of death with PD was also significantly increased among 40,546 second-degree relatives with a Utah DC (RR = 1.44, 95% CI 1.29–1.60) and among 93,398 third-degree relatives with a Utah DC (RR = 1.10, 95% CI 1.03–1.18).Conclusions:Significant evidence for excess familial clustering was observed for PD deaths. The excess familial clustering and the significantly elevated RRs for PD among close and distant relatives strongly support a genetic contribution to PD mortality. These results confirm and expand the results of previous studies of PD by quantifying the risk of PD death among more distant relatives.

Communicating genetic test results within the family: Is it lost in translation? A survey of relatives in the randomized six-step study.

Genetic testing for cancer susceptibility genes is increasingly being integrated into medical care. Test results help inform risks of the individual being tested as well as family members who could benefit from knowing the results. The responsibility for informing relatives of genetic test results falls on the proband, the first family member being tested. However, there are several challenges associated with sharing genetic test results within families including incomplete understanding of test results, emotional distance among family members, and poor communication skills. In this paper we describe the communication process between probands randomized to receive BRCA1/2 genetic test results in an enhanced versus a standard of care counseling session, and their first degree relatives with whom they shared results. We contacted 561 first degree relatives of probands who had undergone BRCA1/2 genetic testing to measure their level of understanding of the test results, their difficulty and distress upon hearing the results, the impact of the test results on their risk perception, and their intention to pursue genetic counseling/testing. 82.1 % of relatives correctly reported the test results of their proband. Distress upon hearing the test result was highest for those relatives whose proband received informative test results. Relatives reported a decrease in cancer risk perception after hearing the test results, regardless of the type of result. Intention to pursue counseling/testing was low, even among those relatives whose proband received informative test results. Male relatives were less likely to be informed of test results and more likely to forget hearing them. These results suggest ways to improve the communication process within families.

Obsessive beliefs in first-degree relatives of probands with Obsessive–Compulsive Disorder: Is the cognitive vulnerability in relatives specific to OCD?

BackgroundSpecific dysfunctional beliefs have been identified as candidate endophenotypes for Obsessive–Compulsive Disorder (OCD). Rector, Cassin, Richter, and Burroughs (2009) investigated cognitive vulnerability for OCD and their results support both the notion of familial-based origin of obsessive beliefs, and the hypothesis that inflated responsibility/overestimation of threat, could represent candidate endophenotypes for OCD. AimsThe primary aim of this study was to replicate previous findings of a familial cognitive vulnerability for OCD. The secondary purpose was to test the hypothesis that obsessive beliefs of patients with OCD and those of their first-degree relatives (FDRs) are correlated, supporting dysfunctional beliefs as candidate endophenotypes for OCD. Method65 patients with DSM-IV-TR (SCID-I) OCD were included together with one healthy FDR. 77 non-affected FDRs of patients with Bipolar Disorder were enrolled as a control group. Obsessive beliefs were measured with the OBQ-44. ResultsFirst-degree relatives of subjects with OCD scored significantly higher than controls on the total score and on the domain tapping inflated responsibility and overestimation of threat. There was no significant correlation between each obsessive belief in patients with OCD and their non-affected FDRs. ConclusionsOur study provides evidence of a specific cognitive vulnerability for OCD in FDRs of probands with OCD.

PROSTATE CANCER AND HEREDITARY SYNDROMES

The aim of this study is to assess relative risk of prostate cancer (PC) and other tumors in families of patients with multiple primary malignancies (MPM) and the syndrome of hereditary nonpolyposis colorectal cancer (HNPCC). The study is based on data from the cancer register of families that includes information on 560 patients with MPM, 126 families with HNPCC and their first-degree relatives. Incidence of these diseases in population served as the control. Among 560 probands with PPN 217 (38.7%) were male and 343 (61.3%) – female. Only 12 (2.1%) male patients had tumor in the prostate. In these patients 24 tumors were identified. Two patients had synchronous tumors, other ten patients had metachronous. Eight patients with prostate cancer had tumors of other organs: 5 – in rectum, 2 – in colon and 1 – in bladder. As a second tumor prostate cancer was diagnosed in 4 patients, three of them had rectal cancer and one – colon cancer. Only 2 (0.3%) patients had prostate cancer as a primary tumor. Clinical and genealogical information achieved from 543 patients with MPM, including in 206 male probands. Among 3637 first-degree relatives of probands with MPM prostate cancer was diagnosed in 2 (0.11 ±2.3%) patients that was 1.7 times higher than in population (0.063±0.0019%). The relative risk of prostate cancer for relatives of patients from families with HNPCC syndrome was 0.8 ± 6.3% that was 12/7 times higher than in the control group (p <0.05). The estimation of the relative risk in families of male probands was perfprmed. Among 1460 male relatives with MPM only 1 (0.14%) case of prostate cancer was diagnosed (son of proband). Among 42 families of male probands with HNPCC syndrome, prostate cancer was detected in 2 (1.3%) brothers that exceeds population risk 20.6 times. Although the molecular mechanisms and pathogenesis of prostate cancer in such families is unknown, its association with a HNPCC-syndrome and possibly MPM-syndrome is obvious. Higher relative risk of developing prostate cancer for male relatives of probands with MPM and HNPCC syndrome presupposes inherited genetically determined predisposition to disease development. Further molecular and genetic studies are needed to determine the genetic basis of predisposition to prostate cancer in these families.

Cancer risk in the relatives of patients with nasopharyngeal carcinoma—a register-based cohort study in Sweden.

Background:Little is known about cancer susceptibility among relatives of nasopharyngeal carcinoma (NPC) patients in non-endemic areas. We conducted a register-based cohort study to assess the relative risks (RRs) of cancer in families of NPC probands in Sweden.Methods:By linking 11 602 616 Swedish-born individuals (defined as ‘general population') identified from national censuses to the Swedish Cancer Register and Multi-Generation Register, we identified 9157 relatives (3645 first-degree and 5512 second-degree) of 1211 NPC probands. Cancer incidence during 1961–2009 was ascertained through the Cancer Register. Relative risks of cancer in the relatives of NPC probands, compared with the rest of the general population, were calculated from Poisson regression models.Results:First-degree relatives had higher risks of NPC (N=2, RR=4.29, 95% confidence interval (CI)=1.07 to 17.17) and cancers of the larynx (N=5, RR=2.53, 95% CI=1.05 to 6.09), prostate (N=76, RR=1.35, 95% CI=1.07 to 1.68), and thyroid (N=10, RR=2.44, 95% CI=1.31 to 4.53) than the rest of the general population. In addition, a raised risk of cancer of the salivary glands was observed among first-degree relatives of probands with undifferentiated NPC (N=2, RR=6.64, 95% CI=1.66 to 26.57). In contrast, a decreased risk of colorectal cancer was observed in first- and second-degree relatives (N=43, RR=0.71, 95% CI=0.53 to 0.96).Conclusion:The increased risk of NPC and certain other cancers among first-degree relatives may be explained by shared genetic and environmental risk factors, the latter including Epstein–Barr virus infection and smoking or by increased diagnostic intensity.

Abstract 154: Heritability of Ischemic White Matter Lesions in a Family Population with Increased Susceptibility of Vascular Disease

Introduction: Ischemic strokes are more likely to occur in the subcortical region of the brain, and also cluster strongly in families. However, the extent to which ischemic white matter lesions (WML) are heritable in a high risk healthy population remains unknown. We thus examined the heritability of ischemic WML volumes in both the periventricular (PV) and subcortical (SC) brain regions in apparently healthy European American (EA) and African American (AA) families with increased susceptibility for vascular disease . Methods: We measured traditional risk factors, and imaged the brains of 579 healthy first degree relatives of probands with early onset CAD prior to 60 years of age. PV and SC WML volumes were directly measured using 3T cranial MRI. The location and volume of lesions were characterized using standard automated software. Maximum-likelihood estimates of polygenic heritability were performed on the unadjusted and adjusted transformed WML traits with the use of variance components models in the ASSOC subroutine of SAGE. Results: Heritability was analyzed in 359 EA from 122 pedigrees as well as in 220 AA from 75 pedigrees. Participants were 58% women, 37% AA; mean age 51.5±11 (range of 29-74 years). Adjusting for age, sex, systolic blood pressure, and intracranial volume we determined the heritability for total WML volumes in EA’s (h2=0.62, SE 0.135, p&lt;0.00001), and AA (h2=0.16, SE 0.24, p=0.25); for PV WML in EA’s (h2=0.31, SE 0.145, p=0.00167) in AA’s (h2=0.037, SE 0.165, p=0.4118); and for SC WML in EA’s (h2=0.581, SE 0.166, p=0.0002) and AA’s (h2=0.582, SE 0.182, p=0.0007). Conclusions: Total WML volumes were highly heritable in EA, as were both PV, and SC WML volumes. In AA, only SC WML volumes were significantly heritable. In general, heritability estimates where greater for the SC than for the PV WML volumes. These findings suggest a heritable precursor state of stroke-related small vessel cerebrovascular disease in EA, generally greater for the subcortical region where subsequent strokes are more likely to occur, and a similar state only in the SC region in AA high risk healthy family members with susceptibility to vascular disease.

Risk of congenital heart disease in relatives of probands with conotruncal cardiac defects: An evaluation of 1,620 families

Current recurrence risk counseling for conotruncal cardiac defects (CTD) is based on empiric estimates from multiple studies. We examined the risk of congenital heart disease (CHD) in relatives of probands with CTDs to assist in counseling practices in the current era. One thousand six-twenty probands with CTDs and no reported chromosomal or genetic abnormalities were recruited sequentially. A three-generation pedigree was obtained for each proband by a genetic counselor detailing the presence and type of CHD in each family member. Risks and 95% confidence intervals (CI) were calculated for sub-groups of relatives based on degree of relationship for all probands and by individual lesion of the proband. For pairs of affected relatives, concordance rates were calculated. Severity of CHD in the affected relative was assessed. The risk of CHD was higher in siblings (4.4%, 95% CI 3.4-5.4) than in parents (1.5%, 95% CI 1.1-1.9). Risk varied by the cardiac lesion of the proband with the highest risk in first-degree relatives of probands with tetralogy of Fallot and the lowest in D-transposition of the great arteries. 39% of affected parents and 69% of affected siblings had a concordant lesion (i.e., CTD). Most affected siblings of probands with severe CTDs had complex defects (58%), whereas very few affected parents had complex defects (20%). These data suggest that recurrence risk varies by lesion and relationship, with substantial concordance observed by cardiac lesion and complexity of disease, particularly among siblings. These findings contribute to risk counseling in the current era.

Extreme Deep White Matter Hyperintensity Volumes Are Associated with African American Race

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl. Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.