Sibling Risk Research Articles

Shared and Nonshared Familial Susceptibility to Surgically Treated Inguinal Hernia, Femoral Hernia, Incisional Hernia, Epigastric Hernia, and Umbilical Hernia

The familial risk of abdominal wall hernia (AWH) is largely unknown. In addition, it is unknown whether inguinal hernia (IH), femoral hernia (FH), incisional hernia (INH), epigastric hernia (EH), and umbilical hernia (UH) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant AWH (same disease in proband and exposed relative) and discordant AWH (different disease in proband and exposed relative). Data from the Swedish Multigeneration Register on individuals aged 0 to 78 years were linked to the Swedish hospital discharge register and the Swedish outpatient register for the period from 1964 to 2010. Standardized incidence ratios (SIRs) and 95% CIs for surgically treated IH (n = 209,814 cases), FH (n = 4,576), INH (n = 19,494), EH (n = 8,257), and UH (n = 22,761) were calculated for siblings of individuals with hernia compared with the siblings of unaffected individuals. The procedure was repeated for spouses. All concordant and most discordant familial sibling risks were increased. Familial concordant SIRs for siblings were IH = 1.97 (95% CI, 1.94-1.99), FH = 3.40 (95% CI, 2.44-4.62), INH = 2.24 (95% CI, 2.04-2.46), EH = 5.57 (95% CI, 4.64-6.64), and UH = 3.61 (95% CI, 3.33-3.91). Concordant familial risks were higher than discordant risks. For example, when the proband sibling had IH, the discordant SIRs were FH = 1.74 (95% CI, 1.61-1.88), INH = 1.22 (95% CI, 1.16-1.28), EH = 1.30 (95% CI, 1.20-1.40), and UH = 1.35 (95% CI, 1.29-1.41). Concordant SIRs for spouses were lower: IH = 1.23 (95% CI, 1.20-1.26), FH = 0.97 (95% CI, 0.64-1.36), INH = 1.56 (95% CI, 1.41-1.71), EH = 1.70 (95% CI, 1.09-2.45), and UH = 1.31 (95% CI, 1.09-1.56). Family history of surgically treated AWH is an important risk factor for surgical treatment of AWH. The 5 forms of AWH studied share familial susceptibility, but site-specific familial factors might exist. Several spouse risks were increased, suggesting the possibility of a nongenetic contribution to familial risks.

Chronic medical conditions in adult survivors of retinoblastoma.

10019 Background: Increased risk of second malignant neoplasms (SMN) in retinoblastoma survivors (RBS) is well documented, but little is known about their long-term burden of chronic non-visual morbidity. Methods: RBS treated in NYC were asked to complete a comprehensive questionnaire, adapted from the Childhood Cancer Survivor Study (CCSS) surveys; frequencies of chronic conditions, excluding SMN, in 470 RBS and 2,377 CCSS siblings were calculated. A severity score, based on the NCI CTCAE v4 (ranging from grade 1 [mild] to grade 4 [disabling/life-threatening]) was assigned to each condition. Logistic regression was used to estimateodds ratios of chronic condition risk in RBS vs CCSS siblings, adjusted for age, sex, and race/ethnicity, reported as relative risks (RR) and 95% confidence intervals (CIs). Results: RBS and CCSS siblings were mean ages of 43 years (SD 11) and 38 years (SD 9), respectively, at the time of questionnaire completion. 53.6% of RBS had bilateral disease. After excluding SMN, 70.2% of RBS had at least one non-visual chronic condition while 14% had a grade 3-4 condition. The adjusted RR of a non-visual chronic condition in a survivor compared to siblings was 1.5 (95% CI, 1.2-1.8); for a grade 3-4 condition, the risk was 1.5 (95% CI, 1.1-2.1). The most common grade 3-4 non-visual conditions in RBS were hearing loss (3.6%; bilateral 5.6%, unilateral 1.3%, p=0.023) and thyroid nodules requiring partial or full thyroidectomy (3.4%; bilateral 5.6%, unilateral 0.9%, p=0.008). Rates of grade 3-4 thyroid nodules and hearing loss did not differ significantly when stratified by treatment received. Rates of all conditions in RBS are reported in the Table. Conclusions: RBS have a modestly increased risk of non-visual chronic conditions when compared to individuals of comparable age, sex and race/ethnicity. [Table: see text]

Shared and non-shared familial susceptibility of coronary heart disease, ischemic stroke, peripheral artery disease and aortic disease

Little is known about whether the four main manifestations of arterial vascular disease (coronary heart disease = CHD, ischemic stroke, peripheral artery disease = PAD, and aortic (i.e. atherosclerosis/aneurysm) disease = AD) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant (same disease in proband and exposed relative) and discordant (different disease in proband and exposed relative) cardiovascular disease (CVD). Data from the Swedish Multigeneration Register on individuals aged 0-76 years were linked to Swedish Hospital Discharge Register data for the period 1964-2008. Standardized incidence ratios (SIRs) for CHD (n = 140,708 cases), ischemic stroke (n = 73,771), PAD (n = 18,982) and AD (n = 7879) were calculated for siblings of individuals hospitalized due to CHD, stroke, PAD or AD compared to those of unaffected siblings. The procedure was repeated for parent-offspring and spouses. All concordant and discordant sibling risks were increased for both males and females. Concordant risks were generally higher than discordant risks. The highest sibling risks were observed for premature concordant disease (<55 years for males and <65 years for females): SIR for CHD = 1.93 (95% CI: 1.90-1.96), SIR for ischemic stroke = 1.45 (1.39-1.50), SIR for PAD = 2.76 (2.54-3.00), and SIR for AD = 6.36 (5.28-7.59). Premature parent-offspring transmission followed the same pattern. The disease risk was modestly increased in spouses, highest for AD (SIR = 1.48 (1.28-1.69)) and PAD (SIR = 1.27 (1.21-1.32)). The four main manifestations of CVD share familial susceptibility, but unique site-specific familial factors may exist.

Heritability and sibling recurrent risk of developmental dysplasia of the hip in Chinese population

Previous familial segregation studies supported that developmental dysplasia of the hip (DDH) is a multifactorial genetic disease. However, the exact extent of genetic effects has not been fully evaluated, especially in Asian population. The aim of this study is to estimate the sibling recurrent risk and heritability of DDH in a large Chinese cohort. Four hundred and twenty-nine DDH probands and 534 matched normal controls were recruited from a screening programme for DDH, including 628 siblings in families of probands and 889 siblings in those of controls, respectively. The detailed information of family history was obtained, and the prevalence of DDH among siblings of probands, as well as controls, was determined. The sibling recurrent risk and heritability was estimated using classical liability threshold model. Eighty-seven siblings (13.85%) in families of proband and 14 siblings (1.57%) in normal control families were diagnosed as DDH. The recurrent risk in siblings of probands was at least tenfolds that in siblings of controls. Compared with the normal controls, the sibling recurrent risk was about 12-fold increase in male sib, and 9-fold increase in female sib. Overall, a high heritability of 83.59 ± 4.90% (h(2) ± SE) was observed. When stratified by genders, it was even higher for female siblings (91.02 ± 7.25%). This study for the first time exhibits a high sibling recurrent risk and heritability for DDH in Asian population. It also shows there is a high probability to identify the underlying predisposition genes in future genetic study.

Low Level of Consanguinity in Moroccan Families at High Risk of Breast Cancer

Breast cancer is worldwide the most common cancer in women and is a major public health problem. Genes with high or low penetrance are now clearly implicated in the onset of breast cancer, mostly the BRCA genes. All women in families at high risk of breast cancer do not develop tumours, even when they carry the familial mutation, suggesting the existence of genetic and environmental protective factors. Several studies have shown that consanguinity is linked to a decreased or an increased risk of breast cancer, but to the best of our knowledge, there is no study concerning the association between consanguinity and the occurrence of tumours in women with high risk of breast cancer. The objective of this study was to examine whether parental consanguinity in families with genetic predisposition to breast cancer affect the risk of siblings for having this cancer. Over a six-year period, 72 different patients with a histological diagnosis of breast or ovarian cancer from 42 families were recruited for genetic counselling to the Department of Medical Genetics, Rabat. Consanguinity rate was determined in cases and compared to the consanguinity rate in the Moroccan general population. Consanguinity rates were 9.72% in patients and 15.3% in controls, but the difference was statistically not significant (p>0.001) and the mean coefficient of consanguinity was lower in breast cancer patients (0.0034) than in controls (0.0065). Despite the relatively small sample size of the current study, our results suggest that parental consanguinity in Moroccan women might not be associated with an altered risk of breast cancer. Large scale studies should be carried out to confirm our results and to develop public health programs.

Sensorineural hearing loss caused by mutations in two alleles of both GJB2 and SLC26A4 genes

BackgroundMost studies of the molecular etiology of sensorineural hearing loss have described deafness as a monogenic disease encompassing double-allele mutations for patients with autosomal recessive deafness. Here, we report the first case of autosomal recessive genetic deafness in an enlarged vestibular aqueduct syndrome (EVAS) patient with biallelic mutations in two deafness genes. MethodsTemporal computed tomography (CT), complete physical and otoscopic examinations, and an audiological study, including tympanometry, pure-tone audiometry or auditory steady-state response (ASSR), were carried out. Exon 2 of GJB2 and the coding exons of SLC26A4 were sequenced. ResultsA patient with an enlarged vestibular aqueduct was found to carry c.1229C>T/c.1079C>T compound heterozygous mutations in SLC26A4.This individual also carried c.257C>G/c.299-300delAT compound heterozygous mutations in GJB2. As a result, the recurrent risk of the patient's siblings increased significantly from 25% for typical autosomal recessive deafness to 43.75%. ConclusionsThe findings of the present study challenge the traditional diagnostic strategy in which testing is generally considered complete upon identification of a double-allele mutation within one gene, with significant implications for genetic counseling and risk prediction. Our results suggest that, with advances in sequencing technology, it will be possible and necessary to test all known deafness genes in the near future, as this will likely allow more accurate genetic counseling of patients.

Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants

Despite recent successes in the identification of genetic susceptibility loci, no familial risk has been demonstrated for childhood acute lymphoblastic leukaemia (ALL). We identified 3994 childhood ALL cases from two cancer registries; family members were obtained from population registers. The standardized incidence ratio for familial risk in singleton siblings and twins was 3·2 (95% confidence interval 1·5-5·9) and 162·6 (70·2-320·4), respectively. The present data constitute the first demonstration of familial risk for singleton siblings; the high risk for twins is believed to result from shared prenatal blood circulation. The data suggest that currently unidentified genetic loci underlie these observed familial effects.

Longitudinal high-risk sibling studies of autism spectrum disorder

Autism spectrum disorder (ASD) is a largely genetic (1, but also see 2) and highly prevalent (3) neurodevelopmental disorder. It is characterized by significant social impairments, and is associated with significant suffering and societal costs (4, 5). Currently, ASD cannot be diagnosed reliably before the age of 2 years. Although biomarkers for ASD are emerging (6), there are no biomarkers available that can prospectively predict diagnostic outcome at early ages. The ASD risk in siblings of individuals with an ASD diagnosis may be as high as 20%, on average (7). The recurrence rate is much higher in boys than in girls, and higher in multiplex families compared to simplex families. Keywords: Autism; sibling; recurrence rate; development; diagnosis; longitudinal design (Published: 24 August 2012) Citation: Microbial Ecology in Health & Disease 2012, 23 : 18983 - http://dx.doi.org/10.3402/mehd.v23i0.18983

Potential risk for healthy siblings to develop schizophrenia

Recent resting-state functional connectivity MRI studies using group-level statistical analysis have demonstrated the inheritable characters of schizophrenia. The objective of the present study was to use pattern classification as a means to investigate schizophrenia inheritance based on the whole-brain resting-state functional connectivity at the individual subject level. One-against-one pattern classifications were made amongst three groups (i.e. patients diagnosed with schizophrenia, healthy siblings, and healthy controls after preprocessing), resulting in an 80.4% separation between patients with schizophrenia and healthy controls, a 77.6% separation between schizophrenia patients and their healthy siblings, and a 78.7% separation between healthy siblings and healthy controls, respectively. These results suggest that the healthy siblings of schizophrenia patients have an altered resting-state functional connectivity pattern compared with healthy controls. Thus, healthy siblings may have a potential higher risk for developing schizophrenia compared with the general population. Moreover, this pattern differed from that of schizophrenia patients and may contribute to the normal behavior exhibition of healthy siblings in daily life.

What have genome-wide association studies contributed to the understanding of the pathogenesis and future management of Type 1 diabetes?

77 ISSN 1758-1907 10.2217/DMT.11.77 © 2012 Future Medicine Ltd Diabetes Manage. (2012) 2(2), 77–80 Diabetes is a major health problem and its prevalence is increasing worldwide. It is estimated that by 2030, there will be 439 million adults affected by diabetes [101]. Today diabetes impacts the lives of approximately 200 million people. Approximately 10% of all cases are Type 1 diabetes (T1D) with around a 3% increase in the incidence of T1D globally per year [1]. T1D is a complex trait that results from the interplay between environmental and genetic factors. Much evidence supports a strong genetic component associated to T1D. The epidemiological data for geographic prevalence differences is one clear indicator, with populations of European ancestry having the highest presentation rate. T1D runs strongly in families, with the sibling risk being approximately ten-times greater than in the general population [2]. It has been a challenge to isolate the susceptibility genes for diabetes. Historically, before the introduction of genome-wide association studies (GWAS), the genetic determinants of T1D consisted of five loci. The first GWAS locus was reported in 2006 [3] and the current tally of T1D GWAS loci stands at 53 [4], including rediscovery of the first five candidate gene loci. Approximately half of the genetic risk for T1D is conferred by the genomic region harboring the HLA class II genes (primarily HLA-DRB1, -DQA1 and -DQB1 genes), which encode the highly polymorphic antigen-presenting proteins. Recent fine mapping efforts of the MHC addressed why the class II genes HLA-DQB1 and HLA-DRB1 cannot completely explain the association between T1D and the MHC region [5]. It turned out that most of the remaining association that could be detected was due to signals in HLA-B and HLA-A, and that the existence of other major T1D genes in the extended MHC was unlikely. Other loci established prior to GWAS are the genes encoding insulin [6], cytotoxic T-lymphocyte-associated protein 4 [7], protein tyrosine phosphatase, nonreceptor type 22 gene [8] and IL-2 receptor a [9]. However, the majority of other reported associations in the pre-GWAS era

Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

Genetics in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models.

Necessary and Sufficient Conditions for Equality of Sibling and Parent-Offspring Risk of a Disease Endophenotype in Case Families

A large number of linkage and association studies of complex diseases focus on analysis of a more common or more easily measured disease endophenotype. The motivation for this approach is that there is a pleiotropic locus common to both the disease and the endophenotype and that this locus is a major genetic determinant of the endophenotype. In this paper, we determine the conditions under which the risk of the endophenotype in siblings of affected probands with disease equals the risk of the endophenotype in the offspring (parents) of affected parents (offspring) with disease. In doing so we prove that this equality holds if and only if the penetrance of either the endophenotype or the disease (but not necessarily both) is additive.

Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes

Celiac Disease (CD) is a polygenic trait, and HLA genes explain less than half of the genetic variation. Through large GWAs more than 40 associated non-HLA genes were identified, but they give a small contribution to the heritability of the disease. The aim of this study is to improve the estimate of the CD risk in siblings, by adding to HLA a small set of non-HLA genes. One-hundred fifty-seven Italian families with a confirmed CD case and at least one other sib and both parents were recruited. Among 249 sibs, 29 developed CD in a 6 year follow-up period. All individuals were typed for HLA and 10 SNPs in non-HLA genes: CCR1/CCR3 (rs6441961), IL12A/SCHIP1 and IL12A (rs17810546 and rs9811792), TAGAP (rs1738074), RGS1 (rs2816316), LPP (rs1464510), OLIG3 (rs2327832), REL (rs842647), IL2/IL21 (rs6822844), SH2B3 (rs3184504). Three associated SNPs (in LPP, REL, and RGS1 genes) were identified through the Transmission Disequilibrium Test and a Bayesian approach was used to assign a score (BS) to each detected HLA+SNPs genotype combination. We then classified CD sibs as at low or at high risk if their BS was respectively < or ≥ median BS value within each HLA risk group. A larger number (72%) of CD sibs showed a BS ≥ the median value and had a more than two fold higher OR than CD sibs with a BS value < the median (O.R = 2.53, p = 0.047). Our HLA+SNPs genotype classification, showed both a higher predictive negative value (95% vs 91%) and diagnostic sensitivity (79% vs 45%) than the HLA only. In conclusion, the estimate of the CD risk by HLA+SNPs approach, even if not applicable to prevention, could be a precious tool to improve the prediction of the disease in a cohort of first degree relatives, particularly in the low HLA risk groups.

Age- and Gender-Specific Familial Risks for Venous Thromboembolism

Background— This nationwide study sought to determine age- and gender-specific familial risks in siblings hospitalized for venous thromboembolism (VTE). Methods and Results— The Swedish Multigeneration Register on 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the years 1987–2007. Standardized incidence ratios were calculated for individuals whose siblings were hospitalized for VTE compared with those whose siblings were not affected. Among a total of 45 362 hospitalized cases with VTE, 2393 affected siblings were identified, with a familial standardized incidence ratio of 2.45 (95% confidence interval [CI], 1.66 to 3.61). Gender-specific differences in incidence rates were observed. The familial risks were significantly increased from the age of 10 to 69 years, with a familial standardized incidence ratio of 4.77 (95% CI, 1.96 to 10.83) at ages 10 to 19 years, which decreased to 2.08 (95% CI, 1.35 to 3.20) at ages 60 to 69 years, although the absolute risk increased with age. The familial standardized incidence ratios for siblings with 2 and ≥3 affected probands were 51.87 (95% CI, 31.47 to 85.00) and 53.69 (95% CI, 25.59 to 108.50), respectively. Spouses had low familial risks (standardized incidence ratio=1.07; 95% CI, 1.04 to 1.10; observed spouse cases=3900). Conclusions— Familial factors, although influenced by age and gender, are important risk factors for VTE. The present study shows that VTE is aggregated in families and suggests that uncovering the sources of familial aggregation (genetic and nongenetic) may be worthwhile. Moreover, in a small fraction of siblings, the familial risk was very high, suggesting segregation of rare but strong genetic risk factors.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Sibling disability risk at onset and during disease progression in familial multiple sclerosis

Background: The objective of this study was to address the differences in onset and disease progression between familial and sporadic multiple sclerosis (MS) and the association within sibling pairs. Methods: Ninety-eight siblings and their controls were included from a database of 763 sporadic MS-patients, randomly pair-matched for age, gender, clinical course, disease duration and treatment. Sixty-eight available siblings completed a prospective six-year follow-up. Outcome parameters included baseline Expanded Disability Status Scale (EDSS), age at onset, mono- or multifocal onset, disease progression and conversion to secondary progression of initially relapsing–remitting MS. For statistical analyses Wilcoxon’s signed-rank statistics for categorical differences, t-statistics for continuous variables, McNemar’s test for relative frequencies of categories, intra-class correlations for within sibling-pair associations, or Kaplan–Meier analysis for survival analyses were used; all two-sided at the 5% level. Results: Disease onset was slightly earlier (29.01 vs. 29.44 years, p = 0.0492) and multifocal onset significantly more often (p = 0.0052) in familial than in sporadic MS. Notably, a substantial within sibling-pair correlation for disease progression (rho = 0.40; p = 0.0062) as well as a higher risk for siblings than for controls to convert into secondary progression (0.545 vs. 0.227; p = 0.018) could be observed. Conclusions: Familial MS differs from sporadic cases with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression. The progression rate of one out of two affected siblings may act as a predictor for the other sib.

Familial recurrence risks for multiple sclerosis in Australia

BackgroundGenetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few...

Neurocognitive and Behavioral Outcomes of Younger Siblings of Children with Autism Spectrum Disorder at Age Five

Later-born siblings of children with Autism Spectrum Disorders (ASD) are at increased risk for ASD as well as qualitatively similar traits not meeting clinical cutoffs for the disorder. This study examined age five neurocognitive and behavioral outcomes of 39 younger siblings of children with ASD (Sibs-ASD) and 22 younger siblings of typically developing children (Sibs-TD) previously assessed in a longitudinal investigation starting in the second year of life. There were few group differences between Sibs-TD and Sibs-ASD on global measures of IQ, language, or behavior problems. Sibs-ASD did show vulnerabilities on measures of executive functioning, social cognition, and repetitive behaviors. These results highlight the importance of following sibling risk groups over an extended time period and employing measures targeting broader aspects of development.

Population-Based Estimate of the Sibling Recurrence Risk Ratio for Rhegmatogenous Retinal Detachment

The influence of genetic predisposition on nonsyndromic primary rhegmatogenous retinal detachment (RRD) is poorly characterized. The purpose of this study was to investigate the magnitude of genetic risk for RRD. All participants (probands) in the Scottish Retinal Detachment Study (N = 922) with known postal addresses were contacted by questionnaire to assess the personal and family history of RRD. Sibling affection status was modeled by logistic regression and generalizing estimating equations accounting for the effect of proband covariates of age, sex, spherical equivalent refraction, index birth order, and body mass index (BMI). Sibling-sibling recurrence risk ratios (λs) and parent-offspring recurrence risk ratios were calculated. Sixty-five percent of probands returned completed questionnaires. Of these, 602 families (parents, siblings, offspring), 7.8% (47) had one affected member, and 0.5% (3) had two affected members. A total of 501 sibships were included in the regression analysis. The odds ratio (OR) that a sibling would be affected, given another affected sibling, was 1.91 (95% confidence interval [CI], 1.18-3.05). With adjustment for age and sex, the OR that a sibling would be affected increased by 9.8% for each additional diopter of spherical equivalent refractive error (SER) toward myopia in the proband. The λs and the parent-offspring recurrence risk ratio of RRD were 2.1 (95% CI, 1.3-3.2) and 2.9 (95% CI, 1.9-4.2), respectively. Genetic factors are important in the etiology of myopic and nonmyopic RRD. The risk of having an affected sibling with RRD increases twofold, given that a sibling has had the condition. The sibling risk increases with the level of spherical equivalent myopia in the proband.