Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

Genetic Pattern of Dental Caries in Families from a City in Southern Brazil

Fatores genéticos desempenham um importante papel na susceptibilidade à carie dentária na população. O objetivo deste estudo foi investigar, por meio da análise de segregação complexa (ASC), o padrão intergeracional da ocorrência da cárie dentária em famílias brasileiras. O estudo foi epidemiológico genético, observacional e transversal. A amostra foi constituída de 21 famílias que exibiam altos níveis de cárie (CPOD>4.5). Os participantes passaram por avaliação bucal, sendo que a cárie dentária foi registrada de acordo com o índice CPOD (dente cariado, perdido e obturado), seguindo as diretrizes da Organização Mundial de Saúde, bem como a presença de gengivite foi avaliada utilizando o índice de sangramento gengival. Foi aplicado um questionário para identificação dos fatores socioenconômicos e práticas de saúde bucal. Análises de regressão linear simples e múltipla foram realizadas para testar a associação entre cárie dentária e as variáveis independentes. A significância estatística foi considerada no nível de 5%, a ASC foi interpretada pelo programa S.A.G.E. A prevalência de cárie foi de 89,2%. Na análise múltipla, apenas a gengivite permaneceu associada (p = 0,005). A análise visual dos genogramas identificou um padrão familiar que sugere a predominância do modelo autossômico dominante. A frequência do alelo de resistência "A" foi estimada em 0,22. O valor médio de cárie foi de 1,35 para os genótipos AA e AB e de 3,95 para o BB. Os resultados do presente estudo fornecem evidências da presença de um gene importante com efeito dominante no controle do desenvolvimento de cárie dentária dentro da mesma família. Palavras-chave: Cárie Dentária. Epidemiologia Genética. Reabilitação Oral. Susceptibilidade. Abstract Genetic factors may play an important role in the susceptibility to dental caries of the human population. The objective of this study was to investigate, by means of complex segregation analysis (CSA), the intergeneration pattern in the occurrence of caries in Brazilian families. This was a cross-sectional, observational genetic epidemiological study. The sample consisted of 21 families whose probands exhibited high levels of caries (DMFT>4.5). All participants underwent an oral examination. Dental caries was recorded according to the DMFT index (decayed, missing, and filled teeth), according to World Health Organization guidelines and the presence of gingivitis was assessed by using the gingival bleeding index. A questionnaire was applied to identify the sociodemographic profile and practices on oral health. Simple and multiple linear regression analysis were performed to test the association between dental caries and the independent variables. Statistical significance was considered at the 5% level. The S.A.G.E program drove the CSA. The prevalence of caries was 89.2%. In the multiple analysis only gingivitis remained associated (p = 0.005). The visual analysis of genograms identified a family pattern that suggests the predominance of the autosomal dominant model. The frequency of resistance allele "A" was estimated at 0.22. The mean decay value was 1.35 for AA and AB genotypes and 3.95 for BB. The results of the present study provide evidence as to the presence of a major gene with a dominant effect controlling the appearance of dental caries, within the same family. Keywords: Dental Caries. Genetic Epidemiology. Oral Rehabilitation. Susceptibility.

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D

Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Molecular genetic aspects of keratoconus pathogenesis

Keratoconus is a bilateral, progressive corneal disease affecting all ethnic groups around the world. It is one of the major ocular problems with significant social impacts as the disease affects young generation, and is the leading cause of corneal transplantation. Although keratoconus is associated with genetic and environmental factors, its precise etiology is not yet established. Results from complex segregation analysis and patterns of gene expression show that genetic abnormalities may play an essential role in the susceptibility to keratoconus. There is a strong association between the polymorphism of a number of genes and corneal curvature. These polymorphisms explain only a small percentage of keratoconus cases, so genetic influences on keratoconus are most likely complex and varied. The aim of this review is to briefly provide the current knowledge on the genetic keratoconus basis - to understand the disease pathogenesis.

Complex Segregation Analysis Provides Evidence for Autosomal Dominant Transmission in the Chinese Han Families with Ankylosing Spondylitis

Introduction. Familial aggregation of ankylosing spondylitis (AS) has been frequently noticed. However, the mode of inheritance in AS remains poorly understood. Our aim was to determine the mode of inheritance best fitting the observed transmission pattern of AS families. Methods. Families with 5 or more AS patients diagnosed with 1984 modified New York criteria were recruited. We performed complex segregation analysis for a binary trait in regressive multivariate logistic models. The inheritance models, including sporadic, major gene, environmental, general, and other 9 models, were compared by likelihood ratio tests and Akaike’s Information Criterion. Results. This research included 9 Chinese Han AS families with a total number of 315 persons, including 74 patients. First, familial association was determined. Sporadic with familial association model was rejected when compared with either the general model or the homogeneous general model (p<0.001). The environmental model was also rejected when compared with general models (p<0.02). Mendelian dominate mode fitted best in 5 AS families, while Tau AB free model best explained the mode of inheritance in these AS families. Conclusion. This study provided evidence in support of Mendelian dominant mode and firstly discovered a non-Mendelian mode called tau AB free inheritance mode in AS.