There is extensive evidence that moyamoya disease has a tendency for multifactorial inheritance, although the pathogenesis of moyamoya disease is not clear. The authors report a case of familial moyamoya disease involving a 51-year-old female and her 24-year-old daughter, both of whom initially presented, within a 1-year period, withintracerebral hemorrhage and intraventricular hemorrhage. Cerebral angiography showed typical features of moyamoya disease in both patients, but the cause of the pathology remains obscure. The pertinent literature is reviewed.
Cerebral Angiography ; Female ; Hemorrhage ; Humans ; Middle Aged ; Moyamoya Disease* ; Multifactorial Inheritance ; Nuclear Family ; Pathology ; Young Adult

Atrial septal defect is one of the most common congenital heart diseases in adult, of which absolute causes is not confirmed, but explained by multifactorial inheritance. In Korea, there has been no case report of atrial septal defect in identical twins in spite of some reports of atrial septal defect in relatives and twins in other countries. We present a first case of atrial septal defect in identical twins whose mother had no infection or medication history during pregnancy.
Adult ; Heart Diseases ; Heart Septal Defects, Atrial* ; Humans ; Korea ; Mothers ; Multifactorial Inheritance ; Pregnancy ; Twins ; Twins, Monozygotic*

Cholesterol gallstone formation is influenced by environmental and genetic factors. Cholesterol gallstone susceptible genes (Lith genes) are complex and show polygenic traits. Quantitative trait locus (QTL) analysis in inbred mice is a powerful method for identifying these genetic defects. More than 20 Lith genes were discovered by QTL in inbred mice models. The co-localized, candidate genes responsible for gallstone susceptible QTL can lead to the discovery of pathophysiologic functions of Lith (gallstone) genes. These genetic studies may reveal novel molecular targets for prevention and medical therapy. Presently, the only effective treament for gallstone is cholecystectomy. In the future, new drugs targeting Lith genes can be available not only for the treatment of gallstone disease, but also for "pre-stone" diagnosis.
Animals ; Cholecystectomy ; Cholesterol* ; Diagnosis ; Gallstones* ; Mice ; Molecular Biology* ; Multifactorial Inheritance ; Quantitative Trait Loci

Humans ; Genetic Predisposition to Disease ; Multifactorial Inheritance ; Genome-Wide Association Study ; Risk Factors

OBJECTIVETo explore the effects of genetic factors on the occurrence of allergic rhinitis (AR).

METHODSThe morbidity rate of AR was surveyed by multistage sampling among 95 300 individuals (23,825 families) in Natong region, Jiangsu province. And a genetic epidemiologic investigation on AR was carried out to estimate the segregation ratio and heritability (h2) of AR by the methods of Li-Mantel-Gart and Falconer respectively.

RESULTSThe morbidity rate of AR in Natong region was 1.20% (Male 1.21%, Female 1.18%, no statistical significance between them); By the data of the AR ancestry, the segregation ratio of AR in Nantong region was 0.078, significantly less than 0.25, and the genetic model belonged to polygenetics. The 1st, the 2nd, and the 3rd generation h2 of AR were (82.6 +/- 2.19)%, (80.8 +/- 2.93)%, (78.4 +/- 7.04)%. The h2 of AR was (81.86 +/- 1.70)%. In the ancestry of AR, the morbidity rate of the 1st generation with AR was 12.11%; the 2nd generation with AR was 5.12%; the 3rd generation with AR was 2.75%; and the morbidity rate of AR in general population was 1.20%.

CONCLUSIONSThe heredity in family with AR is obvious. Several genes plus the environmental factors may cause AR, which accords with the characteristics of the polygene heredity disease.

China ; epidemiology ; Female ; Humans ; Male ; Multifactorial Inheritance ; Prevalence ; Rhinitis, Allergic, Perennial ; epidemiology ; genetics ; Rhinitis, Allergic, Seasonal ; epidemiology ; genetics

Moyamoya disease is a rare occlusive cerebrovascular disease characterized by stenosis or occlusion of the main cerebral arteries. It has a tendency for multifactorial inheritance and familial occurrence, although its pathogenesis is not clear. We observed this disease in two girls from the same family:one was eight years old and the other was 45 months. They presented with transient ischemic attacks. We performed cerebral angiography on both patients and magnetic resonance angiography (MRA) on the younger. Both approaches showed the typical features of moyamoya disease, and MRA successfully revealed abnormal findings specific for the disease in the second child. Both children received encephaloduroarteriosynangiosis (EDAS) and this produced good results. MRA is thus a powerful and noninvasive way of detecting individuals at high risk of developing this disease. Considering the reported familial incidence of moyamoya disease in Japan, a careful search for family members using MRA would probably reveal many more such cases in Korea.
Cerebral Angiography ; Cerebral Arteries ; Child ; Constriction, Pathologic ; Female ; Humans ; Incidence ; Ischemic Attack, Transient ; Japan ; Korea ; Magnetic Resonance Angiography ; Moyamoya Disease* ; Multifactorial Inheritance

Febrile seizure (FS) is the most common seizure disorder of childhood, and occurs in an age-related manner. FS are classified into simple and complex. FS has a multifactorial inheritance, suggesting that both genetic and environmental factors are causative. Various animal models have elucidated the pathophysiological mechanisms of FS. Risk factors for a first FS are a family history of the disorder and a developmental delay. Risk factors for recurrent FS are a family history, age below 18 months at seizure onset, maximum temperature, and duration of fever. Risk factors for subsequent development of epilepsy are neurodevelopmental abnormality and complex FS. Clinicians evaluating children after a simple FS should concentrate on identifying the cause of the child's fever. Meningitis should be considered in the differential diagnosis for any febrile child. A simple FS does not usually require further evaluation such as ordering electroencephalography, neuroimaging, or other studies. Treatment is acute rescue therapy for prolonged FS. Antipyretics are not proven to reduce the recurrence risk for FS. Some evidence shows that both intermittent therapy with oral/rectal diazepam and continuous prophylaxis with oral phenobarbital or valproate are effective in reducing the risk of recurrence, but there is no evidence that these medications reduce the risk of subsequent epilepsy. Vaccine-induced FS is a rare event that does not lead to deleterious outcomes, but could affect patient and physician attitudes toward the safety of vaccination.
Antipyretics ; Child ; Classification ; Diagnosis, Differential ; Diazepam ; Electroencephalography ; Epilepsy ; Fever ; Humans ; Meningitis ; Models, Animal ; Multifactorial Inheritance ; Neuroimaging ; Phenobarbital ; Recurrence ; Risk Factors ; Seizures ; Seizures, Febrile* ; Vaccination ; Valproic Acid

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by selective destruction of pancreatic islet betacells causing insulin deficiency. T1D has been shown to be a polygenic trait, associated with several loci, among which the human leukocyte antigen (HLA) region accounts for 40% of the genetic risk to develop T1D. The betacell autoimmune response is triggered by environmental or unknown events in the predisposing genetic background. The triggers of autoimmunity can lead to a localized imbalance between regulatory T cells and autoimmune effector T cells. The macrophages and autoreactive lymphocytes infiltrate the islets and the interaction of betacells and immune cells leads to inductionamplification of insulitis and loss of betacells. T cells destroy betacells in a direct cytotoxic manner or influence the induction of betacell apoptosis through the release of cytotoxic molecules, such as cytokines. The autoimmune process progresses subclinically for many years in the majority of patients, and clinical symptom do not appear until more than 80% of betacells have been destroyed. Although no current "cure" exists, there is a major effort to develop immunotherapies to prevent or halt the disorder that still requires much research to fully understand exact triggering events leading toautoimmune activation. Other strategies involve beta- cell replacement by islet transplantation, but researchs to enhance the islet mass transplanted and preserve beta-cell function are necessary.
Apoptosis ; Autoimmune Diseases ; Autoimmunity ; Cytokines ; Diabetes Mellitus, Type 1 ; Humans ; Immunotherapy ; Insulin ; Islets of Langerhans ; Islets of Langerhans Transplantation ; Leukocytes ; Lymphocytes ; Macrophages ; Multifactorial Inheritance ; T-Lymphocytes ; T-Lymphocytes, Regulatory ; Transplants

PURPOSE: Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that in females the proportion of lung cancer cases that is unrelated to tobacco smoking reaches fifty percent, making questionable the etiology of the disease. MATERIALS AND METHODS: A never-smoker female with primary EGFR/KRAS/ALK-negative squamous cell carcinoma of the lung and their normal sibswere subjected to a novel integrative “omic” approach using a pedigree-based model for discovering genetic factors leading to cancer in the absence of well-known environmental trigger. A first-stepwhole-exome sequencing on tumor and normal tissue did not identify mutations in known driver genes. Building on the idea of a germline oligogenic origin of lung cancer, we performed whole-exome sequencing of DNA from patients' peripheral blood and their unaffected sibs. Finally, RNA-sequencing analysis in tumoral and matched non-tumoral tissues was carried out in order to investigate the clonal profile and the pathogenic role of the identified variants. RESULTS: Filtering for rare variants with Combined Annotation Dependent Depletion (CADD) > 25 and potentially damaging effect, we identified rare/private germline deleterious variants in 11 cancer-associated genes, none ofwhich, except one, sharedwith the healthy sib, pinpointing to a “private” oligogenic germline signature. Noteworthy, among these, two mutated genes, namely ACACA and DEPTOR, turned to be potential targets for therapy because related to known drivers, such as BRCA1 and EGFR. CONCLUSION: In the era of precision medicine, this report emphasizes the importance of an “omic” approach to uncover oligogenic germline signature underlying cancer development and to identify suitable therapeutic targets as well.
Carcinoma, Squamous Cell* ; Disease Susceptibility ; DNA ; Epithelial Cells* ; Exome ; Female* ; High-Throughput Nucleotide Sequencing ; Humans ; Lung Neoplasms ; Lung* ; Multifactorial Inheritance ; Precision Medicine* ; Smoking

BACKGROUND: A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities. METHODS: We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer. RESULTS: During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93-1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03-1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12-1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk. CONCLUSION These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
Humans ; Prospective Studies ; Stomach Neoplasms/genetics* ; Genetic Predisposition to Disease/genetics* ; Risk Factors ; Multifactorial Inheritance/genetics* ; Polymorphism, Single Nucleotide/genetics* ; Genome-Wide Association Study