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SummaryThe distribution of consanguineous marriages among spouses and husband's and wife's parents, was analysed using data on 9225 families in six widely different areas of Japan. With two exceptions, the consanguinity rates for husband's and wife's parents are higher in related spouses than in unrelated spouses. The familial aggregation of consanguinity was slightly decreased in more recent marriages, a change which began recently with couples who have abandoned the more traditional Japanese way of life.

Although ischemic heart disease tends to cluster in families, previous studies have reported a modest (2-fold increased risk) to strong (10-fold increased risk) contribution of family history to the explanation of disease occurrence. The authors assessed the familial aggregation of early-onset myocardial infarction in 11,307 adults aged <65 years who participated in the Third National Health and Nutrition Examination Survey. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs). A parental history was more common in those with (n = 237) than in those without (n = 11,070) a myocardial infarction (19.8 vs. 7.9%, p ≤ 0.01). Adults with a parental history were also more likely to have multiple risk factors for cardiovascular disease (OR for four or five risk factors compared with none: 2.9, 95% CI: 1.4, 6.3). After multivariate adjustment, the likelihood of myocardial infarction was more than three times greater among adults with a parental history than among those without (95% CI: 1.7, 6.7). A maternal history of myocardial infarction was strongly associated (OR = 6.1, 95% CI: 2.1, 17.4) with an increased likelihood of myocardial infarction, and a paternal history was associated with a 3-fold (95% CI: 1.5, 6.3) increased likelihood of myocardial infarction after adjustment for cardiovascular disease risk factors. These results suggest a familial aggregation of early-onset myocardial infarction and show that family history is strongly associated with cardiovascular disease risk factors.

Objectives: This research examined the familial aggregation of migraine, depression, and their co-occurrence.Methods: Diagnoses of migraine and depression were determined in a sample of 5,319 Australian twins. Migraine was diagnosed by either self-report, the ID migraine™ Screener, or International Headache Society (IHS) criteria. Depression was defined by fulfilling either major depressive disorder (MDD) or minor depressive disorder (MiDD) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The relative risks (RR) for migraine and depression were estimated in co-twins of twin probands reporting migraine or depression to evaluate their familial aggregation and co-occurrence.Results: An increased RR of both migraine and depression in co-twins of probands with the same trait was observed, with significantly higher estimates within monozygotic (MZ) twin pairs compared to dizygotic (DZ) twin pairs. For cross-trait analysis, the RR for migraine in co-twins of probands reporting depression was 1.36 (95% CI: 1.24–1.48) in MZ pairs and 1.04 (95% CI: 0.95–1.14) in DZ pairs; and the RR for depression in co-twins of probands reporting migraine was 1.26 (95% CI: 1.14–1.38) in MZ pairs and 1.02 (95% CI: 0.94–1.11) in DZ pairs. The RR for strict IHS migraine in co-twins of probands reporting MDD was 2.23 (95% CI: 1.81–2.75) in MZ pairs and 1.55 (95% CI: 1.34–1.79) in DZ pairs; and the RR for MDD in co-twins of probands reporting IHS migraine was 1.35 (95% CI: 1.13–1.62) in MZ pairs and 1.06 (95% CI: 0.93–1.22) in DZ pairs.Conclusions: We observed significant evidence for a genetic contribution to familial aggregation of migraine and depression. Our findings suggest a bi-directional association between migraine and depression, with an increased risk for depression in relatives of probands reporting migraine, and vice versa. However, the observed risk for migraine in relatives of probands reporting depression was considerably higher than the reverse. These results add further support to previous studies suggesting that patients with comorbid migraine and depression are genetically more similar to patients with only depression than patients with only migraine.

<i>Background:</i> Familial aggregation of congenital heart disease (CHD) has been well described in different populations, in particular those with a high consanguinity rate. Extensive genetic study of affected families has improved the understanding of basic genetics of different cardiac lesions. <i>Objective:</i> To identify the role of consanguinity as a risk factor among familial cases of CHD in a stable outpatient population of a tertiary care center in the Eastern Province of Saudi Arabia. <i>Methods:</i> All familial cases of CHD seen over 5 years (1996–2000) in the Division of Pediatric Cardiology were identified. The presence or absence of parental consanguinity (first cousin marriage) was defined in each of these families. <i>Results:</i> Ninety-three cases were identified in 37 families. Twenty-three (62%) families resulted from consanguineous marriages. In 4 families where there were 2 marriages, the affected children came from the consanguineous marriage in 3 of these families. Discordant lesions occur only among non-consanguineous cases, while all consanguineous cases were concordant. Five sets of twins of the same sex (one set are monozygotic by DNA analysis) occurred among consanguineous marriages, in 3 of these both twins were affected with the same disease. Affected parents were seen in 2 families with consanguineous marriage and none in the non-consanguineous marriages. The prevalence of dilated cardiomyopathy was much higher among consanguineous cases (26 vs. 2). <i>Conclusions:</i> Familial aggregation of congenital heart disease is common in our population. Consanguinity is common in these families, and the distribution of congenital heart disease differs in this subgroup compared to the rest of the familial cases. Further genetic studies of these families may help to shed more light on basic genetics and the specific pathogenetic mechanisms involved.

Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

Twin and adoption studies point towards a genetic contribution to tinnitus; however, how the genetic risk applies to di erent forms of tinnitus is poorly understood. Here, we perform a familial aggregation study and determine the relative recurrence risk for tinnitus in siblings ( s). Four di erent Swedish studies (N = 186,598) were used to estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population and we defined whether these 4 di erent forms of tinnitus segregate in families from the Swedish Tinnitus Outreach Project (STOP, N = 2305). We implemented a percentile bootstrap approach to provide accurate estimates and confidence intervals for s. We reveal a significant s for all types of tinnitus, the highest found being 7.27 (95% CI (5.56–9.07)) for severe tinnitus, with a higher susceptibility in women (10.25; 95% CI (7.14–13.61)) than in men (5.03; 95% CI (3.22–7.01)), suggesting that severity may be the most genetically influenced trait in tinnitus in a sex-dependent manner. Our findings strongly support the notion that genetic factors impact on the development of tinnitus, more so for severe tinnitus. These findings highlight the importance of considering tinnitus severity and sex in the design of large genetic studies to optimize diagnostic approaches and ultimately improve therapeutic interventions. ; GENDER-Net Co-Plus Fund GNP-182 ; European Union's Horizon 2020 Research and Innovation Programme 848261 ; European Union (EU) 722046 [44] ; Svenska Lakaresallskapet SLS-779681 ; Horselforskningsfonden 503 ; Tysta Skolan ; Karolinska Institutet Summer Course in Medical Research ; Swedish Research Council 2017-00641

<i>Objective:</i> An exploratory analysis of co-aggregation of cancers using registry-based data. <i>Methods:</i> We utilized sibships from over 18,000 families who had been recruited to the NCI-sponsored multi-institutional Cancer Genetics Network. The analysis assesses co-aggregation at the individual and family level and adjusts for ascertainment. <i>Results:</i> We found statistically significant familial co-aggregation of lung cancer with pancreatic (adjusted p < 0.001), prostate (adjusted p < 0.003), and colorectal cancers (adjusted p = 0.004). In addition, we found significant familial co-aggregation of pancreatic and colorectal cancers (adjusted p = 0.018), and co-aggregation of hematopoietic and (non-ovarian) gynecologic cancers (adjusted p = 0.01). <i>Conclusion:</i> This analysis identified familial aggregation of cancers for which a genetic component has yet to be established.

AbstractDiseases of the myoneural junction and muscle are disabling and some are life-threatening. Recent successes in the identification of the underlying genetic mechanisms have had profound implication for their diagnostics, treatment and classification. We define familial risks for siblings who were hospitalized for or deceased from diseases of the myoneural junction and muscle. A nationwide database on diseases of the myoneural junction and muscle was constructed by linking the Multigeneration Register on 0- to 69-year-old siblings to the Hospital Discharge Register and the Causes of Death Register from years 1987 to 2001. Standardized risk ratios (SIRs) were calculated for affected sibling pairs by comparing to those whose siblings had no diseases of myoneural junction and muscle. Among a total of 2307 patients, myasthenia gravis, muscular dystrophy and myotonic disorders were commonest diagnoses. The sibling risks for these disease were 22, 190 and 198, respectively, when a sibling was diagnosed with any disease of the myoneural junction and muscle. The concordant SIRs, both siblings presenting the same disease, were 42 for myasthenia gravis, 737 for muscular dystrophy, 2000 for congenital myopathy, 1211 for myotonic disorder, 909 for periodic paralysis and 209 for unspecified myopathy. Only a few discordant sibling pairs were noted. The very high overall SIRs for the diseases of the myoneural junction and muscle imply that the sporadic forms of these diseases are relatively rare and these diseases are overwhelmingly heritable.