Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.
Background Diabetic cardiomyopathy defined as either systolic or diastolic dysfunction in otherwise healthy diabetic persons is not clearly understood. The prevalence and outcomes of this disease in a community-based population have not been defined. Methods Cross-sectional survey of 2,042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000. All patients underwent Doppler echocardiographic assessment of systolic and diastolic function. Diabetic cardiomyopathy was defined in a person with diabetes and any systolic or at least moderate diastolic dysfunction without a history of coronary disease, hypertension, significant valvular disease or congenital heart disease. Results The diagnosis of diabetic cardiomyopathy was made in 23 persons, corresponding to a community population prevalence rate of 1.1%. Among diabetic patients, 16.9% met criteria for diabetic cardiomyopathy, and 54.4% had diastolic dysfunction. Diabetes was associated with a 1.9 fold increase in risk of any left ventricular dysfunction, a 1.7 fold increase in risk of diastolic dysfunction, and a 2.2 fold increase in risk of systolic dysfunction. Among subjects with diabetic cardiomyopathy, the cumulative probability of death was 18%, development of heart failure was 22%, and development of death or heart failure was 31% at 9 years. Conclusion Diabetic cardiomyopathy is relatively common in the community with a prevalence of 1.1%. The morbidity and mortality of patients with diabetic cardiomyopathy is high.
Summary. Background: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. Objective: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. Patients and methods: In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering agespecific, non-gender-and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) nonMendelian. Results: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-genderand gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. Conclusion: A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.
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