Apolipoprotein E-η4 allele and familial risk in Alzheimer's disease

Recent studies have found an association between presence of apolipoprotein E (APOE) η4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the η4 allele with the relatives of AD probands not carrying η4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying η4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age ≥ 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the η4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the η4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without η4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with η4 (3.1-fold increase) was found compared to relatives of probands without η4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-η4 allele relative to controls suggests that familial factors in addition to APOE-η4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with η4. © 1996 Wiley-Liss, Inc.     

Extended latent class approach to the study of familial/sporadic forms of a disease: Its application to the study of the heterogeneity of schizophrenia

When no method exists for detecting genetic forms of a disorder, epidemiologists classify probands according to the presence or absence of an affected relative (familial or sporadic). Not only is this a surrogate measure but if the risk for the disorder is associated with characteristics such as age and gender, then probands with varied distributions of these characteristics among their relatives are subject to misclassification. A latent class approach is presented which explicitly models the relationship between the affected status of the relatives and the unobservable familial/sporadic status of the proband in order to adjust for these characteristics. Lastly, an approach is introduced to correct for attenuation in measures of association between familial/sporadic status and other variables that could result if probands are misclassified. This approach incorporates the latent class probabilities directly into the regression model without classifying probands. These methods are applied to a study of theheterogeneity of schizophrenia.     

Estimating familial effects on age at onset and liability to schizophrenia. I. Results of a large sample family study

Previous analyses of age at onset in schizophrenia, which is highly variable and appears to be influenced by familial factors, have neglected to consider either (1) the impact of censoring on correlations in age at onset in affected relatives or (2) the impact of correlated ages at onset on the relationship between age at onset in the proband and risk in relatives. In this report, using methods outlined in the companion paper [MacLean et al., Genet Epidemiol 7:419-426, 1990] we examine these questions in the large family data set of schizophrenia collected by Lindelius [Acta Psychiat Scand (Suppl) 216:1-125, 1970]. Ages at onset are positively correlated in pairs of affected relatives (parent-offspring approximately equal to siblings greater than nieces/nephews) and these correlations are substantially higher after correction for censoring. Early age at onset is associated with higher risk of illness in siblings and nieces/nephrews but not in children. These results are consistent with the hypothesis that age at onset in schizophrenia is influenced by familial factors which are probably genetic and which are mostly unrelated to factors influencing disease liability.     

Increased familial risk for non-lung cancer among relatives of lung cancer patients

Reports of two or more anatomically distinct cancer types clustering in families suggest the possible existence of a susceptibility-to-cancer gene. To determine whether a genetic predisposition accounts for such familial aggregation, a retrospective case-control study was conducted in 1976-1979 of 337 southern Louisiana families in each of which a deceased lung cancer patient was used as the proband. A comparison of first-degree relatives of proband families with spouse (control) families revealed a significantly greater overall risk of cancer (odds ratio (OR) = 2.0, p less than 0.0001) in the proband group. Using logistic regression techniques to control for the confounding effects of age, sex, cigarette smoking, and occupational/industrial exposures, relatives of lung cancer probands maintained an increased risk of non-lung cancer (p less than 0.05). The crude odds ratio of a proband family having one family member with cancer was 1.67 compared with control families. Proband families were 2.16 times more likely to have two other family members with cancer. For three cancers and four or more cancers, the risk increased to 3.66 and 5.04, respectively. Each risk estimate was significant at the 0.01 level. The most striking differences in cancer prevalence between proband and control families were noted for cancer of the nasal cavity/sinus, mid-ear, and larynx (OR = 4.6); trachea, bronchus and lung (OR = 3.0); skin (OR = 2.8); and uterus, placenta, ovary, and other female organs (OR = 2.1). These data support the hypothesis of a genetic susceptibility to cancer in families with lung cancer.     

Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study

BACKGROUND AND PURPOSE: Stroke occurs infrequently in young adults. While a familial basis for older onset stroke is well established, the extent of familial clustering in young-onset stroke is unknown. To address this issue, we compared the frequency of stroke in relatives of stroke cases to that in relatives of controls across different ages and by stroke subtype. METHODS: Through a population-based case-control study of stroke, we identified 487 women aged 15-49 years with ischemic stroke and 615 women without stroke matched by age and geographic region. Family history of stroke was collected for 5,749 relatives (parents and siblings) of case and control probands by standardized interview. RESULTS: Strokes were reported in 149 relatives of case patients and 119 relatives of controls. Siblings of stroke case patients had more than four times the risk of stroke compared to siblings of controls (OR, 4.17; 95% CI, 1.9-8.8) and mothers of stroke case patients had twice the risk of stroke compared to mothers of control subjects (OR, 2.02; 95% CI, 1.4-3.0). The association between stroke in probands and family history of stroke was strongest among women aged 15-24 years (OR, 2.5; 95% CI, 0.4-15.1), and diminished with increasing proband age (OR, 1.6; 95% CI, 0.8-3.3 among women 25-34 years and OR, 1.5; 95% CI, 1.1-1.9 among women 35-49 years; P<0.0001 for trend). CONCLUSIONS: We conclude that young-onset stroke aggregates in families and that the magnitude of aggregation increases with decreasing proband age.     

Estimating familial effects on age at onset and liability to schizophrenia. II. Adjustment for censored data

Genetic studies of disorders with adult onset often contain individuals who have not completed their age at risk when last observed. Without correction for such censoring, correlation in ages at onset among relatives is substantially underestimated. Moreover, without correction for the effect of correlated ages at onset, the relationship between age at onset in the proband and liability in relatives is substantially overestimated. The present paper describes methods for correcting the effects of censoring on these estimates. In a companion paper [Kendler and MacLean, Genet Epidemiol 7:409-417, 1990] these methods are applied to a large family study of schizophrenia.     

Etiologic heterogeneity in alcoholism

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type-2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type-1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the late-onset, type-1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial-polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial-polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type-1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) "female-like" families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) "male-like" families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the "male-like" and "female-like" groups. Discriminant function analysis of alcohol-related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in "male-like" families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast, abuse in "female-like" families was characterized by late onset of guilt feelings and loss of control over binge drinking.     

Familial aggregation of morbid obesity

Recent studies have shown major gene effects for obesity in randomly ascertained families. To investigate the familial aggregation of a specific subset of obesity, which is particularly prone to medical complications, families with morbid obesity were studied. This condition occurs in 1%-2% of the population and is defined as 45.5 kg (100 pounds) or more over ideal weight. First-degree relatives of 221 morbidly obese probands (1560 adults) were identified, and height and weight (current and greatest) were obtained from each family member. Morbid obesity occurred in the family members of the probands 8 times more often than in the general population. Of the morbidly obese probands, 48% had one or more first-degree relatives who were also morbidly obese compared to a 6% population estimate. By the ages of 20-24, 12% of the morbidly obese probands were already 45.5 kg or more overweight, and 45% were 22.7 kg (50 pounds) or more overweight. There was little difference in the prevalence of familial morbid obesity by the gender of the probands: 47% of the male probands and 48% of the female probands had another morbidly obese relative, while 67% and 53% of the early onset (before age 25) male and female probands, respectively, had one or more first-degree relatives who were also morbidly obese. In addition to the extreme degree of familial aggregation, the prevalence of morbid obesity in parent-offspring sets was calculated within the morbidly obese families. Morbidly obese families who have one or two morbidly obese parents have a 2.6 times increased risk (p<0.002) of having one or more morbidly obese adult offspring, compared to families who have neither parent morbidly obese. Evidence for trimodality of the body mass index distribution was found for each gender (p = 0.0006 for male relatives and p = 0.075 for female relatives). The strong familial aggregation of morbid obesity indicates the need for further understanding of the genetic determinants of this extreme clinical disorder and how environmental factors affect the genetic expression of the trait.     

Multiple sclerosis recurrence risk for siblings in an isolated population of Central Sardinia, Italy

Studies of twins, adoptees, half siblings, and familial recurrence risk have shown that genetic and non-genetic factors are involved in multiple sclerosis (MS) etiology. Age at onset, gender, and parental MS status seem to influence sibling risk. We studied the recurrence risk in siblings of MS patients in an isolated population of Sardinia, Italy, which is genetically homogeneous, inbred, and very stable, with a high MS frequency. The Aalen-Nelson estimate of the recurrence risk in siblings is 4.7%, and the risk ratio compared with the general population is 31. Proportional hazards models were used to investigate the effect of sibling sex, sex, and age at onset of the proband, and number of affected relatives on a sibling's predicted MS risk. Sib's risk is influenced by age at onset (P = 0.02), and possibly by sex of the proband (P = 0.08). There is also a borderline significant interaction (P = 0.05) between the sex and age at onset of the proband: early age at onset influences sib's risk only if the proband is female. The number of affected relatives in the family is not found to influence sibling risk, but the power is lacking (95% CI 0.50-2.62). This result is consistent with a single dominant gene with an extremely low penetrance, a model that has not yet been disproved as a possible inheritance model for MS.     

Age-dependent expression of familial risk in Alzheimer's disease

There is growing evidence for genetic causes of Alzheimer's disease; therefore, consideration of its age at onset among genetically predisposed individuals is timely. The authors studied the onset of Alzheimer-like dementia in families of 79 probands ascertained clinically for the Bronx Veterans Administration/Mt. Sinai School of Medicine longitudinal studies of Alzheimer's disease. Analyses among their 379 first-degree relatives, living and decreased, suggested that 1) early onsets form a distribution that is distinct from that of later onsets, and thus, different causes or mechanisms may operate in early- and late-appearing disease; 2) age at onset varies as a familial characteristic; 3) with present population survival, only one third of the theoretical predisposition to Alzheimer's disease will become manifest during the lifetime of relatives at risk; and 4) a stable annual incidence of 1.5 per cent in the early ninth decade, reported by others, can be explained by the operation of a dominant gene with a population allele frequency of 0.13. The authors conclude that different (possibly genetic) causes of Alzheimer's disease may operate in different families or individuals, although much of its predisposition remains latent during the lifetime of those at risk.     

Familial aggregation of breast cancer with early onset lung cancer.

Site-specific familial aggregation and evidence supporting Mendelian codominant inheritance have been shown in lung cancer. In characterizing lung cancer families, a number of other cancers have been observed. The current study evaluates whether first-degree relatives of early onset lung cancer cases are at increased risk of breast cancer. Families were identified through population-based lung cancer cases and controls under 40 years of age. Cases were ascertained through the Metropolitan Detroit SEER registry; controls through random-digit dialing. Data were available for 384 female relatives of 118 cases and 465 female relatives of 161 controls. Breast cancer in relatives was evaluated after adjusting for age, race, sex, and smoking status of each family member and the sex and age of the probands. A positive family history of early onset lung cancer increased breast cancer risk among first-degree relatives 5. 1-fold (95% CI, 1.7-15.1). Relatives of cases with adenocarcinoma of the lung were at highest risk (RR = 6.3, 95% CI 2.0-20). Mean age of breast cancer diagnosis among relatives of cases was 52.2 years and not statistically different from relatives of controls. Three case families also reported early ovarian cancers (mean age of diagnosis of 35 years). These findings suggest that shared susceptibility genes may act to increase risk of early onset lung and breast cancer in families.     

Familial risk ratio of sarcoidosis in African-American sibs and parents

While sarcoidosis is thought to aggregate in families, little is known about the risk to relatives of sarcoidosis patients. To estimate the familial risk ratio (lambda) of sarcoidosis in sibs and parents of cases, the authors studied 179 African-American families ascertained through an index sarcoidosis case diagnosed at Henry Ford Hospital in Detroit, Michigan. Among those relatives enrolled between 1997 and 1999, 12 of 327 (3.7%) sibs and 11 of 161 (6.8%) parents reported a history of sarcoidosis. The lambda in this sample of relatives, estimated by computing an age, sex, and race standardized incidence ratio, was 2.24 (95% confidence interval: 1.16, 3.92) for sibs and 2.82 (95% confidence interval: 1.41, 5.05) for parents. For sibs and parents combined, lambda was 2.49 (95% confidence interval: 1.58, 3.73). Results stratified by proband characteristics indicated that lambda was greater for relatives of younger (lambda = 2.93, 95% confidence interval: 1.52, 5.12) and male (lambda = 3.98, 95% confidence interval: 1.99, 7.12) probands. A higher lambda was also found for male family members and sibs born later in the birth order. A Monte Carlo method was also used to estimate lambda, with similar results obtained. Overall, these results indicate that, in African Americans, sibs and parents of sarcoidosis cases have about a 2.5-fold increased risk for sarcoidosis and that heterogeneity in disease risk may exist among family members.     

Prevalence of familial hypertriglyceridemia: The Princeton School District Family Study

Using the Princeton School Family Study cohort, our specific aim was to estimate the prevalence of suspected familial hypertriglyceridemia (FHTG), to study the potential contributions of secondary hypertriglyceridemias in hypertriglyceridemic probands, and to provide empirical risk estimates for the proportion of probands' first-degree relatives who also had top decile triglyceride levels. Suspected FHTG was arbitrarily identified in those kindreds having at least two first-degree relatives in the top age-sex-race-specific triglyceride decile, along with the proband. We studied 177 (125 white, 52 black) randomly recalled and 202 hyperlipidemic (hypertriglyceridemic and/or hypercholesterolemic) recall (147 white, 55 black) probands and their families. None of the 9 top triglyceride decile probands from the random recall group had FHTG. Of the 81 top triglyceride decile probands from the hyperlipidemic recall group, 23 (28%) had suspected FHTG, and 6 (7%) of the top triglyceride decile probands had suspected FHTG with three-generation vertical (and horizontal) transmission of top decile triglyceride. An average of 24% of the first-degree relatives of all hypertriglyceridemic probands themselves had top decile triglycerides. In hypertriglyceridemic probands and their affected relatives, factors that may cause secondary hypertriglyceridemia or exacerbate preexisting hypertriglyceridemia were common: poorly controlled diabetes mellitus, excessive alcohol intake, hepatic dysfunction, use of estrogen-progestin oral contraceptives, and use of antihypertensive agents. Quetelet index and alcohol intake had significant simple correlations with triglyceride levels; after adjusting for Quetelet index, alcohol had no significant independent relationship to triglycerides. There were significant partial correlations of triglycerides with systolic blood pressure and an inverse association of high-density lipoprotein cholesterol (HDLC) with diastolic blood pressure. In 14 of the 23 kindreds with suspected FHTG there were also 2 or more kindred members who had top decile low-density lipoprotein cholesterol (LDLC), suggestive of combined hyperlipidemia. Whatever definition of FHTG is used, identification of hypertriglyceridemia may reveal other underlying risk factors for coronary heart disease, including low HDLC, and/or elevated LDLC. The clustering of atherosclerosis in suspected FHTG kindreds may be related in part to familial clustering of high triglycerides, high LDLC, and/or low levels of HDLC.     

An analytical method for assessing patterns of familial aggregation in case-control studies.

This paper describes an analytical method that is used to assess patterns of disease aggregation within family based on family history information collected in case-control studies. In such a study, cases and controls are thought of as probands whose relatives are identified, and relatives' phenotypes and other covariates such as age, sex, and genealogical relationship with the probands are recorded. By modeling the dependence of relatives' phenotypes on case-control status and other covariates, this method yields adjusted odds ratios that quantify familial aggregation. The estimated standard errors are obtained for statistical inference since the method acknowledges the potential correlations between relatives' phenotypes by using the estimating equations technique. In population-based case-control studies, the estimates and statistical inferences are generalizable to the general population. To illustrate this method, we analyzed a case-control study of colorectal cancer involving 5,190 relatives of 792 cases and 4,478 relatives of 680 population-based controls conducted in Hawaii. Although detailed results will be presented elsewhere, the colorectal cancer was found to aggregate within family with an odds ratio of 2.74 (95% confidence interval (CI): 1.78-4.21). Among parents, the odds ratio for familial aggregation was 2.38 (95% CI: 1.25-4.54). The corresponding value for siblings was 3.09 (95% CI: 1.87-5.11). It was also found that the odds ratio increases from about 2.00 for relatives of the probands who were 50 years or older to 7.66 and 12.84 for relatives of the probands who were between 40 and 50 years and under 40 years, respectively, suggesting that the familial aggregation of colorectal cancer decreases as probands' age increases.     

Criteria for onset critically influence the estimation of familial risk in Alzheimer's disease

The rare early-onset variant of Alzheimer's disease (AD) appears to be transmitted as an autosomal dominant genetic trait. More typical late-onset AD also shows familial aggregation, but possible genetic mechanisms are difficult to examine because the phenotypic expression of the putative AD genotype is often censored by prior death from competing causes. Lifetable methods have been used to examine the age-specific risk of dementia among relatives, and thus to test the hypothesis of genetic transmission of late-onset AD. These methods require the ascertainment of affected relatives and the determination of their age at onset. The latter determination is somewhat arbitrary, since symptoms of AD evolve and develop in a continuous and progressive fashion, and different workers may thus use differing criteria for "onset." This paper demonstrates that the use of divergent thresholds for "caseness" (typically, progressive dementia of several years' duration) and onset (e.g., the first appearance of mild cognitive symptoms, or the first clear evidence of dementia) can introduce substantial bias toward underestimation of risk among relatives. Depending on the definition of onset, familial risk may be underestimated, with apparent cumulative incidence decreased to only 60% of values otherwise expected. We suggest that this problem can be avoided by the use of identical threshold criteria for caseness and for onset.     

Age at onset as an indicator of familial risk of breast cancer

The familial risk of breast cancer was investigated in a large population-based, case-control study conducted by the Centers for Disease Control. The data set included 4,730 histologically confirmed breast cancer cases aged 20-54 years and 4,688 controls who were frequency matched to cases by geographic region and 5-year categories of age. Family history of breast cancer among first-degree female relatives of cases and controls was utilized. To identify factors associated with familial risk of breast cancer, a Cox proportional hazards model was used, modeling time to onset of breast cancer among mothers and sisters. Case relatives were at greater risk than control relatives. Among relatives of cases, a significant increase in the risk of breast cancer was associated with decreasing age at onset of the case and with having an additional relative affected with breast cancer. The hazard ratio for the mother of a case with breast cancer diagnosed at 50 years of age was 1.7 (95% confidence interval (Cl) 1.4-2.0), compared with 2.7 (95% Cl 2.2-3.2) and 4.3 (95% Cl 3.3-5.6) for the mother of a case whose diagnosis occurred at 40 and 30 years of age, respectively. The hazard ratio for the sister of a case with an unaffected mother and at least one affected sister in addition to the case was 3.6 (95% Cl 2.1-6.1) when the case was diagnosed at age 50, compared with 5.8 (95% Cl 3.4-10.0) and 9.4 (95% Cl 5.3-16.7) when the case was diagnosed at 40 and 30 years of age, respectively. The hazard ratio for the sister of a case with an affected mother and no additional affected sisters was 5.9 (95% Cl 3.9-8.9) when the case was diagnosed at age 50, compared with 9.4 (95% Cl 6.2-14.4) and 15.1 (95% Cl 9.4-24.3) when the case was diagnosed at 40 and 30 years of age, respectively. The hazard ratio for the sister of a case with both an affected mother and at least one affected sister aside from the case was 17.1 (95% Cl 9.4-31.3) when the case was diagnosed at age 50, compared with 27.5 (95% Cl 15.0-50.3) and 44.2 (95% Cl 23.5-83.2) when the case was diagnosed at 40 and 30 years of age, respectively. No effect of case's menopausal status and bilaterality was found, indicating that in addition to a positive family history, age at onset is the strongest indicator of a possible genetic subtype of breast cancer in these data.     

Lung cancer risk in families of nonsmoking probands: heterogeneity by age at diagnosis.

In an earlier investigation, we did not detect a major genetic component to lung cancer in families of nonsmoking lung cancer probands. However, heterogeneity with respect to familial aggregation, based on probands' age at diagnosis, was evident. We reanalyzed our previously collected data of 257 families, stratified by age at diagnosis of the probands, using complex segregation analysis. We specifically tested the effects of a Mendelian diallelic gene, history of tobacco use, and history of selected chronic lung diseases in families with a proband diagnosed at the age of 60 years or older and in families with a younger proband (i.e. , under 60 years of age). Cases were identified from the Metropolitan Detroit Cancer Surveillance System. Information on lung cancer occurrence, smoking history, and chronic respiratory diseases in first-degree relatives was obtained for 210 older probands and for 47 younger probands. In older probands' families, no evidence of a major genetic effect was detected. A history of emphysema and tobacco-smoke exposure were found to be significant risk factors. In younger probands' families, a Mendelian codominant model with significant modifying effects of smoking and chronic bronchitis best explained the observed data. Our results suggest the presence of a high-risk gene contributing to early-onset lung cancer in a population where the probands are nonsmokers.     

Prevalence of familial hyper- and hypolipoproteinemias in blacks: The Princeton School District Family Study

Using black subjects from the Princeton School Family Study cohort, our specific aim was to estimate the prevalence of suspected familial hyper- and hypolipoproteinemias, and to provide empirical risk estimates for the proportion of probands' first-degree relatives who were similarly affected. Suspected familial hyper- and hypolipoproteinemias were arbitrarily identified in those kindreds having at least two first-degree relatives in the same decile as the proband, top or bottom, respectively, for low- or high-density lipoprotein cholesterol (LDLC, HDLC). Some cutpoint for identification of elevated LDLC must be arbitrarily selected, and the level chosen here, the top decile, will affect ascertainment of the familial disorder. One hundred and seven probands, 52 randomly recalled, 55 from a hyperlipidemic recall group, and their relatives were assessed. Of the 52 randomly recalled black probands, 2 of whom had top decile LDLC, 1 had suspected familial hyperchlosterolemia (FHA). Of the 55 hyperlipidemic recall probands, 25 of whom had top decile LDLC, 4 had apparent FH: one kindred had three-generation vertical and horizontal transmission of top decile LDLC. In the five kindreds with suspected FH, overt disease, drugs, and dietary excess did not appear to cause the elevated LDLC. After adjustment for Quetelet index, there was a significant positive partial correlation between LDLC and both systolic and diastolic blood pressure in top decile LDLC probands and their first-degree relatives. Of the 52 randomly recalled probands, 8 had top decile HDLC, and 2 had suspected familial hyperalphalipoproteinemia (FHA). Of the 55 hyperlipidemic recall group probands, 10 had top decile HDLC, 1 had suspected FHA. In the three kindreds with suspected FHA, the elevated HDLC could not be accounted for by disease, drugs, or alcohol intake known to elevate HDLC. Whatever definition of FH or FHA is used, the high prevalence of suspected FH and FHA underlines the importance of sampling all first-degree relatives of top decile LDLC and HDLC probands; clustering of CHD (or its absence) in families may be related in part to familial aggregation of LDLC and/or HDLC.     

Segregation analysis of 389 Icelandic pedigrees with Breast and prostate cancer

Breast cancer and prostate cancer are the most commonly occurring cancers in females and males, respectively. The objective of this project was to test the hypothesis that breast cancer in females and prostate cancer in males represent homologous cancers that may be controlled by one or more common unidentified genes that may explain some of the observed familial aggregation. We modeled the transmission of a breast-prostate cancer phenotype in 389 pedigrees ascertained through a breast cancer proband drawn from the Icelandic Cancer Registry. Assuming that age at diagnosis of this combined phenotype followed a logistic distribution, segregation analyses were performed to evaluate residual parental effects, a sibship covariate, and a dichotomous cohort effect. The most parsimonious model was a Mendelian codominant model, which could partly explain the familial aggregation of both cancers. Inheritance of a putative high-risk allele (A) predicted gender-specific mean ages of onset for females as 53.8 years, 59.7 years, and 65.6 years for the putative AA, AB, and BB genotypes, respectively. Similarly, the predicted means were 73.7 years, 75.6 years, and 78.3 years, respectively, among males. Under this codominant model, the lifetime risk of a woman being affected was 19% by age 80 years. This implies that when prostate cancer among male relatives of breast cancer probands (unselected for family history or early-onset disease) is considered a pleiotrophic effect of the same gene that increases the risk for breast cancer, women are predicted to have a less than 1 in 5 risk of developing breast cancer when they carry the putative high-risk allele. However, this is a higher risk than in the general Icelandic population. Our results suggest that BRCA2 mutations alone are inadequate to explain all of the excess clustering of prostate cancer cases in families of breast cancer probands, and that additional genes conferring excess risk to both breast and prostate cancer may exist in this population.     

Heterogeneity of breast cancer risk in families of young breast cancer patients and controls.

Familial heterogeneity of breast cancer risk was assessed among 4,159 first-degree female relatives of 1,074 population-based, young breast cancer cases (aged 20-54 years) diagnosed from December 1, 1980 to December 31, 1982 and 4,120 first-degree female relatives of 998 age- and race-matched, population-based controls from the metropolitan Detroit, Michigan, area. The family risk index method used for analysis considers family size, age, and race differences among families in the assessment of family risk. Families of cases showed a higher risk of breast cancer than did families of controls, with case families 1.80 to 4.24 times more likely to be defined as high risk than control families; the magnitude of the risk differential was dependent on the definition of high risk. Within the case families only, familial heterogeneity of risk was suggested, with a small proportion of families (less than 5%) at lower risk of breast cancer than most case families. A number of reproductive risk factors, age, race, and histologic type of cancer for the proband, and several family characteristics were investigated to help characterize the case families at higher and lower risk.