The Pittsburgh Study of Insulin-Dependent Diabetes Mellitus: Risk for Diabetes Among Relatives of IDDM

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Diabetes (Impact Factor: 8.1). 03/1982; 31(2):136-44. DOI: 10.2337/diabetes.31.2.136
Source: PubMed

ABSTRACT AN analysis has been made of the family histories of a survey of 1280 cases of IDDM entering Children's Hospital of Pittsburgh between December 31, 1964 and January 1, 1981, discharged on insulin and initial age of onset under 17 yr. Family histories revealed an increased occurrence of IDDM among relatives in the affected families. The risk to siblings was estimated by age-corrected proband exclusion (3.3%) by age 20 and by the Li-Mantel segregation ratio estimator (6.0%). The comparison of these risk measures is discussed. The occurrence of IDDM among the parents is 2.6% and of NIDDM among the parents is 2.4%. A comparison of risk to relatives (parents, sibs, uncles, half-sibs) observed in the Pittsburgh Study to those of six other studies reveal essentially equivalent rates. There is no increased risk to siblings of a diabetic who had an early age of onset. There is an increased risk to siblings of a diabetic (10.5%) in families where at least one parent has insulin-dependent diabetes mellitus (IDDM) and also an increased risk to siblings of a diabetic (8.8%) when at least one parent has non-insulin-dependent diabetes (NIDDM). The average age of onset for second cases in a family is significantly older than age of onset in single case families.

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    • "By direct estimation of the recurrence risks in offspring of parents with T1D, it has been shown that the offspring of affected fathers are more likely to develop T1D than those of affected mothers [Warram et al., 1984; Tuomilehto et al., 1995]. These findings seem to have been validated by family-history studies of children with T1D and their parents, which have demonstrated that the prevalence of paternal T1D in families with at least one child with T1D is significantly higher than the prevalence of maternal T1D [Degnbol et al., 1978; Wagener et al., 1982; Dahlquist et al., 1982; Jefferson et al., 1985; Gavard et al., 1989; O'Leary et al., 1991; Tuomilehto et al., 1992; Metcalfe and Baum, 1992; Pociot et al., 1993; Lorenzen et al., 1994]. A summary of studies, by no means exhaustive, that support such a preferential transmission in T1D is given in Table I. "
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    ABSTRACT: It has been widely reported that men with type 1 diabetes (T1D) tend to be more likely to transmit the disease to their offspring than their female counterparts in Caucasoid populations. Several theories to explain this preferential transmission have been proposed, but so far none of them has been unequivocally proven. Whatever the mechanism, confirmation or refutation of this observation is nonetheless important and practical to the design of future genetic studies of T1D. We carried out some statistical modeling of the preferential transmission. The well-established fact that males have higher a prevalence of T1D than females, an apparent sex difference in fecundity, and a possible misclassification of gestational diabetes mellitus (GDM) as T1D in women have been considered. We demonstrated, first, that the ascertainment of study families through the affected offspring with T1D would generate a higher proportion of fathers than mothers having T1D, even though there was no preferential transmission at all. This can be explained by the male preponderance in T1D prevalence as compared with females, coupled with a greater likelihood of being selected and/or recruited for study in families with T1D fathers due to the fecundity difference. Second, when the study population is ascertained through affected parents, misclassification of mothers with GDM as T1D, and the existence of male/female difference in fecundity in conjunction with a birth order effect, can contribute to the observed preferential transmission, even though there was none. In light of the plausibility of assumptions employed in the analysis and, in particular, an apparent failure to critically examine the effects of these causes of bias in earlier studies, it is perhaps prudent to say that the jury for the existence of preferential transmission in T1D is still out.
    Genetic Epidemiology 11/2002; 23(4):323-34. DOI:10.1002/gepi.10183 · 2.60 Impact Factor
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    • "Study subjects were participants in the Pittsburgh EDC Study, an ongoing 10-year prospective study of risk factors for complications of childhood onset Type 1 diabetes. EDC participants were recruited from the Children's Hospital of Pittsburgh registry of Type 1 diabetes, which has been shown to be representative of the local (Allegheny County) community-based population [16]. To be eligible for the EDC Study, subjects had to have been diagnosed (or seen within a year of diagnosis) at this hospital between 1950 and 1980. "
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    ABSTRACT: In the Type 1 diabetes population, coronary heart disease (CHD) and lower-extremity arterial disease (LEAD) are the two common macrovascular complications leading to early mortality and morbidity. However, it is not clear if these two complications share the same risk factors. The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study prospectively examined and compared the risk factors for LEAD and CHD (including CHD morbidity and mortality). EDC subjects (332 men and 325 women), all diagnosed at Children's Hospital of Pittsburgh between 1950 and 1980, were first examined at baseline (1986-1988), and then biennially, for diabetes complications and their risk factors. Data used in the current analysis were from the first 6 years of follow-up, 98% provided at least some follow-up data for these analyses. CHD was defined as the presence of angina (diagnosed by the EDC examining physician) or a history of confirmed myocardial infarction or CHD death. An ankle-to-arm ratio of less than 0.9 at rest was considered to be evidence of LEAD. Among 635 subjects without CHD at baseline, 57 developed CHD (1.69/100 person-years), and among 579 without LEAD at baseline, 70 developed LEAD (2.31/100 person-years). CHD incidence rate was slightly higher in males, while LEAD incidence rate was slightly higher in females. Compared to non-incident cases, subjects who developed either complication were older, had a longer diabetes duration, higher LDL and total cholesterol, and were more likely to be hypertensive. In multivariate analyses, hypertension, low HDL cholesterol level, high white cell count, depression, and nephropathy were the independent risk factors for CHD (including morbidity and mortality). For LEAD, higher HbA1 level, higher LDL cholesterol level and smoking were the important contributing factors. In conclusion, the risk factor patterns differ between the two vascular complications. Glycemic control does not predict CHD overall but does predict LEAD, while hypertension and inflammatory markers are more closely related to CHD than to LEAD.
    Atherosclerosis 02/2000; 148(1):159-69. DOI:10.1016/S0021-9150(99)00217-8 · 3.99 Impact Factor
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    • "and a recurrence risk in sibs of patients of .060. These values are similar to those obtained by Wagener et al. (1982) from the Pittsburgh study of IDDM. Therefore, Xs is approximately 15. "
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    ABSTRACT: The relationship between increased risk in relatives over population prevalence (lambda R = KR/K) and probability of sharing zero marker alleles identical by descent (ibd) at a linked locus (such as HLA) by an affected relative pair is examined. For a model assuming a single disease-susceptibility locus or group of loci tightly linked to a marker locus, the relationship is remarkably simple and general. Namely, if phi R is the prior probability for the relative pair to share zero marker alleles identical by descent, then P (sharing 0 markers/both relatives are affected) is just phi R/lambda R. Alternatively, lambda AR, the increased risk over population prevalence to a relative R due to a disease locus tightly linked to marker locus A, equals the prior probability that the relative pair share zero A alleles ibd divided by the posterior probability that they share zero alleles ibd, given that they are both affected. For example, for affected sib pairs, P (sharing 0 markers/both sibs are affected) = .25/lambda S. This formula holds true for any number of alleles at the disease locus and for their frequencies, penetrances, and population prevalence. Similar formulas are derived for sharing one and two markers. Application of these formulas to several well-studied HLA-associated diseases yields the following results: For multiple sclerosis, insulin-dependent diabetes mellitus, and coeliac disease, a single-locus model of disease susceptibility is rejected, implying the existence of additional unlinked familial determinants. For all three diseases, the effect of the HLA-linked locus on familiality is minor: for multiple sclerosis, it accounts for only a 2.5-fold increased risk to sibs over the population prevalence, compared to an observed value of 20; for coeliac disease, it accounts for approximately a 5.25-fold increased risk to sibs, while the observed value is on the order of 60; for insulin-dependent diabetes mellitus, it accounts for a 3.42-fold increased risk in sibs, while the observed value is 15. In all cases, the secondary determinants must be outside the HLA region. For tuberculoid leprosy, an unlinked familial determinant is also implicated (increased risk to sibs due to HLA = 1.49; observed value = 2.38). For hemochromatosis and Hodgkin's disease, there is little evidence for HLA-unlinked familial determinants. With this formula, it is also possible to examine the hypothesis of pleiotropy versus linkage dis-equilibrium by comparing lambda AS with the increased risk to sibs due to the associated allele(s).(ABSTRACT TRUNCATED AT 400 WORDS)
    The American Journal of Human Genetics 02/1987; 40(1):1-14. · 10.93 Impact Factor
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