The Pittsburgh Study of Insulin-Dependent Diabetes Mellitus: Risk for Diabetes Among Relatives of IDDM
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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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 · 2.95 Impact Factor
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ABSTRACT: Objectives: Several investigations in families with both T1DM and T2DM have been reported to elucidate the genetic interaction between T1DM and T2DM and the clinical consequences for both diseases. The frequent occurrence of T1DM in relatives of patients with T2DM has also been previously observed. This study investigated whether the T2DM parent/grandparents share a specific HLA class II-DRB1and DQB1 alleles and their haplotype combination with the T1DM child. Methods: Twenty four Bahraini families with a T1DM child and either parents or grandparents with T2DM and with no family history of T1DM were selected. HLA class II-DRB1 and DQB1 were examined by SSP-PCR method and the distribution was analyzed. Results: In relation to DRB1*, the most common shared allele was DRB1*04:01:01 83% (n=20), while the most common shared DQB1* allele was DQB1*03:02:01 83% (n=20). In addition, the most common shared haplotype was DRB1*04:01:01-DQB1*03:02:01 83% (n=20). Conclusions: The current study showed that DR4 and DQ3 alleles and its haplotype combination are the highest prevalence in the selected Bahraini families with mixed T1DM and T2DM patients. T2DM parents possessing this haplotype are more likely to have a child with T1DM, especially in families with no history of T1DM. The excess transmission of DR4-linked haplotypes from parents with T2DM to offspring with T1DM has been clearly observed in the present study.
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ABSTRACT: Although the Haptoglobin (Hp) 1-1 genotype is associated with a lower coronary artery disease (CAD) risk in diabetes, we recently reported an increased stroke incidence in type 1 diabetes with Hp 1-1. We, thus, evaluated differences in earlier brain vascular abnormality markers by Hp using neuroimaging. Neuroimaging was completed in 94 participants of the Pittsburgh Epidemiology of Diabetes Complications study with Hp genotyping available (mean age, 49 and duration, 41 years). White matter hyperintensities volume (WMH), lacunar infarcts and gray matter atrophy were quantified. Sixteen percent were homozygous for Hp 1 and 43% for Hp 2. A significant trend toward increased WMH was observed with greater duration and the number of Hp 1 alleles. Associations were strongest for the inter-hemispheric connecting fibers of the corpus callosum. Allowing for duration, gender, waist/hip ratio, HbA1c, systolic blood pressure and lipids in models with backward elimination, results were similar. No significant differences by Hp were noted for atrophy or lacunar infarcts. Consistent with its direct association with stroke, the Hp 1-1 genotype is associated with higher WMH in this population. Further, including mechanistic, studies on the role of the Hp genotype in cerebrovascular disease and the implications for worsening cognitive function are needed.Diabetes 09/2014; 64(2). DOI:10.2337/db14-0723 · 8.47 Impact Factor