Predicting Insulin-Dependent Diabetes

Tarn, A. C.; Dean, B M; Schwarz, G.; Thomas, J. M.; Ingram, David A.; Bottazzo, Gian Franco; Gale, EdwinA.M.

doi:10.1016/s0140-6736(88)91601-7

Cited by 255 publications

(128 citation statements)

References 26 publications

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“…We found the recurrence risk of IDDM in the families of the study population to be higher than hitherto reported from most studies [13,14,[31][32][33] but comparable to the high value of a recent report from Allen et al [19]. The cumulative recurrence risk of siblings at age 60 years was estimated to 9.6 % and interestingly, we also found that the recurrence risk in siblings was significant even after age 30 years (3.2 % from 30 to 60 years).…”

Section: Discussionsupporting

confidence: 85%

Long-term risk of IDDM in first-degree relatives of patients with IDDM

et al. 1994

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SummaryDue to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean "observation" times (age) (+ SD) for siblings (n =553) and offspring (n = 359) were 59.4 + 16.1 years and 33.8 + 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4 % to 22.4 % of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48 % of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4 % and up to age 60 years of 9.6 %. For offspring the risk up to age 34 years was 6.3 %. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports. [ Diabetologia (1994) 37: 321-327] Key words IDDM, first-degree relatives, familial aggregation, recurrence risk, life-table analysis.The aetiology of IDDM is still rather poorly understood. The major genetic predisposition is conferred by HLA-class II genes [1-3] but genes outside this region may also confer susceptibility [4][5][6][7][8]. Furthermore, environmental factors are thought to be important for the initiation of the disease [9][10][11]. Epidemiological studies may be helpful in increasing our understanding of IDDM and are essential for generation of preventive and interventive strategies aimed at the eradication of the disease. When studying familial aggregation of Received: 14 July 1993 and in revised form: 13 October 1993Corresponding author: Dr. J.Nerup, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, DenmarkAbbreviations: IDDM, insulin-dependent diabetes mellitus; SE, standard error.IDDM the composition and representativeness of the study population are obviously important for allowing direct comparisons between results from different regions and centres.Several studies have reported the prevalence of IDDM patients having affected first-degree relatives within a range of 5 to 19 % [13][14][15][16][17][18][19][20][21][22][23][24]. However, many of these studies are not directly comparable, primarily due to methodological differences. Often, the study populations comprised only children or adolescent probands [13,15,18,19,21,24], were designed as incid...

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Section: Discussionsupporting

confidence: 85%

Long-term risk of IDDM in first-degree relatives of patients with IDDM

et al. 1994

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“…However, these specificities, although necessary, are not sufficient since monozygotic twins are only 30-50% concordant for the disease [32][33][34]. Siblings of a Type 1 diabetic patient have a 16-30% risk of developing clinical Type 1 diabetes by the age of 30 years if they are HLA identical, but have only a 5% risk if they are haploidentical [35][36][37]. However, due to this genetic risk, family studies following relatives of Type i diabetic patients provide a unique opportunity to develop possible risk markers and to investigate their predictive value.…”

Section: Resultsmentioning

confidence: 99%

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

et al. 1991

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Summary. First-degree relatives of Type i (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a Mr 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type i diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type i diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n = 6) and low (n = 30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive While six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type i diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the Mr 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years.

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“…Such non-genetic factors may either initiate autoimmunity or accelerate/ precipitate beta cell destruction [7]. Follow-up studies of first-degree relatives of type-1 diabetic patients have shown that autoimmunity often precedes clinical disease by many years [8][9][10]. Not all individuals that carry autoantibodies towards the beta cells ultimately develop clinical diabetes, and the signs of autoimmunity may disappear [11][12][13].…”

Section: Introductionmentioning

confidence: 99%