A Nested Case-Control Study of Siblings of Children With Diabetes

The evidence for the putative role of cow’s milk in the development of type 1 diabetes is controversial. We studied infant feeding patterns and childhood diet by structured questionnaire (n = 725) and HLA-DQB1 genotype by a polymerase chain reaction–based method (n = 556) in siblings of affected children and followed them for clinical type 1 diabetes. In a nested case-control design in a population who had both dietary and genetic data available, we selected as cases those siblings who progressed to clinical diabetes during the follow-up period (n = 33). For each case, we chose as matched control subjects siblings who fulfilled the following criteria: same sex, age within 1 year, not from the same family, the start of the follow-up within 6 months of that of the respective case, and being at risk for type 1 diabetes at the time the case presented with that disease (n = 254). The median followup time was 9.7 years (range 0.2–11.3). Early age at introduction of cow’s milk supplements was not signific a n t l y associated with progression to clinical type 1 diabetes (relative risk adjusted for matching factors, maternal education, maternal and child’s ages, childhood milk consumption, and genetic susceptibility markers was 1.60 [95% CI 0.5–5.1]). The estimated relative risk of childhood milk consumption for progression to type 1 diabetes was 5.37 (1.6–18.4) when adjusted for the matching and aforementioned sociodemographic factors, age at introduction of supplementary milk feeding, as well as for genetic susceptibility markers. In conclusion, our results provide support for the hypothesis that high consumption of cow’s milk during childhood can be diabetogenic in siblings of children with type 1 diabetes. However, further studies are needed to assess the possible interaction between genetic disease susceptibility and dietary exposures in the development of this disease. Diabetes 4 9 :9 1 2–917, 2000 The putative diabetogenicity of cow’s milk has been debated since the animal experiment by Elliott and Martin (1), showing that the risk of diabetes in BB rats could be decreased by feeding a semisynthetic amino acid diet instead of a milk protein supplementation diet from weaning. The findings from our Finnish case-control study were the first to suggest in humans a relationship between the early introduction of supplementary cow’s milk feeding and an increased risk of type 1 diabetes (2) independent of the duration of breast-feeding (3). The results from case-control studies on the role of the consumption of cow’s milk later in childhood as a possible risk factor of type 1 diabetes are conflicting (4–6). The only cohort study available suggests that consumption of cow’s milk during childhood may be an important risk determinant among siblings of affected children (7). Geographical comparisons have shown a strong positive correlation between per capita cow’s milk consumption and the risk of type 1 diabetes in children (8,9). Both increased humoral and cell-mediated immune responses to c o w ’s milk proteins have been observed in newly diagnosed children with type 1 diabetes compared with those in control children (10). Cow’s milk protein antibody levels were also found to be higher in affected children than in control siblings when matched for HLA-DQB1 risk alleles (11). Data on a possible combined effect of cow’s milk consumption and increased genetic predisposition to type 1 diabetes are scanty. The findings of 2 case-control studies indicate that there might be an interaction between increased genetic disease susceptibility based on HLA class II alleles and the early introduction of supplementary milk feeding during infancy on the risk of type 1 diabetes (12,13). In the present prospective follow-up of a cohort of siblings of affected children, we evaluated the effect of cow’s milk exposure during infancy and later in childhood and of increased genetic susceptibility defined by HLA-DQB1 markers on the risk of developing type 1 diabetes.