Increasing incidence of Type 1 diabetes--role for genes?

Abstract

Background: The incidence of Type 1 diabetes (T1DM) is increasing fast in many populations. The reasons for this are not known, although an increase in the penetrance of the diabetes-associated alleles, through changes in the environment, might be the most plausible mechanism. After the introduction of insulin treatment in 1930s, an increase in the pool of genetically susceptible individuals has been suggested to contribute to the increase in the incidence of Type 1 diabetes.

Results: To explore this hypothesis, the authors formulate a simple population genetic model for the incidence change driven by non-Mendelian transmission of a single susceptibility factor, either allele(s) or haplotype(s). A Poisson mixture model is used to model the observed number of cases. Model parameters were estimated by maximizing the log-likelihood function. Based on the Finnish incidence data 1965-1996 the point estimate of the transmission probability was 0.998. Given our current knowledge of the penetrance of the most diabetic gene variants in the HLA region and their transmission probabilities, this value is exceedingly unrealistic.

Conclusions: As a consequence, non-Mendelian transmission of diabetic allele(s)/haplotype(s) if present, could explain only a small part of the increase in incidence in Finland. Hence, the importance of other, probably environmental factors modifying the disease incidence is emphasized.

Figure 1

Predicted allele frequencies in annual population of children 0–15 years of age plotted against calendar year, using the population genetic model for the incidence change. Transmission probability of the susceptibility allele 'A' from a heterozygous parent, τ, is 0.52 (---), 0.55 (-- --) and 0.6 (-- ··· --). Allele frequency of 'A' starts from = 0.15 in both figures. The transmission distortion effect is assumed to have been acting since the introduction of insulin in 1930s.

Figure 2

Predicted genotype frequencies in annual population of children 0–15 years of age plotted against calendar year, using the population genetic model for the incidence change. Transmission probability of the susceptibility allele 'A' from a heterozygous parent, τ, is 0.52 (---), 0.55 (-- --) and 0.6 (-- ··· --). Allele frequency of 'A' starts from = 0.15 in both figures. The transmission distortion effect is assumed to have been acting since the introduction of insulin in 1930s.

Figure 3

Predicted curves for disease incidence (/100,000/year) of a population experiencing transmission distortion as a function of allele frequency, where for homozygote AA the penetrance is λ_AA = 160 and λ_aa = 10. Four models of gene expression were explored ('A' dominant to 'a' (---), alleles codominant (-- --), allele effects multiplicative (-- ··· --), and 'A' recessive to 'a' (·········)). The penetrance for heterozygous genotype is always between (or equal to) those of homozygotes.

Figure 4

Predicted curves for disease incidence (/100,000/year) of a population experiencing transmission distortion as a function of allele frequency, where for homozygote AA the penetrance is λ_AA = 40 and λ_aa = 10 (low differences in penetrances). Four models of gene expression were explored ('A' dominant to 'a' (---), alleles codominant (-- --), allele effects multiplicative (-- ··· --), and 'A' recessive to 'a' (·········)). The penetrance for heterozygous genotype is always between (or equal to) those of homozygotes.

Figure 5

Predicted curves for disease incidence (/100,000/year) of a population experiencing transmission distortion as a function of allele frequency, where for homozygote AA the penetrance is λ_AA = 500 and λ_aa = 0 (high differences in penetrances). Four models of gene expression were explored ('A' dominant to 'a' (---), alleles codominant (-- --), allele effects multiplicative (-- ··· --), and 'A' recessive to 'a' (·········)). The penetrance for heterozygous genotype is always between (or equal to) those of homozygotes.

Figure 6

The observed incidence of Type 1 diabetes in Finland from 1965 to 1996 and expected incidence under two models: (M1) no transmission distortion (τ fixed 0.5) and (M2) allowing transmission distortion (τ has been set to the estimated value of 0.998).