Genetic random effects model for family data with long-term survivors: analysis of diabetic nephropathy in type 1 diabetes.

A shared and additive genetic variance component-long-term survivor (LTS) model for familial aggregation studies of complex diseases with variable age-at-onset phenotype and non-susceptible subjects in the study cohort is proposed. LTS has been used from the early 1970s, especially in epidemiological studies of cancer. The LTS model utilizes information on the age at onset (survival) distribution to make inference on partially latent susceptibility. Bayesian modeling with uninformative priors is used and estimates of the posterior distribution of age at onset and susceptibility parameters of interest have been obtained using Bayesian Markov chain Monte Carlo (MCMC) methods with OpenBugs program. A simulation study confirms that we obtain posterior estimates of the model parameters on shared and genetic variance components of age at onset and susceptibility with good coverage rates. Further, we analyze familial aggregation of diabetic nephropathy (DN) in large Finnish cohort of 528 sibships with type 1 diabetes (T1D). According to the variance components estimated a substantial familial variation in the susceptibility to DN exist among families, while time to DN is less influenced by shared familial factors.

Cardiac autonomic nervous dysfunction in diabetic patients with a mitochondrial DNA mutation: assessment by heart rate variability.

OBJECTIVE: To elucidate the degree and characteristics of cardiac autonomic nervous dysfunction in diabetic patients associated with a mitochondrial DNA mutation at base pair 3243. RESEARCH DESIGN AND METHODS: We investigated heart rate variability using 24-h Holter monitoring in 10 diabetic patients with the mutation compared with 55 ordinary diabetic patients and 45 nondiabetic control subjects. RESULTS: Age and sex were similar in the three groups. Between patients with the mutation and ordinary diabetic patients, the duration of diabetes and blood glycemic levels were not different. In the time domain analysis of heart rate variability, patients with the mutation and ordinary diabetic patients had significantly smaller SDNN index and pNN50 than control subjects. Compared with ordinary diabetic patients, patients with the mutation had smaller SDNN index (P < 0.02), but rMSSD and pNN50 were not different. In the frequency domain analysis, total, low frequency (LF), and high frequency (HF) spectra were significantly smaller in patients with the mutation and ordinary diabetic patients than in control subjects. Compared with ordinary diabetic patients, patients with the mutation had smaller total and LF spectra (P < 0.02). However, HF spectra were not significantly different. Notably, the LF/HF spectra ratio was lower in patients with the mutation than in ordinary diabetic patients and control subjects (P < 0.05), but this ratio was similar in ordinary diabetic patients and control subjects. CONCLUSIONS: Our results suggest that diabetic patients with the mitochondrial DNA mutation have more severely impaired cardiac autonomic nervous function with sympathovagal imbalance, as compared with ordinary diabetic patients.