To identify genetic variants causing T2D by sequencing families showing linkage to T2D
We have over the years demonstrated linkage to T2D and several chromosomal regions in families from the Botnia study, e.g.linkage to chromosome 12 in families with impaired insulin secretion (16), to chromosome 9 in families with T2D (17) and to chromosome 18 in obese T2D individuals (18). The rapid development of next generation sequencing tools should make this possible.
Exome sequencing of families with extremes of quantitative traits
From studies on lipids it has been shown that exome sequencing is an efficient tool to identify less frequent variants with stronger effects on the trait. In the Botnia study we have calculated family means of a number of metabolic traits (insulin secretion and action, lipids, FFA, measures of body compositio). We will now select extremes of these traits defined as highest and lowest decentile of the trait for sequencing.
Exploring parent-of-origin specific transmission of genetic variants increasing risk of T2D
T2D is more common in offspring of diabetic mothers than fathers (2) and several studies have shown increased risk of T2D if the risk allele is transmitted from the mother rather than from the father (12,13, 27). Children with low birth weight have an increased risk to develop T2D later in life (14), a phenomenon which has been ascribed to intrauterine programming (14,28). This could include imprinting of genes important for β-cell development and mass. The most likely mechanism for imprinting would be silencing of a gene through DNA methylation. In general, diabetes develops when people no longer can increase their insulin secretion capacity to meet increased demands imposed by obesity and insulin resistance (8). The hypothesis can therefore be advanced that intrauterine imprinting of key genes for β-cell development will result in reduced β-cell mass and make these people more susceptible to develop T2D later in life. Studies of parent-of-origin specific transmissions have been hampered by the paucity of family trios, i.e. pedigrees with DNA from both parents and offspring (29). The Botnia study provides a rich resource of trios which can be further enlarged by searching for so called “surrogate parents” by taking advantage of the isolated nature of the region and that people share long stretches of the chromosomes (haplotypes).
Describing the spectrum of diabetic subgroups
It can be assumed that a better classification of diabetes into subgroups may aid in better individualized treatment. The current subdivision into T1D and T2D most likely reflects an oversimplification of the situation where T1D and T2D represent extreme forms at the ends of the spectrum with insulin deficiency and autoimmunity dominating for T1D and insulin resistance and features of the metabolic syndrome for T2D. In the middle is LADA (Latent Autoimmune Diabetes in Adults), a common form of diabetes with features of both T1D and T2D. In an attempt to provide a better characterization of diabetes we initiated the DIREVA project (Diabetes Registry Vaasa) in 2010, a registry of all known diabetic patients in the Vaasa Central Hospital Region . The registry currently includes more than 4,500 patients but is predicted to include 10,000 well characterized patients at the end of 2015. For the purpose of better diabetes classification we will combine genetic and non-genetic (biomarkers, metabolites, circulating miRNAs) with information from the hospital discharge records and the Drug Prescription Registry. This will allow us to use baseline information to predict progression of the disease, development of complications and response to or side effects from treatment.
The Botnia Study
The Botnia Study was initiated 1990 on the Western Coast of Finland near the Gulf of Bothnia. The study includes information on 25962 individuals from 1131 families. In addition, the Botnia Prospective Study (BPS) includes 2700 persons followed for 10 years, 300 of whom developed T2D. The population-based PPP-study( Prevalence Prediction Prevention of T2D) includes 5200 individuals aged 18-75 yrs with a 5-year follow-up carried out in more than 3000 persons.. The DIREVA (Diabetes Registry Vaasa) currently includes more than 4,500 patients from the region but is predicted to include most patients including information on disease progression, complications and treatment.
The aims of the Botnia Study are:
- Describe the metabolic disturbances leading to T2D
- Identify the genetic causes of T2D
- Use this information to predict the disease
- Use this information to prevent the disease
Last updated: September 6, 2016
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