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It was formerly known as Insulin Dependent Diabetes Mellitus.It occurs due to autoimmune destruction of the pancreatic insulin secreting islet cells which leads to insulin deficiency. There is presence of antibodies towards islet cells. It typically tends to affect the younger population (<35years).Patients with Type 1 Diabetes require insulin from the onset of disease for maintenance of euglycemia. The major gene implicated in Type 1 DM is HLA locus (DRB1, DRQA1, DRQB1) which imparts approximately half of the disease risk (1).
Type 2 Diabetes
It was formerly known as Non-Insulin Dependent Diabetes Mellitus (NIDDM).It mainly occurs due to insulin resistance. The levels of insulin in such patients can be decreased, normal or even higher than the normal. It chiefly affects adults more than 35 years of age. These patients have no insulin requirement at onset but they may require insulin at some point of time. They do not have antibodies against their own islet cells. TCF7L2 is believed to have strong association with Type 2 Diabetes.
Latent Auto-immune Diabetes in Adults (LADA)
It is widely accepted that autoantibody-positive diabetes in adults more than 35 years of age presents with no insulin requirements at the point of diagnosis and has a slower progression toward insulin deficiency than T1D. These observations led to the definition of LADA (2,3,4) as its own subgroup in the World Health Organization (WHO) criteria for diabetes (5), but LADA is still considered a subdivision of T1D based on the rate of disease progression. Despite the recognition of this specific phenotype, there is still little agreement on the diagnostic criteria for LADA, including what is considered the "adult" age of onset, which has varied from 25 to 40 yr (6,7). It is estimated that approximately 20% of all persons diagnosed with type 2 diabetes might actually have LADA. This number accounts for an estimated 5%-10% of the total diabetes population in the U.S. or, as many as 3.5 million persons with LADA (8,9). Due to recent advances in SNP genotyping arrays there have been GWAS studies on T1D and T2D loci. Combined with the well-established genes known for many years, at least 20 loci each have now been uncovered to date for T1D and T2D.Hypothesis as well as non hypothesis-driven genetic studies (GWAS) of LADA are sorely lacking, with no novel loci described to date. Despite there being a large body of data supporting the role of genetic factors in T1D and T2D, there is still relatively little known about the genetics of LADA, which has been considered to be at the intersection of these two disorders.
The key issues that still need to be fully resolved in the genetics of LADA are: Does LADA represent
1) the genetic intersection of T1D and T2D?
2) a unique disease entity?
I would like to carry out a population based case control study. The cases would be recently diagnosed patients with Latent Autoimmune Diabetes and controls would be patients with Type1 Diabetes and Type 2 Diabetes. The patients would be screened for the eligibility using a self reported questionnaire and would require to have it confirmed with a onetime blood draw to check for the presence or absence of depending on which they would be categorized as either case or control. 100 subjects with LADA and 200 subjects with each T1D and T2D will be recruited into the study.
To assess exposure the cheek DNA of the cases as well as the controls would be sampled and checked for the presence of or absence of the genes of interest in the cases as well as the controls using the genotyping array technologies. Also I would like to have them self-report their race and sex to see if there is potential confounding or effect-modification which would be reported as categorical variables in the study.
Criteria for selection of LADA patients -
1) Age at onset >35 years
2) Presence of antibodies against islet cells
3) Insulin independence at time of diagnosis
Criteria for selection of Type 1 Diabetes patients -
Age at onset <=35 years
Presence of antibodies against islet cells
Insulin dependence at time of diagnosis
Criteria for selection of Type 2 Diabetes patients -
Age at onset >35 years
Absence of antibodies against islet cells
Insulin independence at time of diagnosis
The outcome variable would be reported as a categorical variable as yes or no.
To estimate the association of the genes with LADA I would calculate the Odds Ratio and the corresponding 95% CI using logistic regression. Both outcome and exposure variables are categorized as binary. As there was no matching of cases and controls at baseline I would like to control for sex and race in all logistic regression models. To assess the presence or absence of confounding a change of 10% in the point estimate would be used.
Strengths and Limitations
The study I propose is a very initial study regarding LADA. So it does have some limitations. The study focuses only on one gene each associated with T1D and T2D to check its genetic overlap with LADA. There could be potential for more genes confounding the association. Also the information on the genetic loci associated with T1D and T2D is not complete; a lot more is still unknown about their genetics, the knowledge of which in future may change the associations found between them and LADA. But my study being hypothesis driven is cost effective as it has little genotyping requirements and has low false positive rates which help to negate some of the limitations of the study. Also the evidence of genetic overlap if found would encourage more people to take up genome wide association studies and thereby help in establishing more firmly the identity of LADA as either an admixture of T1D and T2D or as a unique disease identity.
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