**3. Phenotyping type 1 diabetes families**

Translational research aims to integrate basic life science (genomics, transcriptomics, proteomics, and metabolomics) with insights gained from clinical experience to comprehensively study complex biological system and complex human diseases. Translation requires, among others, methods that relate molecular and cellular phenotypes

Therefore, standardised autoantibody screenings should be combined with the detection of autoreactive T cells. Unfortunately, none of the currently available T cell assays satisfies all the features of a good assay: small blood sample required, simplicity, specificity, low intraand inter-assay variability (Fierabracci, 2011). Notwithstanding recent developments based on immunosorbent spot and immunoblotting techniques, the International Workshops of the Immunology Diabetes Society concluded that T cell results are still inconclusive and

In conclusion, it may be that in the future combination screening predicts type 1 diabetes clinical onset, but actually genetic risk, serum autoantibody profiling and T cell assays are

**Autoantibodies against Abbreviation Method** 

associated protein GLIMA Immunoprecipitation

decarboxylase AADC Immunoprecipitation 52-kDa rat insulinoma 52-kDa RIN Immunoblot Aminoacyl-tRNA synthetase ARS ELISA\* Carbonic anydrase II CA II ELISA\* Carboxypeptidase H CPHA Radiobinding assay

pancreatic Immunoblot analysis DNA topoisomerase II TopIIA ELISA\* and Western blot Ganglioside GM2-1 GM2-1 Indirect immunoperoxidase

Glutamic acid decarboxylase GADA Radiobinding assay, ELISA\*

Table 2. List of islet autoantibodies detected in type 1 diabetes (modified from Winter &

Translational research aims to integrate basic life science (genomics, transcriptomics, proteomics, and metabolomics) with insights gained from clinical experience to comprehensively study complex biological system and complex human diseases. Translation requires, among others, methods that relate molecular and cellular phenotypes

Gangliosides GM1, 2, 3, etc. \*ELISA Glucose type-2 transporter GLUT2 Western blot

Heat shock proteins HSP \*ELISA Insulin IAA Radiobinding assay Insulinoma-associated antigen-2 IA-2A Radiobinding assay, ELISA\* Insulinoma-associated antigen 2 IA-2 Radiobinding assay Islet cell ICA Indirect immunofluorescence Islet cell surface ICSA Radiobinding assay Proinsulin PIAA Radiobinding assay Zinc transporter 8 ZnT8 Radiobinding assay

technique

novel approaches are currently being investigated.

38-kDa glycated islet cell membrane-

51-kDa aromatic-L-amino-acid

Chymotrypsinogen-related 30-kDa

\* Enzyme linked immunosorbent assay

**3. Phenotyping type 1 diabetes families** 

Schatz, 2011).

uneconomical when applied in the general population.

to clinical characteristics (Bebek et al., 2011). Indeed, the correlation between quantitative phenotypes and traits allows for a more efficient use of the genetic information; hence the importance of accurate family phenotyping studies. Unaffected family members can contribute as much to the analysis as individuals with the disease diagnosis. For example, the finding of cognitive deficits in individuals with schizophrenia and in the clinically unaffected relatives of these individuals suggested that these deficits are part of the innate underlying distinct differences that make some individuals vulnerable to schizophrenia. Examining these complementary biological phenotypes in genetic studies has been found to provide valuable information about the pathway that connects genotype to clinical disease (Almasy et al., 2008). Similarly, large-scale genetic fine mapping and genotype-phenotype associations implicated polymorphisms in the IL2RA region in type 1 diabetes: IL2RA type 1 diabetes susceptibility genotypes were associated with lower circulating levels of the biomarker, soluble IL-2RA (Lowe et al., 2007). However, despite the theoretical advantages of quantitative trait analysis and testing of multiple plausible domains, some matters have emerged since quantitative traits may not be the most relevant phenotypes to investigate in search for the genetic etiology of disease. Identifying the "best" phenotype for genetic studies needs to survey family members and examine coexisting features and familial segregation patterns. A focus on careful assessment of the most genetically relevant phenotypes has been recommended (Brzustowicz & Bassett, 2008).

Over the years, our research efforts have sought primarily to gain a comprehensive understanding of the common phenotypic elements that characterise families with a sporadic case of type 1 diabetes. Here we provide a research-based overview of these familial peculiarities that include multifaceted, easily detectable, clinical perturbations: physical (BMI), cardiovascular (blood pressure response to exercise and circadian blood pressure pattern), biochemical (fasting plasma glucose, HbA1c, lipids, homeostasis model assessment of insulin sensitivity, plasma markers of oxidative damage), cellular (cellular markers of oxidative damage, transplasma membrane electron transport systems, mitochondrial membrane potential), and immunological (lymphocyte subsets).
