Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed allelic/genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians (p_value = 9.066*10-7). We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared.

Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases : a proof of principle on type 2 diabetes / P. Garagnani, C. Giuliani, C. Pirazzini, F. Olivieri, M. Bacalini, R. Ostan, D. Mari, G. Passarino, D. Monti, A. Bonfigli, M. Boemi, A. Ceriello, S. Genovese, F. Sevini, D. Luiselli, P. Tieri, M. Capri, S. Salvioli, J. Vijg, Y. Suh, M. Delledonne, R. Testa, C. Franceschi. - In: AGING. - ISSN 1945-4589. - 5:5(2013 May), pp. 373-385.

Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases : a proof of principle on type 2 diabetes

D. Mari;
2013-05

Abstract

Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed allelic/genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians (p_value = 9.066*10-7). We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared.
Type 2 diabetes; TCF7L2; centenarians; extreme phenotypes; age-related diseases
Settore MED/09 - Medicina Interna
Ruolo dell'epigenetica nella longevità
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/296778
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