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 /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 / Garagnani, P; Giuliani, C; Pirazzini, C; Olivieri, Fabiola; Bacalini, Mg; Ostan, R; Mari, D; Passarino, G; Monti, D; Bonfigli, Ar; Boemi, M; Ceriello, A; Genovese, S; Sevini, F; Luiselli, D; Tieri, P; Capri, M; Salvioli, S; Vijg, J; Suh, Y; Delledonne, M; Testa, R; Franceschi, C.. - In: AGING. - ISSN 1945-4589. - ELETTRONICO. - (2013), pp. 373-385. [10.18632/aging.100562]

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.

OLIVIERI, Fabiola;
2013-01-01

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 /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.
2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/107882
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