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.
Garagnani P, Giuliani C, Pirazzini C, Olivieri F, Bacalini MG, Ostan R, et al. (2013). 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. AGING, 5(5), 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
GARAGNANI, PAOLO;GIULIANI, CRISTINA;PIRAZZINI, CHIARA;BACALINI, MARIA GIULIA;OSTAN, RITA;SEVINI, FEDERICA;LUISELLI, DONATA;CAPRI, MIRIAM;SALVIOLI, STEFANO;FRANCESCHI, CLAUDIO
2013
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.