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 F; 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. - STAMPA. - 5:5(2013), 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

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.
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 / Garagnani P; Giuliani C; Pirazzini C; Olivieri F; 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. - STAMPA. - 5:5(2013), pp. 373-385.
Garagnani P; Giuliani C; Pirazzini C; Olivieri F; 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.
File in questo prodotto:
Eventuali allegati, non sono esposti

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/173875
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 28
  • Scopus 49
  • ???jsp.display-item.citation.isi??? 44
social impact