Fig. 6. A functional SNP in the human SIRT3 gene is associated with human metabolic syndrome and encodes a point-mutation.

(A) Heat map detailing the pairwise LD among the 7 SNPs spanning the SIRT3 coding region; the pairwise correlations (D’) are rendered within each diamond with greater LD reflected by darker shades of gray; SIRT3 gene structure is depicted above the LD heat map: exons are depicted in gray boxes, introns as connecting black lines, and untranslated regions as smaller boxes shades in pink; approximately 10 kbp of flanking DNA sequence was included in the tagSNP selection procedure; tagSNPs the promoter region is included in the diagram to the right of the transcription start site indicated by the arrow found directly above the SIRT3 gene structure diagram; SNPs rendered in bold are included in the haploblock outlined in the black triangle; the two SNPs that encode for nonsynonymous polymorphisms (rs11246020 and rs28365927; green). (B) Association of SIRT3 rs11246020 with the metabolic syndrome in the NASH-CRN cohort. Abbreviations: P, p-value for the test statistic; OR (95% CI), the odds ratio and 95% confidence interval for the test statistic; VNTR, variable number tandem repeat; UNADJ, unadjusted; ADJ, adjusted for age, sex, and BMI unless otherwise indicated. (C) Association of SIRT3 rs11246020 with the metabolic syndrome in the METSIM cohort, adjusted for age and BMI. ^†Metabolic syndrome criteria based on the IDF guidelines, excluding the presence of type 2 diabetes. *p-value for the overall model. (D) Schematic of SIRT3 protein; mitochondrial targeting sequence (MTS), mitochondrial processing peptidase (MPP) site. (E, F) Steady-state kinetic analyses of SIRT3 activity; rates of activity were measured as a function of [NAD⁺] (E) or [³H-histone H4 peptide] (F), as measured by organic-soluble radioactive signal, n=3 independent measurements/sample, ±SEM.