Table 2. Evaluation of Variants in FOXO3 From the dbSNP Public Database

Chromosome mRNA dbSNP rs# dbSNP Protein Codon Amino Acid Position Position Cluster ID MAF Function Allele Residue Position Position Present Results 108882570 502 rs11757217 0.1283 Synonymous T Ala [A] 3 53 ZNF286B Contig reference C Ala [A] 3 53 108882706 638 rs79884776 Missense T Trp [W] 1 99 Not conf. Contig reference C Arg [R] 1 99 108882830 762 rs111556510 0.0345 Missense T Val [V] 2 140 Not conf. Contig reference C Ala [A] 2 140 108882855 787 rs13204476 Missense T Ser [S] 3 148 Not conf. Contig reference G Arg [R] 3 148 108882873 805 rs146186567 Synonymous A Arg [R] 3 154 Not conf. Contig reference G Arg [R] 3 154 108882888 820 rs61758963 Synonymous T Asn [N] 3 159 Not conf. Contig reference C Asn [N] 3 159 108882891 823 rs139172563 Synonymous A Leu [L] 3 160 Not conf. Contig reference G Leu [L] 3 160 108882906 838 rs149906214 Synonymous A Leu [L] 3 165 Not conf. Contig reference G Leu [L] 3 165 108882915 847 rs150320900 Synonymous T Arg [R] 3 168 Not conf. Contig reference C Arg [R] 3 168 108882933 865 rs149189425 Synonymous A Pro [P] 3 174 Not conf. Contig reference G Pro [P] 3 174 108882987 919 rs142429317 Synonymous G Pro [P] 3 192 Not conf. Contig reference C Pro [P] 3 192 108984783 1090 rs61756661 Synonymous A Arg [R] 3 249 Not conf. Contig reference G Arg [R] 3 249 108984823 1130 rs141893794 Missense G Gly [G] 1 263 Not conf. Contig reference A Ser [S] 1 263 108984834 1141 rs147028825 Synonymous T Arg [R] 3 266 Not conf. Contig reference C Arg [R] 3 266 108984867 1174 rs112124249 Synonymous T Ala [A] 3 277 Not conf. Contig reference C Ala [A] 3 277 108984882 1189 rs138297794 Synonymous T Asp [D] 3 282 Not conf. Contig reference C Asp [D] 3 282 108984883 1190 rs140968061 Missense A Asn [N] 1 283 Not conf. Contig reference G Asp [D] 1 283 108984951 1258 rs150216371 Synonymous T Ala [A] 3 305 Not conf. Contig reference G Ala [A] 3 305 108985003 1310 rs145756480 Missense T Cys [C] 1 323 Not conf. Contig reference C Arg [R] 1 323 108985057 1364 rs145259784 Missense A Thr [T] 1 341 Not conf. Contig reference G Ala [A] 1 341 108985080 1387 rs149503832 Synonymous T Tyr [Y] 3 348 Not conf. Contig reference C Tyr [Y] 3 348 108985092 1399 rs149158541 Synonymous G Ala [A] 3 352 Misalign Contig reference C Ala [A] 3 352 108985094 1401 rs11551770 Missense T Ile [I] 2 353 Not conf. Contig reference G Ser [S] 2 353 108985119 1426 rs146009555 Synonymous C Pro [P] 3 361 Not conf. Contig reference G Pro [P] 3 361 108985136 1443 rs34223850 Missense T Leu [L] 2 367 Misalign Contig reference C Pro [P] 2 367 108985149 1456 rs34754045 Synonymous C Asp [D] 3 371 Misalign Contig reference T Asp [D] 3 371 108985176 1483 rs34133353 Frameshift G Glu [E] 3 380 Misalign Contig reference Asp [D] 3 380 108985269 1576 rs34079373 0.0147 Synonymous T Ser [S] 3 411 Misalign Contig reference C Ser [S] 3 411 108985274 1581 rs138742093 Missense C Thr [T] 2 413 Not conf. Contig reference G Ser [S] 2 413 108985277 1584 rs148296241 Missense A Tyr [Y] 2 414 Not conf. Contig reference T Phe [F] 2 414 108985280 1587 rs141876866 Missense T Leu [L] 2 415 Not conf. Contig reference C Pro [P] 2 415 108985306 1613 rs34488332 0.0090 Missense A Ser [S] 1 424 Misalign

Table 2. (Continued)

Table 2. (Continued)

mRNA dbSNP rs# dbSNP Protein Codon Amino Acid Position Cluster ID MAF Function Allele Residue Position Position Present Results Contig reference G Gly [G] 1 424 1633 rs146169955 Synonymous C Phe [F] 3 430 Not conf. Contig reference T Phe [F] 3 430 1859 rs148405845 Missense T Cys [C] 1 506 Not conf. Contig reference C Arg [R] 1 506 1864 rs142533192 Synonymous C Arg [R] 3 507 Not conf. Contig reference G Arg [R] 3 507 1888 rs150535671 Synonymous A Pro [P] 3 515 Not conf. Contig reference G Pro [P] 3 515 1925 rs147010831 Missense G Val [V] 1 528 ZNF286B Contig reference T Leu [L] 1 528 2040 rs138174682 Missense C Ala [A] 2 566 This study Contig reference G Gly [G] 2 566 2163 rs34600091 Frameshift C Ser [S] 2 607 Not conf. Contig reference Phe [F] 2 607

Note: Chromosome position is in reference to the Genome Reference Consortium (GRCh37.2, NCBI dbSNP Build 132 [NT_025741]) released November 2010. The mRNA position is in reference to the “A” in the AUG start codon, and codon refers to the position in the amino acid codon at which the variant occurs. “ZNF286B” indicates that the SNP has been assigned to the ZNF286B gene on chromosome 17; “not conf.” indicates that there is no evidence for this SNP in the present study; “misalign” indicates that the SNP appears to result from misalignment of FOXO3 and FOXO3B sequences. Variant “rs138174682” was identified in the present study and is now listed in dbSNP. MAF = minor allele frequency, mRNA = messenger RNA, and SNP = single nucleotide polymorphism.

the functional SNP in FOXO3 is not known—nor is the mechanism(s) of influence over human aging.

(mean attained age 97.9 years), and the controls had an “aver- age-lived phenotype” defined as death by age 81 years (mean attained age 78.5 years). There were 675 study participants. For these men, the allele frequency was 0.01, with only 14 heterozygotes. The small number of carriers precluded any meaningful statistical power for association studies.

The functions of FOXO3 are highly pleiotropic, ranging from tumor suppression to energy metabolism and thus could affect specific age-related diseases, such as cancer and cardiovascular diseases and/or influence organismal processes, such as oxidative stress, that have wider implications for aging and its related phenotypes (6,21). Important down- stream targets of FOXO3 include autophagy, apoptosis, glycolysis and gluconeogenesis, cell proliferation/differentia- tion, and stress resistance. Therefore, finding the functional variant and its mechanism would be an important step in understanding human aging.