(SIRT1) Genetic variation in Sirtuin 1 is associated with lipid profiles but not with longevity in Ashkenazi

JEEHAE HAN, GIL ATZMON, NIR BARZILAI, and YOUSIN SUH BRONX, NY; AND DONGGUAN, CHINA

overexpression of which has been shown to extend lifespan and delay age-related phenotypes in model organisms. To investigate the role of SIRT1 in healthy aging in SIRT1 humans, we performed comprehensive resequencing analysis of to identify all possible variants in the exons, exon-intron junctions, and 3.1kb proximal promoter region in 16 centenarians and 16 controls of Ashkenazi Jewish (AJ) population. Gen- SIRT1 otyping analysis of 19 common SNPs discovered to have minor allele frequency greater than 5% was performed in 213 AJ centenarians and 169 AJ controls and showed that their allele and genotype frequencies were not significantly different be- tween centenarians and controls. Further association analysis of 5 tagSNPs (rs10997854, rs142194353, rs12778366, rs35706870, and rs932658) that capture all SIRT1 $ common SNP information across the gene region (r2 0.9) with lipid profile showed that 2 tagSNPs were significantly associated after multiple testing correc- P 5 P 5 tions; rs3758391 with large LDL ( 0.0365) and large HDL ( 0.0412) and P 5 P 5 rs142194353 with large HDL ( 0.0035) and HDL size ( 0.0033). Taken together, these results suggest that genetic variation in SIRT1 may contribute to healthy aging by affecting lipid profiles in humans but not to longevity. (Translational Research -

Abbreviations: AJ ¼ Ashkenazi Jewish; AMPK ¼ AMP-activated protein kinase; BMI ¼ body mass index; FDR ¼ False Discovery Rate; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; NAD ¼ nicotinamide adenine dinucleotide; NMR ¼ nuclear magnetic resonance; PGC-1a ¼ PPARgcoactivator1a; PPARg¼peroxisomeproliferator-activatedreceptorgamma;SD¼ stan- dard deviation; SIRT1 ¼ Sirtuin 1; SNP ¼ single-nucleotide polymorphism; VLDL ¼ very low-density lipoprotein

uman Sirtuin

(SIRT

) is a nicotinamide adenine dinucleotide dependent protein deace- tylase with homologs reported to extend lifespan in yeast, worms, fruit flies, and mice.

In partic-

ular, studies in mice have indicated that SIRT1 plays a key role in regulating metabolism and mitochondrial function in different tissues through targets that include peroxisome proliferator-activated receptor g, PPARg

From the Department of Genetics, Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; Institute of Aging Research, Guangdong Medical College, Dongguan, China. Submitted for publication July 21, 2014; revision submitted

Reprint requests: Yousin Suh, Departments of Genetics and Medicine, Albert Einstein College of Medicine,

Morris Park Avenue, Bronx, NY

; e-mail: yousin.suh@einstein.yu.edu.

-

/$ - see front matter

Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.trsl.2014.09.008

Table I. Discovery, genotyping, and association analysis of SIRT1 gene region with longevity

Control Centenarian Control Centenarian SNP ID Position* Region Maj.min MAF† MAF† MAF‡ MAF‡ P value‡ rs10997854 Chr10: 69641369 Upstream C.A 0.34 0.25 0.39 0.40 0.865 rs10997855 Chr10: 69641401 Upstream G.A 0.34 0.25 0.39 0.40 0.865 rs142194353 Chr10: 69641539 Upstream C.T 0.06 0.06 0.06 0.06 0.967 rs10823100 Chr10: 69641693 Upstream G.C 0.09 0.03 0.05 0.04 0.501 rs10997856 Chr10: 69641706 Upstream C.T 0.34 0.25 0.39 0.40 0.865 rs10823101 Chr10: 69641711 Upstream T.A 0.09 0.03 0.05 0.04 0.501 rs10997857 Chr10: 69641715 Upstream T.A 0.09 0.03 0.05 0.04 0.501 rs10823102 Chr10: 69641833 Upstream T.A 0.34 0.25 0.39 0.40 0.833 rs12250285 Chr10: 69641954 Upstream C.T 0.37 0.25 0.43 0.42 0.840 rs148743102 Chr10: 69642058 Upstream Ins T 0.09 0.09 0.10 0.12 0.527 Novel Chr10: 69642546 Upstream Ins T 0 0.03 n.a. n.a. n.a. rs10740280 Chr10: 69642668 Upstream T.A 0 0 n.a. n.a. n.a. Novel Chr10: 69642675 Upstream Del T 0.06 0 n.a. n.a. n.a. Novel Chr10: 69642766 Upstream C.T 0 0.06 n.a. n.a. n.a. rs12778366 Chr10: 69643079 Upstream T.C 0.16 0.13 0.15 0.15 0.960 rs3758391 Chr10: 69643342 Upstream T.C 0.34 0.25 0.39 0.40 0.905 Novel Chr10: 69643586 Upstream T.A 0 0.03 n.a. n.a. n.a. rs35706870 Chr10: 69643617 Upstream A.C 0.09 0.09 0.10 0.13 0.362 rs3740051 Chr10: 69643959 Upstream A.G 0.09 0.03 0.05 0.03 0.227 rs932658 Chr10: 69644217 Upstream A.C 0.34 0.25 0.42 0.46 0.561 rs3740053 Chr10: 69644335 Upstream A.G 0.09 0.03 0.05 0.03 0.406 rs2394443 Chr10: 69644341 Upstream G.C 0.41 0.25 0.45 0.42 0.739 Novel Chr10: 69647182 Exon 2 Del TCT 0 0.03 n.a. n.a. n.a. rs932657 Chr10: 69647332 Intron G.T 0.06 0 n.a. n.a. n.a. rs7896005 Chr10: 69651125 Intron A.G 0.37 0.25 0.38 0.39 0.909 rs36107781 Chr10: 69651319 Intron T.C 0.03 0 n.a. n.a. n.a. rs2273773 Chr10: 69666598 Exon 5 T.C 0.09 0.03 0.05 0.04 0.613 rs149313098 Chr10: 69672556 Exon 8 G.A 0.03 0 n.a. n.a. n.a. rs61666042§ Chr10: 69676547 3UTR Ins T 0.5 0.47 n.a. n.a. n.a. rs2394445§ Chr10: 69676560 3UTR T.A 0.13 0.13 n.a. n.a. n.a. rs35461348§ Chr10: 69676610 3UTR Del CTTT 0.37 0.28 n.a. n.a. n.a. rs752578 Chr10: 69677060 3UTR C.T 0 0 n.a. n.a. n.a. rs34934649 Chr10: 69677458 3UTR Del C 0.03 0 n.a. n.a. n.a. rs200236450 Chr10: 69677699 3UTR C.T 0.03 0 n.a. n.a. n.a. rs199731267 Chr10: 69677758 3UTR G.A 0.03 0 n.a. n.a. n.a. rs2234975 Chr10: 69678078 3UTR C.T 0.06 0.03 n.a. n.a. n.a.

Abbreviations: AJ, Ashkenazi Jewish; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; UTR, untranslated region. Bold underlined SNPs indicate common SNPs that have total MAF . 0.05 that were chosen for genotyping. n.a. indicates SNPs that were not