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Genome-Wide Association Study of Biochemical Traits in Korčula Island

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Genome-Wide Association Study of Biochemical Traits in Korčula Island GENOMICS 23 doi: 10.3325/cmj.2009.50.23 Genome-wide Association Tatijana Zemunik1, Mladen Boban1, Gordan Lauc2,3, Stipan Janković1, Study of Biochemical Traits in Krešimir Rotim4, Zoran Vatavuk4, Goran Benčić4, Zoran Đogaš1, Korčula Island, Croatia Vesna Boraska1, Vesela Torlak5, Jelena Sušac6, Ivana Zobić7, Diana Aim To identify genetic variants underlying biochemical Rudan8, Dražen Pulanić9, Darko traits – total cholesterol, low-density lipoprotein (LDL) cho- 1 1 lesterol, high-density lipoprotein (HDL) cholesterol, triglyc- Modun , Ivana Mudnić , Grgo 1 1 erides, uric acid, albumin, and fibrinogen, in a genome- Gunjača , Danijela Budimir , 10 wide association study in an isolated population where Caroline Hayward , Veronique rare variants of larger effect may be more easily identified. Vitart10, Alan F. Wright10, Harry Campbell11, Igor Rudan1,4,11 Methods The study included 944 adult inhabitants of the 1School of Medicine, University of Split, Split, island of Korčula, as a part of larger DNA-based genetic ep- Croatia idemiological study in 2007. Biochemical measurements 2 were performed in a single laboratory with stringent in- School of Pharmacy and Biochemistry, ternal and external quality control procedures. Examinees University of Zagreb, Zagreb, Croatia were genotyped using Human Hap370CNV chip by Illu- 3Genos Ltd., Osijek, Croatia mina, with a genome-wide scan containing 346 027 single 4Sisters of Mercy University Hospital, Zagreb, nucleotide polymorphisms (SNP). Croatia 5University Hospital Split, Split, Croatia Results A total of 31 SNPs were associated with 7 inves- tigated traits at the level of P < 1.00 × 10−5. Nine of SNPs 6Vrapče Psychiatric Hospital, Zagreb, Croatia implicated the role of SLC2A9 in uric acid regulation 7Merkur University Hospital, Zagreb, Croatia −6 −12 (P = 4.10 × 10 -2.58 × 10 ), as previously found in oth- 8Dubrava University Hospital, Zagreb, Croatia er populations. All 22 remaining associations fell into the 9Rebro University Hospital, Zagreb, Croatia P = 1.00 × 10−5-1.00 × 10−6 significance range.. One of them replicated the association between cholesteryl ester trans- 10Human Genetics Unit, Medical Research fer protein (CETP) and HDL, and 7 associations were more Council, Edinburgh, United Kingdom than 100 kilobases away from the closest known gene. 11The University of Edinburgh Medical Nearby SNPs, rs4767631 and rs10444502, in gene kinase School, Edinburgh, United Kingdom suppressor of ras 2 (KSR2) on chromosome 12 were asso- ciated with LDL cholesterol levels, and rs10444502 in the same gene with total cholesterol levels. Similarly, rs2839619 in gene PBX/knotted 1 homeobox 1 (PKNOX1) on chromo- some 21 was associated with total and LDL cholesterol levels. The remaining 9 findings implied possible associa- tions between phosphatidylethanolamine N-methyltrans- ferase (PEMT) gene and total cholesterol; USP46, RAP1GDS1, and ZCCHC16 genes and triglycerides; BCAT1 and SLC14A2 genes and albumin; and NR3C2, GRIK2, and PCSK2 genes and fibrinogen. Conclusion Although this study was underpowered for Received: January 2, 2009 most of the reported associations to reach formal thresh- Accepted: January 27, 2009 old of genome-wide significance under the assumption Correspondence to: of independent multiple testing, replications of previous Igor Rudan findings and consistency of association between the iden- Croatian Centre for Global Health tified variants and more than one studied trait make such University of Split School of Medicine findings interesting for further functional follow-up stud- Šoltanska 2 ies. Changed allele frequencies in isolate population may 21000 Split, Croatia contribute to identifying variants that would not be easily [email protected] identified in much larger samples in outbred populations. www.cmj.hr 24 GENOMICS Croat Med J. 2009; 50: 23-33 It is known that human lipid levels in circulation show functionally significant than urate transporter 1 – URAT1, considerable heritability (1-3). Recently, genome-wide as- a gene previously thought to play a major role in the reg- sociation studies proved their value as a reliable tool for ulation of uric acid levels (15-18). A recent study with in- identifying genetic variants underlying complex human creased power has identified further 2 genes that also diseases and traits (4,5). The first applications of genome- contribute to uric acid regulation: ATP-binding cassette, wide association studies to identify genetic variants un- sub-family G (WHITE) member 2 – ABCG2 and solute car- derlying human lipid levels yielded a total of 19 loci con- rier family 17 member 3 – SLC17A3 (19). Unlike for uric acid, trolling serum high-density lipoprotein cholesterol (HDL), we could not find any genome-wide association studies low-density lipoprotein cholesterol (LDL), and triglycerides that searched specifically for loci influencing the levels of (6-10) and implicated a number of potential genes and 3 human albumin in plasma. Some genome-wide associa- genetic regions with multiple associated genes. Many of tion studies investigating biochemical traits also included these genes have already been known as very likely can- searching for fibrinogen loci, but none of them reached didates for lipid level regulation (11,12). The most recent the required threshold for genome-wide significance (20). study also found that ATP-binding cassette gene (ABCG5) predicted triglycerides and LDL; transmembrane protein We performed a comprehensive genome-wide associa- 57 gene (TMEM57) predicted triglycerides; regulator pro- tion studies of total cholesterol, LDL and HDL cholester- tein with 11 highly conserved zinc finger-protein arginine ol, triglycerides, uric acid, albumin, and fibrinogen in the methyltransferase 8 regions (CTCF-PRMT8 region) predict- isolated population of the island of Korčula in Croatia. The ed HDL; dynein, axonemal, heavy chain 11 (DNAH11) pre- study is a part of genetic epidemiology research program dicted LDL; fatty acid desaturase 3 – fatty acid desaturase 2 in Croatian island isolates, “10,001 Dalmatians.” The genet- gene (FADS3-FADS2) predicted triglycerides and LDL; and ic epidemiology research program in Croatian island iso- MAP-kinase activating death domain-folate hydrolase 1 lates began in 1999 (21), expanded to study human ge- gene (MADD-FOLH1 region) predicted HDL (13). However, netic variation and effects of isolation and inbreeding all these loci combined can still not explain a substantial (22-34), and then broadened its focus to include diseases share of noted heritabilities, leaving room for further find- and gene mapping studies (18,35-41). By now, the research ings of genetic and epigenetic factors that control serum project has included more than 3000 examinees from iso- lipid levels in humans (14). Those are likely to include struc- lated populations, while it aims to eventually reach 10 001 tural variants, such as copy number variants, and also very examinees. rare genetic variants that may only be identified in special populations (4,5). MatErials AND MEthOds Apart from the lipid levels, other clinically relevant bio- This study was performed in the eastern part of the island chemical measurements in human serum and/or plasma of Korčula, Croatia between March and December 2007. that are usually studied include uric acid, albumin, and fi- Healthy volunteers aged 18 and over from the town of brinogen. Recently, several studies have identified and rep- Korčula and villages Lumbarda, Žrnovo, and Račišće (Fig- licated the finding of a novel major uric acid transporter ure 1) were invited to the study through mail, posters, ra- – solute carrier family 2 (facilitated glucose transporter) dio, and personal contacts. member 9 – SLC2A9 (GLUT9), which is several times more The study was approved by the Ethical Committee of the Figure 1. Medical School, University of Zagreb, and all examinees had signed an informed consent. There was a total of 969 examinees included who had a number of quantitative phenotypic traits measured. Biochemical analyses of 7 traits were performed on blood samples taken from the examinees after overnight fast- ing (collected between 8:30 and 9:30 am). We collected 9 mL clotted serum-gel sample for serum biochemis- try, 2 × 10mL EDTA samples for DNA extraction or liquid Settlements on the island of Korčula, Croatia, included in the study. nitrogen storage of aliquots for future transformation, www.cmj.hr Zemunik et al: Genome-wide Association Study of Biochemical Traits 25 TablE 1. A summary of single-nucleotide polymorphisms (SNP) that showed association with biochemical traits that reached levels of genome-wide significance ofP < 10−5*† Effect allele Effect allele Effect frequency frequency Standard SNP for trait Chromosome Position allele Korčula HapMap P value β error (β) Gene Total cholesterol rs7678182 4 32117038 A 0.428 0.367 9.9 × 10−06 0.119 0.027 no genes +/− 200kb rs1493762 12 90604046 C 0.158 0,180 7.6 × 10−06 -0.224 0.050 no genes +/− 200kb rs10777332 12 90688433 A 0,113 0.161 5.1 × 10−06 -0.235 0.051 no genes +/− 200kb rs10444502 12 116838254 C 0.279 0,267 6.1 × 10−06 -0.165 0.036 kinase supressor of ras 2 (KSR2) phosphatidylethanolamine N-methyl- rs8081810 17 17463669 G 0.1692 0.083 9.8 × 10−06 0.222 0.050 transferase (PEMT) rs2839619 21 43309246 G 0.396 0.525 7.6 × 10−06 0.127 0.028 PBX/knotted 1 homeobox 1 (PKNOX1) LDL cholesterol rs4767631 12 116796126 A 0.313 0.333 5.5 × 10−07 -0.167 0.033 kinase supressor of ras 2 (KSR2) rs10444502 12 116838254 C 0.280 0.267 6.4 × 10−07 -0.182
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