Modeling of Environmental Effects in Genome-Wide Association Studies Identifies and as Novel Loci Influencing Serum Cholesterol Levels

English version České info

Genome-wide association studies (GWAS) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. We modeled diet and physical activity in a GWAS in order to identify novel loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. The Swedish (SE) EUROSPAN cohort (N_SE = 656) was screened for candidate genes and the non-Swedish (NS) EUROSPAN cohorts (N_NS = 3,282) were used for replication. In total, 3 SNPs were associated in the Swedish sample and were replicated in the non-Swedish cohorts. While SNP rs1532624 was a replication of the previously published association between CETP and HDL cholesterol, the other two were novel findings. For the latter SNPs, the p-value for association was substantially improved by inclusion of environmental covariates: SNP rs5400 (p_{SE,unadjusted} = 3.6×10⁻⁵, p_SE,adjusted = 2.2×10⁻⁶, p_{NS,unadjusted} = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (p_{SE,unadjusted} = 1.1×10⁻³, p_SE,adjusted = 3.8×10⁻⁴, p_{NS,unadjusted} = 0.035) in the HP gene (Haptoglobin-related protein precursor). Both showed evidence of association with total cholesterol. These results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci.

Vyšlo v časopise: Modeling of Environmental Effects in Genome-Wide Association Studies Identifies and as Novel Loci Influencing Serum Cholesterol Levels. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000798
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000798

Souhrn

Zdroje

1. AulchenkoYS

RipattiS

LindqvistI

BoomsmaD

HeidIM

2009 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41 47 55 doi:10.1038/ng.269

2. SabattiC

ServiceSK

HartikainenA

PoutaA

RipattiS

2009 Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 41 35 46 doi:10.1038/ng.271

3. KathiresanS

WillerCJ

PelosoGM

DemissieS

MusunuruK

2009 Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41 56 65 doi:10.1038/ng.291

4. ManolioTA

2009 Cohort studies and the genetics of complex disease. Nat Genet 41 5 6 doi:10.1038/ng0109-5

5. JohanssonA

MarroniF

HaywardC

FranklinCS

KirichenkoAV

2009 Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum Mol Genet 18 373 380 doi:10.1093/hmg/ddn350

6. RossAB

JohanssonA

IngmanM

GyllenstenU

2006 Lifestyle, genetics, and disease in Sami. Croat Med J 47 553 65 doi:16909452

7. RossA

JohanssonÅ

Vavruch-NilssonV

HasslerS

SjölanderP

2009 Adherence to a traditional lifestyle affects food and nutrient intake among modern Swedish Sami. International Journal of Circumpolar Health 68 313 416

8. PearlJ

2003 Statistics and causal inference: A review. TEST 12 281 345 doi:10.1007/BF02595718

9. BaronRM

KennyDA

1986 The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51 1173 82

10. GuillamMT

HümmlerE

SchaererE

YehJI

BirnbaumMJ

1997 Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17 327 330 doi:10.1038/ng1197-327

11. SanterR

SchneppenheimR

DombrowskiA

GötzeH

SteinmannB

1997 Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 17 324 326 doi:10.1038/ng1197-324

12. ManzF

BickelH

BrodehlJ

FeistD

GellissenK

1987 Fanconi-Bickel syndrome. Pediatr Nephrol 1 509 518

13. CerfME

2007 High fat diet modulation of glucose sensing in the beta-cell. Med Sci Monit 13 RA12 17

14. KilpelainenTO

LakkaTA

LaaksonenDE

LaukkanenO

LindstromJ

2007 Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes. Physiol Genomics 31 264 272 doi:10.1152/physiolgenomics.00036.2007

15. AslehR

MarshS

ShilkrutM

BinahO

GuettaJ

2003 Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ Res 92 1193 1200 doi:10.1161/01.RES.0000076889.23082.F1

16. DullaartRPF

SluiterWJ

2008 Common variation in the CETP gene and the implications for cardiovascular disease and its treatment: an updated analysis. Pharmacogenomics 9 747 763 doi:10.2217/14622416.9.6.747

17. World Medical Association (WMA) 2000 World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects [Internet]. Available: http://www.wma.net/e/policy/pdf/17c.pdf. Accessed 30 Sep 2009

18. MascalzoniD

JanssensACJ

StewartA

PramstallerP

GyllenstenU

2009 Comparison of participant information and informed consent forms of five European studies in genetic isolated populations. Eur J Hum Genet Available: http://www.ncbi.nlm.nih.gov/pubmed/19826451. Accessed 19 Oct 2009

19. McQuillanR

LeuteneggerA

Abdel-RahmanR

FranklinCS

PericicM

2008 Runs of homozygosity in European populations. Am J Hum Genet 83 359 372 doi:10.1016/j.ajhg.2008.08.007

20. BaraćL

PericićM

KlarićIM

RootsiS

JanićijevićB

2003 Y chromosomal heritage of Croatian population and its island isolates. Eur J Hum Genet 11 535 542 doi:10.1038/sj.ejhg.5200992

21. RudanI

CampbellH

RudanP

1999 Genetic epidemiological studies of eastern Adriatic Island isolates, Croatia: objective and strategies. Collegium Antropologicum 23 531 46 doi:10646227

22. VitartV

BiloglavZ

HaywardC

JanicijevicB

Smolej-NarancicN

2006 3000 years of solitude: extreme differentiation in the island isolates of Dalmatia, Croatia. Eur J Hum Genet 14 478 87 doi:5201589

23. PattaroC

MarroniF

RieglerA

MascalzoniD

PichlerI

2007 The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives. BMC Med Genet 8 29 doi:1471-2350-8-29

24. AulchenkoY

HeutinkP

MackayI

Bertoli-AvellaAM

PullenJ

2004 Linkage disequilibrium in young genetically isolated Dutch population. Eur J Hum Genet 12 527 34 doi:15054401

25. FriedewaldWT

LevyRI

FredricksonDS

1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18 499 502

26. JohanssonI

HallmansG

WikmanA

BiessyC

RiboliE

2002 Validation and calibration of food-frequency questionnaire measurements in the Northern Sweden Health and Disease cohort. Public Health Nutr 5 487 96 doi:10.1079/PHNPHN2001315

27. TobinMD

SheehanNA

ScurrahKJ

BurtonPR

2005 Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat Med 24 2911 2935 doi:10.1002/sim.2165

28. ChenW

AbecasisGR

2007 Family-based association tests for genomewide association scans. Am J Hum Genet 81 913 926 doi:10.1086/521580

29. ProschanMA

WaclawiwMA

2000 Practical guidelines for multiplicity adjustment in clinical trials. Control Clin Trials 21 527 539

30. R Development Core Team 2006 R: A language and environment for statistical computing. R Foundation for Statistical Computing

31. AulchenkoY

RipkeS

IsaacsA

van DuijnC

2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 6 doi:btm108