Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10−4; Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10−10; Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
Vyšlo v časopise: Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers. PLoS Genet 7(8): e32767. doi:10.1371/journal.pgen.1002215 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002215
1. IlligTGiegerCZhaiGRömisch-MarglWWang-SattlerR 2010 A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42 2 137 141
2. GiegerCGeistlingerLAltmaierEHrabé de AngelisMKronenbergF 2008 Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 4 e1000282 doi:10.1371/journal.pgen.1000282
3. HicksAAPramstallerPPJohanssonAVitartVRudanI 2009 Genetic determinants of circulating sphingolipid concentrations in European populations. PLoS Genet 5 e1000672 doi:10.1371/journal.pgen.1000672
4. KimAMTingenCMWoodruffTK 2010 Sex bias in trials and treatment must end. Nature 2010 Jun 10;465 7299 688 689
5. GellerSEAdamsMGCarnesM 2006 Adherence to federal guidelines for reporting of sex and race/ethnicity in clinical trials. J Womens Health (Larchmt) 2006 Dec;15 10 1123 1131
6. TingenCMKimAMWuP-HWoodruffTK 2010 Sex and sensitivity: the continued need for sex-based biomedical research and implementation. Womens Health (Lond Engl) 2010 Jul;6 4 511 516
7. FairweatherDRoseNR 2004 Women and autoimmune diseases. Emerging Infect. Dis 2004 Nov;10 11 2005 2011
8. MostertzWStevensonMAcharyaCChanIWaltersK 2010 Age - and sex-specific genomic profiles in non-small cell lung cancer. JAMA 2010 Feb 10;303 6 535 543
9. HolleRHappichMLöwelHWichmannHE 2005 KORA–a research platform for population based health research. Gesundheitswesen 2005 Aug;67 Suppl 1 S19 25
10. LorberAWangenLEKowalskiBR 1987 A theoretical foundation for the PLS algorithm. Journal of Chemometrics 1987;1 1 19 31
11. KrumsiekJSuhreKIlligTAdamskiJTheisFJ 2011 Gaussian graphical modeling reconstructs pathway reactions from high-throughput metabolomics data. BMC Systems Biology 2011;5 1 21
12. DöringAGiegerCMehtaDGohlkeHProkischH 2008 SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 2008 Apr;40 4 430 436
13. HollandWLSummersSA 2008 Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocrine reviews 2008;29 4 381
14. YeboahJMcNamaraCJiangXCTabasIHerringtonDM 2010 Association of plasma sphingomyelin levels and incident coronary heart disease events in an adult population: Multi-Ethnic Study of Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 2010;30 3 628
15. NikkiläJSysi-AhoMErmolovASeppänen-LaaksoTSimellO 2008 Gender-dependent progression of systemic metabolic states in early childhood. Molecular systems biology 2008;4 1
16. RodriguesCMKrenBTSteerCJSetchellKD 1996 Formation of delta 22-bile acids in rats is not gender specific and occurs in the peroxisome. Journal of lipid research 1996;37 3 540
17. SlupskyCMRankinKNWagnerJFuHChangD 2007 Investigations of the effects of gender, diurnal variation, and age in human urinary metabolomic profiles. Analytical chemistry 2007;79 18 6995 7004
18. ReuterSEEvansAMChaceDHFornasiniG 2008 Determination of the reference range of endogenous plasma carnitines in healthy adults. Annals of clinical biochemistry 2008;45 6 585
19. PurnellJQWeigleDSBreenPCummingsDE 2003 Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. Journal of Clinical Endocrinology & Metabolism 2003;88 12 5747
20. BrandstätterALaminaCKiechlSHuntSCCoassinS 2010 Sex and age interaction with genetic association of atherogenic uric acid concentrations. Atherosclerosis 2010;210 2 474 478
21. SummarMLHallLChristmanBBarrFSmithH 2004 Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab 2004 Apr;81 Suppl 1 S12 19
22. ParéGChasmanDIParkerANZeeRRYMälarstigA 2009 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study. Circ Cardiovasc Genet 2009 Apr;2 2 142 150
23. LangeLACroteau-ChonkaDCMarvelleAFQinLGaultonKJ 2010 Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. Hum Mol Genet 2010 May 15;19 10 2050 2058
24. KöttgenAPattaroCBögerCAFuchsbergerCOldenM 2010 New loci associated with kidney function and chronic kidney disease. Nat Genet 2010 May;42 5 376 384
25. AulchenkoYSRipattiSLindqvistIBoomsmaDHeidIM 2009 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009 Jan;41 1 47 55
26. WichmannH-EGiegerCIlligT 2005 KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 2005Aug ;67 Suppl 1 S26 30
27. LöwelHMeisingerCHeierMHörmannA 2005 The population-based acute myocardial infarction (AMI) registry of the MONICA/KORA study region of Augsburg. Gesundheitswesen 2005 Aug;67 Suppl 1 S31 37
28. SteffensMLaminaCIlligTBetteckenTVoglerR 2006 SNP-based analysis of genetic substructure in the German population. Hum Hered 2006;62 1 20 29
29. FilzmoserPMaronnaRWernerM 2008 Outlier identification in high dimensions. Computational Statistics & Data Analysis 2008;52 3 1694 1711
30. PaternosterRBrameRMazerollePPiqueroA 1998 Using the correct statistical test for the equality of regression coefficients. Criminology 1998;36 4 859 866
31. Pe'erIYelenskyRAltshulerDDalyMJ 2008 Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genetic epidemiology 2008;32 4 381 385
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
