A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Vyšlo v časopise:
A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol. PLoS Genet 7(10): e32767. doi:10.1371/journal.pgen.1002333
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002333
Souhrn
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Zdroje
1. CooneyMCooneyHDudinaAGrahamI 2010 Assesment of cardiovascular risk. Curr Hypertens Rep 12 384 393
2. TeslovichTMusunuruKSmithAEdmondsonAStylianouI 2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 707 713
3. GazianoJMansonJ 1996 Diet and heart disease. The role of fat, alcohol, and antioxidants. Cardiol Clin 14 69 83
4. BullenC 2008 Impact of tobacco smoking and smoking cessation on cardiovascular risk and disease. Expert Rev Cardiovasc Ther 6 883 895
5. KrausWSlentzC 2009 Exercise training, lipid regulation, and insulin action: a tangled web of cause and effect. Obesity (Silver Spring) 17 Suppl 3 S21 26
6. CzerwinskiSMahaneyMRainwaterDVandebergJMacCluerJ 2004 Gene by smoking interaction: evidence for effects on low-density lipoprotein size and plasma levels of triglyceride and high-density lipoprotein cholesterol. Hum Biol 76 863 876
7. GreenfieldJSamarasKJenkinsAKellyPSpectorT 2004 Do gene-environment interactions influence fasting plasma lipids? A study of twins. Eur J Clin Invest 34 590 598
8. WangXDingXSuSSpectorTManginoM 2009 Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene-obesity interaction. Diabetologia 52 2578 2584
9. SentíMAuboCBoschM 1998 The relationship between smoking and triglyceride-rich lipoproteins is modulated by genetic variation in the glycoprotein IIIa gene. Metabolism 47 1040 1041
10. SentíMElosuaRTomásMSalaJMasiáR 2001 Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men. Hum Genet 109 385 392
11. JunyentMTuckerKSmithCGarcia-RiosAMatteiJ 2009 The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study. J Lipid Res 50 565 573
12. CorbexMPoirierOFumeronFBetoulleDEvansA 2000 Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction. Genet Epidemiol 19 64 80
13. Brand-HerrmannSKuznetsovaTWiechertAStolarzKTikhonoffV 2005 Alcohol intake modulates the genetic association between HDL cholesterol and the PPARgamma2 Pro12Ala polymorphism. J Lipid Res 46 913 919
14. Marques-VidalPBongardVRuidavetsJFauvelJHanaire-BroutinH 2003 Obesity and alcohol modulate the effect of apolipoprotein E polymorphism on lipids and insulin. Obes Res 11 1200 1206
15. AryaRDuggiralaRJenkinsonCAlmasyLBlangeroJ 2004 Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in Mexican Americans. Am J Hum Genet 74 272 282
16. InouyeMKettunenJSoininenPSilanderKRipattiS 2010 Metabonomic, transcriptomic, and genomic variation of a population cohort. Mol Syst Biol Dec 21 441
17. MoranTKatzLPlata-SalamanCSchwartzG 1998 Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol 273 R618 R625
18. FriedewaldWLevyRFredricksonD 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18 499 502
19. SoininenPKangasAWürtzPTukiainenTTynkkynenT 2009 High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. Analyst 134 1781 1785
20. OkazakiMUsuiSIshigamiMSakaiNNakamuraT 2005 Identification of unique lipoprotein subclasses for visceral obesity by component analysis of cholesterol profile in high-performance liquid chromatography. Thromb Vasc Biol 25 578 584
21. AulchenkoYStruchalinMvan DuijnC 2010 ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 16 134
22. de BakkerPFerreiraMJiaXNealeBRaychaudhuriS 2008 Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 17 R122 128
23. DevlinBRoederKWassermanL 2001 Genomic control, a new approach to genetic-based association studies. Theor Popul Biol 600 155 166
24. R Development Core Team: R: A language and environment for statistical computing, Access date: 2010 Dec 13, http://R-project.org
25. Pe'erIYelenskyRAltshulerDDalyM 2008 Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 32 381 385
26. BenjaminiYHochbergY 1995 Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Static Soc Ser B 57 289 300
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 10
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- The Glycobiome Reveals Mechanisms of Pentose and Hexose Co-Utilization in Bacteria
- Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation
- Genetic Determinants of Serum Testosterone Concentrations in Men
- Identification of Widespread Ultra-Edited Human RNAs