Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10−8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%–3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10−25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10−16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10−13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10−16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
Vyšlo v časopise:
Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation. PLoS Genet 6(10): e32767. doi:10.1371/journal.pgen.1001184
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001184
Souhrn
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10−8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%–3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10−25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10−16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10−13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10−16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
Zdroje
1. CaminiPG
CreaF
2007 Coronary microvascular dysfunction. N Engl J Med 356 830 840
2. WatkinsH
FarrallM
2006 Genetic susceptibility to coronary artery disease: from promise to progress. Nat Rev Genet 7 163 173
3. Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678
4. HubbardLD
BrothersRJ
KingWN
CleggLX
KleinR
1999 Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 106 2269 2280
5. IkramMK
De JongFJ
VingerlingJR
WittemanJC
HofmanA
2004 Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 45 2129 2134
6. WongTY
MitchellP
2004 Hypertensive retinopathy. N Engl J Med 351 2310 2317
7. WongTY
KleinR
SharrettAR
DuncanBB
CouperDJ
2004 Atherosclerosis Risk in Communities Study. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med 140 248 255
8. WongTY
KleinR
SharrettAR
SchmidtMI
PankowJS
2002 Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA 287 2528 2533
9. QiuC
CotchMF
SigurdssonS
GarciaM
KleinR
2008 Retinal and cerebral microvascular signs and diabetes: the age, gene/environment susceptibility-Reykjavik study. Diabetes 57 1645 1650
10. McGeeshanK
LiewG
MacaskillP
IrwigL
KleinR
2009 Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. Am J Epidemiol 170 1323 1332
11. McGeechanK
LiewG
MacaskillP
IrwigL
KleinR
2009 Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med 151 404 413
12. IkramMK
De JongFJ
Van DijkEJ
PrinsND
HofmanA
2006 Retinal vessel diameters and cerebral small vessel disease: The Rotterdam Scan Study. Brain 129 182 188
13. LongstrethWJr
LarsenEK
KleinR
WongTY
SharrettAR
2007 Associations between findings on cranial magnetic resonance imaging and retinal photography in the elderly: the Cardiovascular Health Study. Am J Epidemiol 165 78 84
14. JeganathanVS
KawasakiR
WangJJ
AungT
MitchellP
2008 Retinal vascular caliber and age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol 146 954 959
15. NguyenTT
WangJJ
SharrettAR
IslamFM
KleinR
2008 Relationship of retinal vascular caliber with diabetes and retinopathy: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 31 544 549
16. KleinR
KleinBE
MossSE
WongTY
2007 Retinal vessel caliber and microvascular and macrovascular disease in type 2 diabetes: XXI: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 114 1884 1892
17. XingC
KleinBE
KleinR
JunG
LeeKE
2006 Genome-wide linkage study of retinal vessel diameters in the Beaver Dam Eye Study. Hypertension 47 797 802
18. WangJJ
WongTY
2006 Genetic determinants of retinal vascular caliber: additional insights into hypertension pathogenesis. Hypertension 47 644 645
19. LiewG
ShankarA
WangJJ
KleinR
BrayMS
2007 Apolipoprotein E gene polymorphisms and retinal vascular signs: the atherosclerosis risk in communities (ARIC) study. Arch Ophthalmol 125 813 818
20. De JongFJ
IkramMK
DesprietDD
UitterlindenAG
HofmanA
2007 Complement factor h polymorphism, inflammatory mediators, and retinal vessel diameters: the rotterdam study. Invest Ophthalmol Vis Sci 48 3014 3018
21. PsatyBM
O'DonnellCJ
GudnasonV
LunettaKL
FolsomAR
2009 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from five cohorts. Circ Cardiovasc Genet 2 73 80
22. HarrisTB
LaunerLJ
EiriksdottirG
KjartanssonO
JonssonPV
2007 Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics. Am J Epidemiol 165 1076 1087
23. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives 1989 The ARIC investigators. Am J Epidemiol 129 687 702
24. FriedLP
BorhaniNO
EnrightP
FurbergCD
GardinJM
1991 The Cardiovascular Health study: design and rationale. Ann Epidemiol 1 263 276
25. HofmanA
BretelerMM
van DuijnCM
JanssenHL
KrestinGP
2009 The Rotterdam Study: 2010 objectives and design update. Eur J Epidemiol 24 553 572
26. MackeyDA
MackinnonJR
BrownSA
KearnsLS
RuddleJB
2009 Twins Eye Study in Tasmania (TEST): Rationale and Methodology to Recruit and Examine Twins. Twin Res Hum Genet 12 441 454
27. HammondCJ
SniederH
SpectorTD
GilbertCE
2000 Genetic and environmental factors in age-related nuclear cataracts in monozygotic and dizygotic twins. N Engl J Med 342 1786 1790
28. PsatyBM
HeckbertSR
KoepsellTD
SiscovickDS
RaghunathanTE
1995 The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 274 620 625
29. KlungelOH
HeckbertSR
LongstrethWTJr
FurbergCD
KaplanRC
2001 Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 161 37 43
30. Newton-ChehC
JohnsonT
GatevaV
TobinMD
BochudM
2009 Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 41 666 676
31. VoightBF
ScottLJ
SteinthorsdottirV
MorrisAP
DinaC
2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42 579 589
32. TamaiK
MatsubaraA
TomidaK
MatsudaY
MoritaH
2002 Lipid hydroperoxide stimulates leukocyte-endothelium interaction in the retinal microcirculation. Exp Eye Res 75 69 75
33. ChesterAH
BorlandJA
ButteryLD
MitchellJA
CunninghamDA
1998 Induction of nitric oxide synthase in human vascular smooth muscle: interactions between proinflammatory cytokines. Cardiovasc Res 38 814 821
34. WongTY
IslamFM
KleinR
KleinBE
CotchMF
2006 Retinal vascular caliber, cardiovascular risk factors and inflammation: the Multi-Ethnic Study of Atherosclerosis. Invest Ophthalmol Vis Sci 47 2341 2350
35. XuK
ChongDC
RankinSA
ZornAM
CleaverO
2009 RASIP1 is required for endothelial cell motility, angiogenesis and vessel formation. Dev Biol 329 269 279
36. XiaoJ
XiaH
ZhouJ
AzmiIF
DaviesBA
2008 Structural Basis of Vta1 Function in the Multivesicular Body Sorting Pathway. Dev Cell 14 37 49
37. MatusiakD
GloverS
NathanielR
MatkowskyjK
YangJ
2005 Neuromedin B and its receptor are mitogens in both normal and malignant epithelial cells lining the colon. Am J Physiol Gastrointest Liver Physiol 288 718 728
38. SmythDJ
PlagnolV
WalkerNM
CooperJD
DownesK
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359 2767 2777
39. SoranzoN
SpectorTD
ManginoM
KühnelB
RendonA
2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41 1182 1190
40. GaneshSK
ZakaiNA
Van RooijFJ
SoranzoN
SmithAV
2009 Multiple loci influence erythrocyte phenotypes in the CHARGE consortium. Nat Genet 41 1191 1198
41. LevyD
EhretGB
RiceK
VerwoertGC
LaunerLJ
2009 Genome-wide association study of blood pressure and hypertension. Nat Genet in press
42. MaK
ChanJK
ZhuG
WuZ
2005 Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Mol Cell Biol 25 3575 3582
43. ManolioTA
CollinsFS
CoxNJ
GoldsteinDB
HindorffLA
2009 Finding the missing heritability of complex diseases. Nature 461 747 753
44. KnudtsonMD
LeeKE
HubbardLD
WongTY
KleinR
2003 Revised formulas for summarizing retinal vessel diameters. Curr Eye Res 27 143 149
45. SchlesselmanJJ
1997 Risk of endometrial cancer in relation to use of combined oral contra-ceptives: a practitioner's guide to meta-analysis. Human Reprod 12 1851 1863
46. GordonA
GlazkoG
QiuX
YakovlevA
2007 Control of the mean number of false discoveries, Bonferroni and stability of multiple testing. Ann Appl Statistics 1 179 190
47. HoggartCJ
ClarkTG
De IorioM
WhittakerJC
BaldingDJ
2008 Genome-wide significance for dense SNP and resequencing data. Genet Epidemiol 32 179 185
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 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
- Genome-Wide Identification of Targets and Function of Individual MicroRNAs in Mouse Embryonic Stem Cells
- Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer
- Allele-Specific Down-Regulation of Expression Induced by Retinoids Contributes to Climate Adaptations
- Simultaneous Disruption of Two DNA Polymerases, Polη and Polζ, in Avian DT40 Cells Unmasks the Role of Polη in Cellular Response to Various DNA Lesions