Admixture Mapping Scans Identify a Locus Affecting Retinal Vascular Caliber in Hypertensive African Americans: the Atherosclerosis Risk in Communities (ARIC) Study

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Retinal vascular caliber provides information about the structure and health of the microvascular system and is associated with cardiovascular and cerebrovascular diseases. Compared to European Americans, African Americans tend to have wider retinal arteriolar and venular caliber, even after controlling for cardiovascular risk factors. This has suggested the hypothesis that differences in genetic background may contribute to racial/ethnic differences in retinal vascular caliber. Using 1,365 ancestry-informative SNPs, we estimated the percentage of African ancestry (PAA) and conducted genome-wide admixture mapping scans in 1,737 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) representing summary measures of retinal arteriolar and venular caliber, respectively, were measured from retinal photographs. PAA was significantly correlated with CRVE (ρ = 0.071, P = 0.003), but not CRAE (ρ = 0.032, P = 0.182). Using admixture mapping, we did not detect significant admixture association with either CRAE (genome-wide score = −0.73) or CRVE (genome-wide score = −0.69). An a priori subgroup analysis among hypertensive individuals detected a genome-wide significant association of CRVE with greater African ancestry at chromosome 6p21.1 (genome-wide score = 2.31, locus-specific LOD = 5.47). Each additional copy of an African ancestral allele at the 6p21.1 peak was associated with an average increase in CRVE of 6.14 µm in the hypertensives, but had no significant effects in the non-hypertensives (P for heterogeneity <0.001). Further mapping in the 6p21.1 region may uncover novel genetic variants affecting retinal vascular caliber and further insights into the interaction between genetic effects of the microvascular system and hypertension.

Vyšlo v časopise: Admixture Mapping Scans Identify a Locus Affecting Retinal Vascular Caliber in Hypertensive African Americans: the Atherosclerosis Risk in Communities (ARIC) Study. PLoS Genet 6(4): e32767. doi:10.1371/journal.pgen.1000908
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000908

Souhrn

Zdroje

1. WongTY

ShankarA

KleinR

KleinBE

HubbardLD

2004 Prospective cohort study of retinal vessel diameters and risk of hypertension. BMJ 329 79

2. WongTY

KleinR

SharrettAR

DuncanBB

CouperDJ

2004 Retinal arteriolar diameter and risk for hypertension. Ann Intern Med 140 248 255

3. WongTY

KleinR

SharrettAR

DuncanBB

CouperDJ

2002 Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA 287 1153 1159

4. KaushikS

KifleyA

MitchellP

WangJJ

2007 Age, blood pressure, and retinal vessel diameter: separate effects and interaction of blood pressure and age. Invest Ophthalmol Vis Sci 48 557 561

5. LiewG

SharrettAR

WangJJ

KleinR

KleinBE

2008 Relative importance of systemic determinants of retinal arteriolar and venular caliber: the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 126 1404 1410

6. 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

7. WongTY

DuncanBB

GoldenSH

KleinR

CouperDJ

2004 Associations between the metabolic syndrome and retinal microvascular signs: the Atherosclerosis Risk in Communities Study. Invest Ophthalmol Vis Sci 45 2949 2954

8. WongTY

IslamFM

KleinR

KleinBE

CotchMF

2006 Retinal vascular caliber, cardiovascular risk factors, and inflammation: the Multi-Ethnic Study of Atherosclerosis (MESA). Invest Ophthalmol Vis Sci 47 2341 2350

9. WongTY

KamineniA

KleinR

SharrettAR

KleinBE

2006 Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the Cardiovascular Health Study. Arch Intern Med 166 2388 2394

10. BakerML

HandPJ

WangJJ

WongTY

2008 Retinal signs and stroke: revisiting the link between the eye and brain. Stroke 39 1371 1379

11. IkramMK

de JongFJ

Van DijkEJ

PrinsND

HofmanA

2006 Retinal vessel diameters and cerebral small vessel disease: the Rotterdam Scan Study. Brain 129 182 188

12. IkramMK

de JongFJ

BosMJ

VingerlingJR

HofmanA

2006 Retinal vessel diameters and risk of stroke: the Rotterdam Study. Neurology 66 1339 1343

13. de JongFJ

VernooijMW

IkramMK

IkramMA

HofmanA

2008 Arteriolar oxygen saturation, cerebral blood flow, and retinal vessel diameters: the Rotterdam Study. Ophthalmology 115 887 892

14. SunC

WangJJ

MackeyDA

WongTY

2009 Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol 54 74 95

15. RochtchinaE

WangJJ

TaylorB

WongTY

MitchellP

2008 Ethnic variability in retinal vessel caliber: a potential source of measurement error from ocular pigmentation?-the Sydney Childhood Eye Study. Invest Ophthalmol Vis Sci 49 1362 1366

16. LeeKE

KleinBE

KleinR

KnudtsonMD

2004 Familial aggregation of retinal vessel caliber in the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 45 3929 3933

17. TaarnhojNC

LarsenM

SanderB

KyvikKO

KesselL

2006 Heritability of retinal vessel diameters and blood pressure: a twin study. Invest Ophthalmol Vis Sci 47 3539 3544

18. SunC

ZhuG

WongTY

HewittAW

RuddleJB

2009 Quantitative Genetic Analysis of the Retinal Vascular Caliber. The Australian Twins Eye Study. Hypertension

19. RifeDC

1954 Populations of hybrid origin as source material for the detection of linkage. Am J Hum Genet 6 26 33

20. ChakrabortyR

WeissKM

1988 Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci U S A 85 9119 9123

21. McKeiguePM

1997 Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations. Am J Hum Genet 60 188 196

22. HoggartCJ

ShriverMD

KittlesRA

ClaytonDG

McKeiguePM

2004 Design and analysis of admixture mapping studies. Am J Hum Genet 74 965 978

23. PattersonN

HattangadiN

LaneB

LohmuellerKE

HaflerDA

2004 Methods for high-density admixture mapping of disease genes. Am J Hum Genet 74 979 1000

24. SmithMW

PattersonN

LautenbergerJA

TrueloveAL

McDonaldGJ

2004 A high-density admixture map for disease gene discovery in African Americans. Am J Hum Genet 74 1001 1013

25. FreedmanML

HaimanCA

PattersonN

McDonaldGJ

TandonA

2006 Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A 103 14068 14073

26. HaimanCA

PattersonN

FreedmanML

MyersSR

PikeMC

2007 Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39 638 644

27. KaoWH

KlagMJ

MeoniLA

ReichD

Berthier-SchaadY

2008 MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40 1185 1192

28. NallsMA

WilsonJG

PattersonNJ

TandonA

ZmudaJM

2008 Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. Am J Hum Genet 82 81 87

29. ReichD

NallsMA

KaoWH

AkylbekovaEL

TandonA

2009 Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet 5 e1000360 doi:10.1371/journal.pgen.1000360

30. ReichD

PattersonN

RameshV

De JagerPL

McDonaldGJ

2007 Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 80 716 726

31. InbalA

FreimarkD

ModanB

ChetritA

MatetzkyS

1999 Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood 93 2186 2190

32. SiscovickDS

SchwartzSM

RosendaalFR

PsatyBM

1997 Thrombosis in the young: effect of atherosclerotic risk factors on the risk of myocardial infarction associated with prothrombotic factors. Thromb Haemost 78 7 12

33. DoggenCJ

CatsVM

BertinaRM

RosendaalFR

1998 Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 97 1037 1041

34. SzolnokiZ

SomogyvariF

KondacsA

SzaboM

FodorL

2003 Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke. J Neurol Neurosurg Psychiatry 74 1615 1620

35. PezziniA

GrassiM

Del ZottoE

ArchettiS

SpeziR

2005 Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults. Stroke 36 533 539

36. de LeeuwFE

RichardF

de GrootJC

van DuijnCM

HofmanA

2004 Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke 35 1057 1060

37. ReichD

PattersonN

2005 Will admixture mapping work to find disease genes? Philos Trans R Soc Lond B Biol Sci 360 1605 1607

38. NagaokaT

TakahashiA

SatoE

IzumiN

HeinTW

2006 Effect of systemic administration of simvastatin on retinal circulation. Arch Ophthalmol 124 665 670

39. SaldivarE

CabralesP

TsaiAG

IntagliettaM

2003 Microcirculatory changes during chronic adaptation to hypoxia. Am J Physiol Heart Circ Physiol 285 H2064 H2071

40. WongTY

MitchellP

2004 Hypertensive retinopathy. N Engl J Med 351 2310 2317

41. SuzumaI

HataY

ClermontA

PokrasF

RookSL

2001 Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2: potential mechanisms for exacerbation of diabetic retinopathy by hypertension. Diabetes 50 444 454

42. SwiftMR

WeinsteinBM

2009 Arterial-venous specification during development. Circ Res 104 576 588

43. WongTY

KleinR

KleinBE

MeuerSM

HubbardLD

2003 Retinal vessel diameters and their associations with age and blood pressure. Invest Ophthalmol Vis Sci 44 4644 4650

44. EmbletonSJ

HoskingSL

Roff HiltonEJ

CunliffeIA

2002 Effect of senescence on ocular blood flow in the retina, neuroretinal rim and lamina cribrosa, using scanning laser Doppler flowmetry. Eye 16 156 162

45. XingC

KleinBE

KleinR

JunG

LeeKE

2006 Genome-Wide Linkage Study of Retinal Vessel Diameters in the Beaver Dam Eye Study. Hypertension 47 797 802

46. 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

47. ParraEJ

KittlesRA

ShriverMD

2004 Implications of correlations between skin color and genetic ancestry for biomedical research. Nat Genet 36 S54 S60

48. StoneJ

ItinA

AlonT

Pe'erJ

GnessinH

1995 Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15 4738 4747

49. AlonT

HemoI

ItinA

Pe'erJ

StoneJ

1995 Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1 1024 1028

50. DarlandDC

MassinghamLJ

SmithSR

PiekE

Saint-GeniezM

2003 Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264 275 288

51. BoonCJ

den HollanderAI

HoyngCB

CremersFP

KleveringBJ

2008 The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res 27 213 235

52. PalczewskiK

SokalI

BaehrW

2004 Guanylate cyclase-activating proteins: structure, function, and diversity. Biochem Biophys Res Commun 322 1123 1130

53. HortonR

WilmingL

RandV

LoveringRC

BrufordEA

2004 Gene map of the extended human MHC. Nat Rev Genet 5 889 899

54. KelleyJ

TrowsdaleJ

2005 Features of MHC and NK gene clusters. Transpl Immunol 14 129 134

55. de BakkerPI

McVeanG

SabetiPC

MirettiMM

GreenT

2006 A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38 1166 1172

56. The ARIC investigators 1989 The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol 129 687 702

57. CouperDJ

KleinR

HubbardLD

WongTY

SorliePD

2002 Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study. Am J Ophthalmol 133 78 88

58. National Heart, Lung and Blood Institute 1987 ARIC manuals of operation: no. version 2.0 Chapel Hill, NC ARIC Coordinating Center, School of Public Health, University of North Carolina

59. SharrettAR

PatschW

SorliePD

HeissG

BondMG

1994 Associations of lipoprotein cholesterols, apolipoproteins A-I and B, and triglycerides with carotid atherosclerosis and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb 14 1098 1104

60. 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

61. ChengCY

ReichD

CoreshJ

BoerwinkleE

PattersonN

2010 Admixture mapping of obesity-related traits in African Americans: the Atherosclerosis Risk in Communities (ARIC) Study. Obesity 18 563 572

62. HindsDA

StuveLL

NilsenGB

HalperinE

EskinE

2005 Whole-genome patterns of common DNA variation in three human populations. Science 307 1072 1079