ten epidemiologischen Studien widersprüchlich waren 1 [16, 21, 267, 276, 279, 280, 287–291]. In der BDES zeigte sich ein Zusammenhang zwischen Hypertonie und der 10-Jahres-Inzidenzrate der späten AMD, insbesondere für CNV [292]. Im Vergleich zu Personen mit normalem Blutdruck ergab sich für Personen mit behandelter, doch unkontrollierter Hypertonie eine RR von 2,26 für späte AMD (95%-CI 1,00–5,13) und eine RR von 3,29 für CNV (95%-CI 1,24–8,79). Personen mit behandelter und gut eingestellter Hypertonie wiesen ebenfalls ein erhöhtes Risiko für CNV auf (RR 2,29; 95%-CI 1,12–4,69). Es zeigte sich ein Zusammenhang zwischen höherem systolischen Blutdruck bei Ausgangsmessung und der Inzidenz einer Depigmentierung des RPE (RR pro 10 mmHg systolischem Blutdruck: 1,10; 95%-CI 1,01–1,18) und CNV (RR 1,22; 95%-CI 1,06–1,41). Eine höhere Pulsamplitude bei Ausgangsmessung war mit der Inzidenz einer Depigmentierung des RPE (RR pro 10 mmHg: 1,17; 95%-CI 1,07–1,28), mit vermehrtem retinalen Pigment (RR 1,10; 95%-CI 1,01–1,19), mit CNV (RR 1,34; 95%- CI 1,14–1,60) und AMD-Progression (RR 1,08; 95%-CI 1,01–1,17) assoziiert. In der RS fand sich eine klare dosisabhängige Assoziation zwischen erhöhtem systolischem Blutdruck und einem erhöhten Risiko für das Neuauftreten einer AMD (OR pro 10 mmHg-Anstieg: 1,08; 95%-CI 1,03–1,14) [293]. Im Gegensatz dazu zeigte sich in der BMES kein Hinweis auf einen Zusammenhang zwischen Pulsamplitude, systolischem oder diastolischen Blutdruck oder dem Vorliegen einer Hypertonie zu Beginn der Untersuchung und dem Neuauftreten einer

AMD [289].

1.5.5 Kataraktchirurgie

Verschiedene Gruppen haben von einem Zusammenhang zwischen Kataraktchirurgie und AMD berichtet [294–304]. Querschnittsdaten der BDES zeigten eine Assoziation zwischen Kataraktchirurgie und früher AMD [295]. Die NHANES berichtete von einer QuerschnittsAssoziation zwischen Aphakie und AMD [294]. Freeman und Kollegen unternahmen Querschnittserfassungen in drei Populationen und fanden einen Zusammenhang zwischen Kataraktchirurgie und später AMD [300]. Die Prävalenzerhebung der BMES hingegen erbrachte keine signifikante Assoziation zwischen Kataraktchirurgie und früher oder später AMD [305]. Querschnittsanalysen der Rotterdam-Studie zeigten kein erhöhtes Risiko für GA oder CNV in pseudophaken Augen, jedoch ein erhöhtes Risiko für frühe AMD [306]. 5-Jahres-Inzidenzanalysen gepoolter Daten aus der BDES und der BMES (jede späte AMD: OR 5,7; 95%-CI 2,4–13,6) [304] sowie der

Rotterdam-Studie (nur trockene AMD: OR 3,44; 95%-CI 1,68–7,08) [306] ergaben eine positive Korrelation von später AMD und Kataraktchirurgie. Aufgrund der zeitlichen Abfolge der Ereignisse haben solche Daten mehr Gewicht.

In zusätzlichen Nachuntersuchungsdaten der BDES zeigte sich eine Assoziation zwischen Inzidenz der späten AMD sowie AMD-Progression und Kataraktoperationen, die mindestens 10 Jahre zuvor stattgefunden hatten (OR 3,81; 95%-CI 1,89–7,69 sowie OR 1,97; 95%-CI 1,29–3,02) [301]. In der Rotterdam-Studie ergab sich eine mögliche Interaktion zwischen CFH und Kataraktchirurgie; die CFH Y402H-Variante bedeutete ein zusätzliches Risiko für geographische Atrophie [306]. Längsschnittdaten der AREDS zeigten kein erhöhtes Risiko für jeden Subtyp der späten AMD mit Kataraktchirurgie [307]. Ursächlich für die Widersprüche zwischen epidemiologischen Querschnittund Längsschnittstudien könnten Unterschiede im Studiendesign und in der Verteilung wichtiger genetischer und umweltbedingter Risikofaktoren (wie z. B. Lebensalter, Rauchen, sozioökonomischer Status und Sonnenlichtexposition) sein, von denen man glaubt, dass sie die Entwicklung und Progression sowohl von Katarakt (operationswürdig) als auch AMD begünstigen.

1.6Interaktion zwischen Risikofaktoren

1.6.1Kombinierte Effekte von CFH-Y402H und genetischen sowie umweltbedingten Faktoren

In der Rotterdam-Studie wurde von einer Interaktion zwischen CFH-Y402H und Rauchen, C-reaktivem ProteinLevel und Erythrozytensedimentationsrate (ESR) berichtet [66], was bedeutet, dass der Synergieeffekt jeder dieser Faktoren mit Y402H signifikant größer war als die Summe der einzelnen Effekte. Im Vergleich zu Personen des homozygoten Nicht-Risiko-(TT)-Genotyps und normalen ESR-Level hatten Personen des homozygoten Risiko- (CC)-Genotyps und erhöhtem ESR-Level ein Risiko von 20,2 (95%-CI 9,5–43,0) für späte AMD. Höhere Serum- CRP-Konzentrationen bei Personen des CC-Genotyps erhöhten das AMD-Risiko zusätzlich auf 27,7 (95%-CI 10,7–72,0) verglichen mit Personen des TT-Genotyps und den niedrigsten CRP-Konzentrationen. Im Vergleich zu TT-Trägern, die niemals geraucht hatten, ergab sich für derzeit aktive Raucher des CC-Genotyps eine OR von 34,0 (95%-CI 13,0–88,6) für späte AMD. Ein stärkerer Effekt von CFH-Y402H bei Rauchern wurde auch durch andere Studien bestätigt [65, 73, 78, 99, 308, 309].

1.6 · Interaktion zwischen Risikofaktoren

Eine weitere Spezifizierung nahmen DeAngelis et al. vor und schätzten, dass zehn »pack-years« oder mehr in Kombination mit dem CC-Genotyp das Risiko für eine CNV im Vergleich zu weniger als 10 »pack-years« Rauchen in Kombination mit einem CToder TT-Genot- yp 144-fach erhöht [78]. Eine signifikante Interaktion von CFH-Y402H und BMI wurde in der AREDS beschrieben [73]. Ein höherer BMI (≥25) erhöhte das AMD-Risiko nicht bei Personen des TT-Genotyps (OR 0,7; 95%-CI 0,4–1,2), jedoch bei Personen mit CT- (OR 2,2; 95%-CI 1,3–4,0) und CC-Genotyp (OR 5,9; 95%-CI 3,1–11,4). Gold et al. berichteten, dass der protektive Effekt von C2 und/oder BF am stärksten bei Personen mit CFH CC-Genotyp (OR=0,27), mittelgradig beim CT-Geno- typ (OR=0,36) und am schwächsten beim TT-Genotyp (OR=0,44) ausgeprägt war, doch überlappten die Konfidenzintervalle all dieser Schätzungen [49].

Die Interaktion zwischen genetischen Varianten und Antioxidanzien bei der Entstehung der späten AMD wurde in zwei Studien untersucht. In der AREDS wurde das Progressionsrisiko für späte AMD für die CFH-Y402H- und die LOC387715-A69S-Genotypen in verschiedenen Behandlungsarmen mit Antioxidanzien berechnet. Eine hohe Zinkdosis entfaltete den höchsten protektiven Effekt gegen AMD bei Trägern des homozygoten Nicht- Risiko-CFH-Genotyps, jedoch auch, wenngleich nicht signifikant für Träger der Risikovariante von LOC387715 [310]. In der BMES erwirkte ein hoher Fischkonsum eine bessere Protektion gegen späte AMD bei homozygoten Trägern von Y402H als bei Nichtträgern [311]. Des Weiteren ergab die RS, dass eine höhere Nahrungsaufnahme von Zink, Omega-3-Fettsäuren, β-Carotin und Lutein/ Zeaxanthin die Inzidenz einer frühen AMD bei Personen mit diesen genetischen Risikovarianten vermindern kann.

1.6.2Kombinierte Effekte von 10q26-SNP und anderen genetischen sowie umweltbedingten Faktoren

Wenngleich nicht alle Studien eine statistische Interaktion fanden, so unterstützte die Mehrzahl einen starken kombinierten Effekt von Rauchen und LOC387715A69S für eine AMD-Prädisposition [53, 99, 153, 309, 312–316]. Eine Interaktionsanalyse von Schmidt et al. für die Anzahl der »Raucher-Pack-Years« und A69SGenotypen ergab einen linearen Anstieg der Häufigkeit des homozygoten Risikogenotyps TT bei betroffenen Personen mit steigender Anzahl von »pack-years« unabhängig von Lebensalter und Geschlecht mit einer korrespondierenden Abnahme des Nicht-Risiko-Genotyps

GG (p<0,05) [99]. Bei einem Vergleich aktueller Raucher mit Personen, die niemals rauchten, erhöhte sich das Risiko für Heterozygote (GT) um das 3- bis 6-fache, und für Homozygote (GG) um das 10bis 27-fache [309, 312]. Zusätzlich zeigte die BMES bei A69S-GT und -TT- Genotypen mittels des hochsensitiven CRP Markers eine kombinierte Auswirkung auf das Risiko, eine frühe und späte AMD auszubilden (OR 1,2 für das höchste Tertil allein, 1,6 nur für GTund TT-Genotypen und 2,2 für GTund TT-Genotypen in Kombination mit dem höchsten Tertil im Vergleich zum GG-Genotyp mit den zwei niedrigeren Tertilen). Auch die entsprechenden OR für eine Kombination der verschiedenen A69S-Genotypen mit weiteren Blutmarkern wurden berechnet: für IL-6 (1,1; 1,6 und 2,2), für sICAM-1 (1,0; 1,5 und 2,3) und für PAI-1 (1,3; 1,7 und 2,3), nicht jedoch für WCC, Fibrinogen, Homozystein und den Von-Willebrand-Faktor [315].

1.6.3Kombinierte Effekte von CFH und ARMS2/HTRA1-SNP

Zahlreiche Studien haben den kombinierten Effekt von

CFH-Y402H und LOC387715-A69S/HTRA1-rs11200638 untersucht [62, 74, 139, 309, 316–320]. Im Vergleich zum Nicht-Risiko-Genotyp (TTGG) hatten Personen mit homozygotem Risikogenotyp an beiden Genorten (CFH-CC – LOC387715-TT) OR zwischen 27 in einer finnischen Fall-Kontroll-Studie und 228 in der klinischbasierten AREDS an einer kaukasischen Population. Für Personen, die für beide Risikogenotypen CFH-Y402H und HTRA1-rs11200638 homozygot waren, variierten die kombinierten OR im Vergleich zu Personen mit keinerlei Risikoallelen dieser Genorte von 8 in einer japanischen Fall-Kontroll-Studie bis 193 in der AREDS. Neben dem kombinierten Risiko durch CFH-Y402H und LOC387715-A69S beobachteten Schmidt et al. eine zusätzliche Risikoerhöhung für AMD durch Rauchen [99]. Im Vergleich zur Kombination Nichtraucher/TT (Y402H)/ GG (A69S) erhöhte sich die OR bei Personen des CC (Y402H)/TT (LOC387715)-Genotyps von 10,2 bei Nichtrauchern auf 34,5 für Raucher. Auch Seitsonen et al. schlossen, dass Rauchen ein zusätzliches AMD-Risiko bedeutet, jedoch nur in Verbindung mit Geschlecht und C3-Genotyp [316]. Die univariate OR betrug für das Tragen wenigstens eines Risikoallels von CFH-Y402H 5,45 (95%-CI 2,18–16,83), von LOC387715-A69S 4,89 (95%- CI 1,73–16,43) sowie von C3-R102G 2,12 (95%-CI 0,52– 8,70) und für Rauchen 3,22 (95%-CI 1,81–6,09), während die gemeinsame OR aller drei Genorte und Rauchen 74,3 (95%-CI 10,81–2123,6) ergab.

22 Kapitel 1 · Epidemiologie der AMD

1.6.4 Kombinierte Effekte des ApoE-Gens 1 und anderen genetischen sowie

umweltbedingten Faktoren

Eine geschlechtsspezifische Rolle der ApoE-Allele bei Entwicklung oder Progression der AMD wird diskutiert, doch gibt es dazu widersprüchliche Ergebnisse. Schmidt et al. fanden eine signifikante Interaktion zwischen einem ε2-Träger-Status und Geschlecht [184]. Die ε2-Allele bedeuteten ein Risiko von 0,74 (95%-CI 0,52–1,06) bei Frauen und von 1,54 (95%-CI 0,97–2,45) bei Männern. Daher schlossen die Autoren, dass ε2-Allele nur bei Männern ein erhöhtes Risiko für AMD bedingen. Im Gegensatz dazu berichteten Baird et al. ein signifikant um das 4,8-fache (95%-CI 1,19–19,09) erhöhtes Risiko für AMDProgression bei ε2-Trägern verglichen mit ε4-Trägern und ein fast 2,8-faches Risiko (95%-CI 0,96–19,09) gegenüber ε3-Trägern [195]. Da diese Risikoerhöhung nur bei Frauen vorlag, schlossen die Autoren auf eine mögliche geschlechtsspezifische Rolle der ε2-Allele für die AMD-Progression. Fritsche et al. wiederum konnten gar keine geschlechtsspezifische Wirkung der ApoE-Allele feststellen [197].

Schmidt et al. berichteten von einem modifizierenden Effekt der ApoE-Genotypen auf das raucherabhängige Risiko für AMD [187], insbesondere für CNV [321]. Der schädliche Effekt des Rauchens zeigte sich am stärksten bei ApoE-ε2-Trägern verglichen mit ApoE-ε4-Trägern und Personen des ApoE-ε3/ε3-Genotyps. Die Risikoerhöhung für CNV fiel am deutlichsten bei ApoE-ε2-Trägern aus, wobei das Genotyp-abhängige Risiko im Verhältnis zu Nichtrauchern mit ApoE-ε3/ε3 von 1,9 für ApoE-ε4- Trägern (p=0,11) über 2,2 für ApoE-ε3/ε3-Homozygote (p=0,007) auf 4,6 (p=0,001) für ApoE-ε2-Träger zunahm. Die Datenmengen in anderen Studien waren zu klein, um statistische Ergebnisse zu den Subgruppen zu erhalten [188, 196].

Fazit

Im klinischen Alltag kann der Ophthalmologe das AMDRisiko im Wesentlichen aufgrund des Patientenalters, dessen Rauchgewohnheiten, sowie klinischen Zeichen von weichen Drusen und Pigmentveränderungen einschätzen. Die Identifikation prädisponierender Gene, der berichtete protektive Effekt bestimmter Nährstoffe, der angedeutete nachteilige Effekt von Katarakteingriffen auf die AMD-Progression sowie die mögliche Interaktion zwischen genetischen und umweltbedingten Faktoren bergen möglicherweise Informationen, die der Ophthalmologe für eine effizientere Therapie und individuelle Beratung des Patienten nutzen kann. So sollte

z. B. Patienten mit früher AMD eine ausreichende Versorgung mit Antioxidanzien, Zink und Omega-3-Fettsäuren empfoh-

len werden. Des Weiteren sollten AMD-Patienten auf das Rauchen verzichten und sich gegen Hypertonie schützen. Die betrifft vor allem Patienten mit hohem genetischem Risiko. Zukünftige Studien müssen die neuen Anhaltspunkte bestätigen und weitere Hinweise liefern, ob eine genetische Testung und die Bestimmung von Biomarkern routinemäßig angewandt werden sollten, um die AMD-Prognose zu bestimmen.

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24Kapitel 1 · Epidemiologie der AMD

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