GENETIC VARIANTS INCREASE THE RISK OF AGE-RELATED

专利名称：GENETIC VARIANTS INCREASE THE RISK OF

AGE-RELATED MACULAR DEGENERATION

发明人：PERICAK-VANCE, M.A.,HAINES,

JONATHAN,POSTEL, ERIC,AGARWAL,ANITA,HAUSER, MICHAEL A.,SCHMIDT,SILKE,SCOTT, WILLIAM K.

申请号：EP067369申请日：20060306公开号：EP1861511A4公开日：20100120

摘要：Age-related macular degeneration (AMD) is a leading cause of visualimpairment and blindness in the elderly whose etiology remains largely unknown.Previous studies identified chromosome Iq32 as harboring a susceptibility locus for AMD,but it was not identified. We identified a strongly associated haplotype in two

independent data sets. DNA sequencing of the complement factor H gene (CFH) withinthis haplotype revealed a coding variant, Y402H, that significantly increases the risk forAMD with odds ratios between 2.45 and 5.57. This identifies Complement factor H asinvolved in pathogenesis of AMD. This single variant alone is so common that it likelyexplains 43 percent of AMD in older adults. In addition, we have replicated and refinedprevious reports implicating a coding change in LOC387715 as the second major AMDsusceptibility allele. The effect of rsl0490924 appears to be completely independent ofthe Y402H variant in the CFH gene. The joint effect of these two susceptibility genes isconsistent with a multiplicative model, and together, they may explain as much as 65% of

the PAR of AMD. In contrast, the effect of rsl0490924 appears to be strongly modifiedby cigarette smoking. Smoking and LOC387715 together may explain as much as 34% ofAMD. Our data indicate that variant genotypes at rsl0490924 confer a substantiallylarger AMD risk to cigarette smokers than non-smokers. This observation is supportedby traditional case-control modeling, by ordered subset linkage analysis (OSA)incorporating pack-years of cigarette smoking as a covariate, and by family- basedassociation analysis using a more homogeneous set of families as defined by OSA.

申请人：DUKE UNIVERSITY,VANDERBILT UNIVERSITY MEDICAL CENTER

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