TY - JOUR
T1 - Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration
AU - Schmidt, Silke
AU - Hauser, Michael A.
AU - Scott, William K.
AU - Postel, Eric A.
AU - Agarwal, Anita
AU - Gallins, Paul
AU - Wong, Frank
AU - Chen, Yu Sarah
AU - Spencer, Kylee
AU - Schnetz-Boutaud, Nathalie
AU - Haines, Jonathan L.
AU - Pericak-Vance, Margaret A.
N1 - Funding Information:
This study was supported by grants EY12118 (to M.A.P.-V. and J.L.H.) and EY015216 (to S.S.) from the National Eye Institute, National Institutes of Health (NIH), and by grant AG11268 from the National Institute on Aging, NIH (to Dr. Harvey Cohen). It was also supported in part by a General Clinical Research Center award (RR 00095) to Vanderbilt University. We express our appreciation to all the participants and their relatives who generously participated in the study. We thank Dr. Monica de la Paz, Jennifer Caldwell, Molly Klein, Ruth Domurath, Katie Haynes, Valerie Mitchell, Maureen Shaw, and Jason Galloway for participant ascertainment and data management. We also thank the following clinics and clinicians for referring individuals to the study: Southern Retina (Dr. Charles Harris), Vitreo-Retinal Surgeons (Dr. Michael E. Duan and Dr. Christopher J. Devine), Georgia Retina, and The Retina Group of Washington.
PY - 2006/5
Y1 - 2006/5
N2 - We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors-smoking and the Y402H variant of the complement factor H gene (CFH)-we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.
AB - We used iterative association mapping to identify a susceptibility gene for age-related macular degeneration (AMD) on chromosome 10q26, which is one of the most consistently implicated linkage regions for this disorder. We employed linkage analysis methods, followed by family-based and case-control association analyses, using two independent data sets. To identify statistically the most likely AMD-susceptibility allele, we used the Genotype-IBD Sharing Test (GIST) and conditional haplotype analysis. To incorporate the two most important known AMD risk factors-smoking and the Y402H variant of the complement factor H gene (CFH)-we used logistic regression modeling to test for gene-gene and gene-environment interactions in the case-control data set and used the ordered-subset analysis to account for genetic linkage heterogeneity in the family-based data set. Our results strongly implicate a coding change (Ala69Ser) in the LOC387715 gene as the second major identified AMD-susceptibility allele, confirming earlier suggestions. This variant's effect on AMD is statistically independent of CFH and is of similar magnitude to the effect of Y402H. The overall effect is driven primarily by a strong association in smokers, since we observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction is supported by statistically independent family-based and case-control analysis methods. We estimate that CFH, LOC387715, and cigarette smoking together explain 61% of the population-attributable risk (PAR) of AMD. The adjusted PAR percentage estimates are 20% for smoking, 36% for LOC387715, and 43% for CFH. We demonstrate, for the first time, that a genetic susceptibility coupled with a modifiable lifestyle factor such as cigarette smoking confers a significantly higher risk of AMD than either factor alone.
UR - http://www.scopus.com/inward/record.url?scp=33646070308&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646070308&partnerID=8YFLogxK
U2 - 10.1086/503822
DO - 10.1086/503822
M3 - Article
C2 - 16642439
AN - SCOPUS:33646070308
SN - 0002-9297
VL - 78
SP - 852
EP - 864
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -