The role of genetic markers and environmental factors in the development of AMD
MyVisionTest
more risk to the bilaterality of geographic atrophy, whereas the gene
for HTRA1/LOC387715 contributes more to the bilaterality of choroidal
neovascularization (CNV).
Because AMD is one of the most studied common eye diseases of the past
5 years, knowledge of its genetic basis has increased exponentially.
Genetic variants at 2 gene regions: complement factor H (CFH [OMIM
134370]) high-temperature requirement factor A-1 (HTRA1 [OMIM
602194])/LOC387715 confer major disease risks, together likely
accounting for approximately 40% to 60% of the genetic risks of AMD in
whites.
A number of other genetic variants, such as complement component 2 (C2
[OMIM 217000]), complement factor B (CFB [OMIM 138470]), and
complement component 3 (C3 [OMIM 120700]), have also been identified
to be strongly and consistently associated with AMD.
Of the environmental risk factors, age and smoking have most
consistently been identified as major risks.
IT REMAINS UNCLEAR TO WHAT EXTENT THESE RISK FACTORS AS A GROUP COULD
EXPLAIN THE OCCURRENCE OF AMD.
Early detection and risk prediction could potentially improve disease
prognosis and outcomes by allowing for gene-based treatment or
spurring patients to modify lifestyle habits. Joint effects of genetic
variants and environmental factors are implicated to have better
prediction of susceptibility to advanced AMD.
In this study, we used a combined data set consisting of cohorts from
Utah and the Age-Related Eye Disease Study (AREDS) to refine the
association of known genetic and environmental factors with advanced
AMD. Effects of potential gene-gene (GxG) and gene-environment (GxE)
interactions were also estimated. We aimed to develop an AMD risk
model to distinguish individuals who would be infected with advanced
AMD from those who would not.
Methods & Results
Demographic information, including age at onset, smoking status, and
body mass index, was collected for 1844 participants. Genotypes were
evaluated for 8 variants in 5 genes related to AMD. Unconditional
logistic regression analyses were performed to generate a risk
predictive model.
All genetic variants showed a strong association with AMD.
Multivariate odds ratios (95% confidence interval) were: 3.52
(2.08-5.94) for CFH rs1061170 CC 4.21 (2.30-7.70) for CFH rs2274700 CC
0.46 (0.27-0.80) for C2 rs9332739 CC/CG 0.44 (0.30-0.66) for CFB
rs641153 TT/CT 10.99 (6.04-19.97) for HTRA1/LOC387715 rs10490924 TT
2.66 (1.43-4.96) for C3 rs2230199 GG
Smoking was independently associated with advanced AMD after
controlling for age, sex, body mass index, and all genetic variants.
Discussion & Conclusions
We demonstrate a significant association between AMD and known genetic
polymorphisms of CFH, HTRA1/LOC387715, C2, CFB, and C3. The results of
allele frequencies and the ORs for each marker confirmed the findings
of previously published reports.
The risk allele of C3 rs2230199 was significantly higher in GA (32.4%)
than in CNV (26.4%) (P < 001) when adjusted for age and sex. This
result, for the first time to our knowledge, shows that C3 rs2230199
predisposes individuals to GA more than CNV. A similar trend was also
observed in an earlier study. The ways in which C3 contributes
differently to the pathogenesis of GA vs CNV require further
investigation.
Vision-related quality of life is strongly associated with visual
acuity and the presence of bilateral AMD. Bilateral AMD corresponds to
a more severe stage of the disease and is a sign of progression. It is
not surprising to find that all the risk alleles are more common in
the bilaterally affected group than in the unilaterally affected group
but only significantly for CFH rs2274700, CFH rs1410996,
HTRA1/LOC387715 rs10490924, and HTRA1/LOC387715 rs11200638.
Although not statistically significant, SNPs in CFH showed a tendency
to have a higher risk allele frequency in GA, whereas SNPs in
HTRA1/LOC387715 have higher allele frequencies in CNV. Overall,
neither CFH nor HTRA1/LOC387715 has been shown to be responsible for
directing AMD toward a specific late phenotype (GA or CNV). However,
both genes may play a role in increasing its severity once a late
phenotype develops. Our results show that CFH increases the severity
of GA, whereas HTRA1/LOC387715 heightens CNV. This is in agreement
with the findings from other authors that the HTRA1/LOC387715 gene is
more strongly related to the progression of CNV than to GA.
Our results showed that of the environmental risk factors, smoking and
age were identified as major risk factors, which was consistent with
the combined analysis of population-based eye studies from 3
continents. Smoking was confirmed as an independent risk factor for
AMD in this study. Patients have a 1.8-fold higher chance of
developing AMD if they ever smoked compared with those who never
smoked. The risk was elevated to 3.7-fold for current smokers. As
another risk factor, BMI showed a weak contribution to the occurrence
of AMD. Neither smoking nor BMI was found to have a significant
interaction with genotypes. Although a single study found an
interaction between smoking and HTRA1/LOC387715 rs10490924,
interaction between smoking and genotypes was eliminated when stepwise
logistic regression was performed, which was consistent with data from
multiple reports. However, an interaction is still a possibility
because logistic regression has only modest power for distinguishing
interactions.
In terms of interactions among genotypes, we found weak interactions
of CFH rs1061170CTHTRA1/LOC387715 rs10490924TT and CFH rs2274700CT
HTRA1/LOC387715 rs10490924TG. Because our model was not improved by
inclusion of these interactions, for the sake of simplicity, no
interaction term was included in our risk model. This result is
similar to that of a study in Finland in which a tentative interaction
between CFH and LOC387715 with a marginal P value (.06) was observed.
However, most studies have not found an interaction between these 2
genes. Our final model supported the notion that CFH and
HTRA1/LOC387715 act independently, and the log-linear additive model
fits well for the joint effects of these 2 genes.
We developed a risk model that predicts the individual’s risk for
AMD. Targeting high-risk individuals could lead to more frequent
surveillance and clinical interventions. Patients would benefit from
more targeted education regarding a healthy lifestyle. However, the
risk predictions resulting from this model are directly applicable
only to the population from which it was developed; we still need to
be careful when extending the results to other populations.
Sensitivities and specificities for a variety of risk factors were
evaluated to assess the optimal use of the model for individual risk
prediction. The sensitivity, specificity, and area under the ROC curve
established in this study were analogous to those reported by previous
studies. To improve the AMD prediction model, more genetic- or
environmental-influencing factors need to be clarified.
In summary, CFH confers more risk to the bilaterality of geographic
atrophy, whereas HTRA1/LOC387715 contributes more to the bilaterality
of choroidal neovascularization. Early detection and risk prediction
of AMD could help to improve the prognosis of AMD and to reduce the
outcome of blindness. Targeting high-risk individuals for surveillance
and clinical interventions may help reduce disease burden.
Arch Ophthalmol. 2011 Mar;129(3):344-51
http://www.ncbi.nlm.nih.gov/pubmed/21402993
======================
ABOVE IS A PLAIN TEXT REPRODUCTION OF A NEWS STORY THAT APPEARS ON
MYVISIONTEST.COM. ANY HYPERLINKS, IMAGES, TABLES, OR OTHER
ENHANCEMENTS HAVE BEEN REMOVED. TO VIEW THE ORIGINAL VISIT THE BELOW
LINK.
http://www.myvisiontest.com/newsarchive.php?id=1363