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Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).

Grassmann F, Cantsilieris S, Schulz-Kuhnt AS, White SJ, Richardson AJ, Hewitt AW, Vote BJ, Schmied D, Guymer RH, Weber BH, Baird PN - J Neuroinflammation (2016)

Bottom Line: We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10(-5)), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)).Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany.

ABSTRACT

Background: Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.

Methods: We used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models.

Results: Here, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10(-5)), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.

Conclusions: Our data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.

No MeSH data available.


Related in: MedlinePlus

Association analysis of multiallelic complement C4A (a), C4B (b), and total C4 (c) copy numbers in AMD. Multivariate logistic regression models, adjusted for age and gender, were fitted for C4A, C4B, and total C4 copy number in each study. Log odds ratios and standard errors obtained from each study were combined and a meta-analysis performed assuming a random effects model. The combined estimates for the odds ratios and 95 % confidence intervals (CI) were computed from the random effects model. For C4B CNV, there was statistically significant evidence for heterogeneity of the effect sizes between the studies (Pheterogeneity < 0.05)
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Fig2: Association analysis of multiallelic complement C4A (a), C4B (b), and total C4 (c) copy numbers in AMD. Multivariate logistic regression models, adjusted for age and gender, were fitted for C4A, C4B, and total C4 copy number in each study. Log odds ratios and standard errors obtained from each study were combined and a meta-analysis performed assuming a random effects model. The combined estimates for the odds ratios and 95 % confidence intervals (CI) were computed from the random effects model. For C4B CNV, there was statistically significant evidence for heterogeneity of the effect sizes between the studies (Pheterogeneity < 0.05)

Mentions: Logistic regression models adjusted for age and gender were computed for each study separately, and meta-analyses of effect sizes and standard errors were subsequently conducted assuming a random effects model (Fig. 2). While there was no statistically significant association for multiallelic CNVs at C4B or total C4 with AMD (P > 0.05), we identified a statistically significant association ofC4Acopy number with AMD risk in each study (Puncorrected < 0.05, Fig. 2). In the combined study and after correcting for multiple testing, there was a highly significant association of C4A copy number with AMD (P = 4.4 × 10−5,Pcorrected = 1.3 × 10−4, Fig. 2). We observed odds ratios (ORs) lower than one per C4A copy, indicating a protective effect for each additional C4A copy (OR 0.81 (0.73; 0.89)). In a sensitivity analysis, C4A copy numbers from each independent study were pooled and analyzed jointly. An unadjusted model was fitted for C4A association (Additional file 5: Table S4) identifying statistical significance with AMD in the pooled study (OR 0.83 (0.76; 0.92)). We also computed a logistic regression model adjusted jointly for age, gender, and study and found ORs similar to the unadjusted model (OR 0.82 (0.74; 0.90)) (Additional file 5: Table S4).Fig. 2


Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD).

Grassmann F, Cantsilieris S, Schulz-Kuhnt AS, White SJ, Richardson AJ, Hewitt AW, Vote BJ, Schmied D, Guymer RH, Weber BH, Baird PN - J Neuroinflammation (2016)

Association analysis of multiallelic complement C4A (a), C4B (b), and total C4 (c) copy numbers in AMD. Multivariate logistic regression models, adjusted for age and gender, were fitted for C4A, C4B, and total C4 copy number in each study. Log odds ratios and standard errors obtained from each study were combined and a meta-analysis performed assuming a random effects model. The combined estimates for the odds ratios and 95 % confidence intervals (CI) were computed from the random effects model. For C4B CNV, there was statistically significant evidence for heterogeneity of the effect sizes between the studies (Pheterogeneity < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835888&req=5

Fig2: Association analysis of multiallelic complement C4A (a), C4B (b), and total C4 (c) copy numbers in AMD. Multivariate logistic regression models, adjusted for age and gender, were fitted for C4A, C4B, and total C4 copy number in each study. Log odds ratios and standard errors obtained from each study were combined and a meta-analysis performed assuming a random effects model. The combined estimates for the odds ratios and 95 % confidence intervals (CI) were computed from the random effects model. For C4B CNV, there was statistically significant evidence for heterogeneity of the effect sizes between the studies (Pheterogeneity < 0.05)
Mentions: Logistic regression models adjusted for age and gender were computed for each study separately, and meta-analyses of effect sizes and standard errors were subsequently conducted assuming a random effects model (Fig. 2). While there was no statistically significant association for multiallelic CNVs at C4B or total C4 with AMD (P > 0.05), we identified a statistically significant association ofC4Acopy number with AMD risk in each study (Puncorrected < 0.05, Fig. 2). In the combined study and after correcting for multiple testing, there was a highly significant association of C4A copy number with AMD (P = 4.4 × 10−5,Pcorrected = 1.3 × 10−4, Fig. 2). We observed odds ratios (ORs) lower than one per C4A copy, indicating a protective effect for each additional C4A copy (OR 0.81 (0.73; 0.89)). In a sensitivity analysis, C4A copy numbers from each independent study were pooled and analyzed jointly. An unadjusted model was fitted for C4A association (Additional file 5: Table S4) identifying statistical significance with AMD in the pooled study (OR 0.83 (0.76; 0.92)). We also computed a logistic regression model adjusted jointly for age, gender, and study and found ORs similar to the unadjusted model (OR 0.82 (0.74; 0.90)) (Additional file 5: Table S4).Fig. 2

Bottom Line: We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10(-5)), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)).Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, 93053, Germany.

ABSTRACT

Background: Age-related macular degeneration (AMD) is the leading cause of vision loss in Western societies with a strong genetic component. Candidate gene studies as well as genome-wide association studies strongly implicated genetic variations in complement genes to be involved in disease risk. So far, no association of AMD with complement component 4 (C4) was reported probably due to the complex nature of the C4 locus on chromosome 6.

Methods: We used multiplex ligation-dependent probe amplification (MLPA) to determine the copy number of the C4 gene as well as of both relevant isoforms, C4A and C4B, and assessed their association with AMD using logistic regression models.

Results: Here, we report on the analysis of 2645 individuals (1536 probands and 1109 unaffected controls), across three different centers, for multiallelic copy number variation (CNV) at the C4 locus. We find strong statistical significance for association of increased copy number of C4A (OR 0.81 (0.73; 0.89);P = 4.4 × 10(-5)), with the effect most pronounced in individuals over 78 years (OR 0.67 (0.55; 0.81)) and females (OR 0.77 (0.68; 0.87)). Furthermore, this association is independent of known AMD-associated risk variants in the nearby CFB/C2 locus, particularly in females and in individuals over 78 years.

Conclusions: Our data strengthen the notion that complement dysregulation plays a crucial role in AMD etiology, an important finding for early intervention strategies and future therapeutics. In addition, for the first time, we provide evidence that multiallelic CNVs are associated with AMD pathology.

No MeSH data available.


Related in: MedlinePlus