Median C3d/C3 ratios for non-genetic factors.

<p>IQR  =  interquartile range (1^st quartile – 3^rd quartile).</p

Logarithmic C3d/C3 ratios for haplotypes in the <i>CFB</i> gene rs4151667 and rs641153.

<p>Logarithmic C3d/C3 ratios for haplotypes in the <i>CFB</i> gene rs4151667 and rs641153.</p

Median C3d/C3 ratios for single nucleotid polymorphisms (SNPs).

<p>*Due to small number of cases excluded from univariate ANOVA analysis; IQR  =  interquartile range (1^st quartile – 3^rd quartile).</p

Logarithmic C3d/C3 ratios for haplotypes in the <i>CFH</i> gene rs1061170, rs800292 and rs12144939.

<p>Logarithmic C3d/C3 ratios for haplotypes in the <i>CFH</i> gene rs1061170, rs800292 and rs12144939.</p

Haplotypes for <i>CFH/CFB</i> and median C3d/C3 ratios.

<p>For CFH single nucleotides polymorphisms rs1061170, rs800292, and rs12144939 and for CFB rs4151667 and rs641153 were chosen.</p><p>*T- test with comparison to reference haplotypes TGG and TG; **Due to small number of cases excluded from analysis; IQR  =  interquartile range (1^st quartile – 3^rd quartile).</p

Logistic regression analysis between AMD and single nucleotide polymorphisms SNPs⁺.

+<p>Adjusted for age and gender; *analysis not performed due to small group size.</p

Analysis of Rare Variants in the <i>C3</i> Gene in Patients with Age-Related Macular Degeneration

<div><p>Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15–65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (<i>C3</i>) gene have been associated with AMD and recently a rare <i>C3</i> variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the <i>C3</i> gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated <i>C3</i> mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (<i>P</i> = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2–136; <i>P</i> = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0–25; <i>P</i> = 0.05) at the <i>C3</i> locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.</p></div

Genotyping of <i>C3</i> variants in EUGENDA and Rotterdam samples.

<p>Major and minor allele indicated in capital and lower case respectively, MAF: Minor allele frequency, ND: OR could not be determined, NA: Not applicable.</p><p>EUGENDA: a multicenter database comprising participants from Germany and the Netherlands.</p

Rare variants in AMD studies.

<p>NL: The Netherlands, ISL: Iceland, GER: Germany, USA: United states of America, FRA: France.</p><p>NA: Not applicable.</p

Conditional analysis of Arg735Trp for SNPs Arg102Gly/rs2230199 and Pro314Leu/rs1047286.

<p>EUGENDA: a multicenter database comprising participants from the Cologne area, Germany and the Nijmegen area, the Netherlands.</p