Hemopexin Levels Lack Association with Genetic Variants in Patients with AMD

Professor Anneke den Hollander

Credit: The Academy of Europe

A recent analysis of hemopexin (HPX) levels in patients with age-related macular degeneration (AMD) suggested no association between HPX levels and AMD or AMD-associated genetic variants at the complement factor H (CFH) locus.¹

The investigative team, led by Professor Anneke den Hollander, from the department of ophthalmology at Radboud University Medical Center, indicated the findings did not confirm the strong associations between HPX levels and genetic variants reported in a previous protein quantitative trait locus (pQTL) study.

“We then tested whether we could confirm the associations of rs61818956, rs10494745, and rs10801582 with the HPX levels identified in the pQTL study by Suhre et al. 2016²,” investigators wrote.¹ “This was not the case, as we did not observe significant differences in HPX levels between any of the genotype groups investigators wrote.”

In previous literature, 4 AMD-associated variants at the CFH locus (rs10922109, rs570619, rs187328863, and rs61818925) have been shown to be associated with altered factor H related (FHR) 4 levels in the blood, suggesting alterations in factor H and FHR protein levels could affect the pathogenesis of AMD. Other identified variants at the CHF locus (rs61818956, rs10494745, and rs10801582) were found to be strongly associated with HPX levels in a large pQTL analysis, with the 3 variants accounting for 61% of variance in HPX levels.²

For this analysis, Hollander and colleagues compared HPX levels in plasma samples from patients with AMD and plasma samples from controls using enzyme-linked immunosorbent assay. They further investigated the genotypes of the HPX- and AMD-associated variants at the CFH locus in all subjects, to elucidate the association with plasma HPX levels. Overall, a total of 200 patients with advanced AMD and 200 controls were identified from the European Genetic Database (EUGENDA).

After selecting the samples, investigators analyzed the HPX levels per genotype group of the HPX-associated genetic variants (rs61818956, rs10494745, and rs10801582), as well as the 4 AMD-associated variants at the CFH locus (rs794362 [proxy for rs187328863], rs570618, rs10922109, and rs61818924 [proxy for rs61818925]).

Upon analysis, investigators found associations between HPX levels and sex (P = .001), BMI (P = .003), and smoking (P = .012). However, in a multivariate analysis correcting for age, sex, BMI, and smoking, investigators found no significant differences in HPX levels between the AMD and control groups.

Hollander and colleagues tested if their data could confirm the associations of rs61818956, rs10494745, and rs10801582 with HPX levels identified in a previously identified pQTL study. Upon analysis, the team found no significant differences in HPX levels between any of the genotype groups.

Moreover, the analysis investigated the genotypes of the AMD-associated variants at the CFH locus. For the 4 common variants (rs794362, rs570618, rs10922109, and rs61818924), investigators assessed the association of genotypes of the variants with HPX levels, finding no significant association between any variant and the HPX level.

Hollander and colleagues indicated interest in analyzing causation in future analyses, noting only associations between HPX levels and variants in the CFH locus and between HPX and FHR4 levels are known.

“Furthermore, on the basis of this study, we cannot exclude the possibility that HPX protein levels might be differently regulated locally in patients with AMD compared with controls, which might not be reflected in the blood,” investigators wrote.

References

1. Lauwen S, Bakker B, de Jong EK, et al. Analysis of hemopexin plasma levels in patients with age-related macular degeneration. Mol Vis. 2022;28:536-543. Published 2022 Dec 31.
2. Suhre K, Arnold M, Bhagwat AM, Cotton RJ, Engelke R, Raffler J, Sarwath H, Thareja G, Wahl A, DeLisle RK, Gold L, Pezer M, Lauc G, El-Din Selim MA, Mook-Kanamori DO, Al-Dous EK, Mohamoud YA, Malek J, Strauch K, Grallert H, Peters A, Kastenmüller G, Gieger C, Graumann J. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun 2017; 8:14357- [PMID: 28240269].