Haptoglobin genotype and aneurysmal subarachnoid hemorrhage

Abstract

ObjectiveTo perform an individual patient-level data (IPLD) analysis and to determine the relationship between haptoglobin (HP) genotype and outcomes after aneurysmal subarachnoid hemorrhage (aSAH). MethodsThe primary outcome was favorable outcome on the modified Rankin Scale or Glasgow Outcome Scale up to 12 months after ictus. The secondary outcomes were occurrence of delayed ischemic neurologic deficit, radiologic infarction, angiographic vasospasm, and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons (WFNS) scale, Fisher grade, age, and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As preplanned, a 2-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) 1-stage analysis; (7) exclusion of studies not in Hardy-Weinberg equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; and (10) including only covariates significant in univariate analysis. ResultsEleven studies (5 published, 6 unpublished) totaling 939 patients were included. Overall, the study population was in HWE. Follow-up times were 1, 3, and 6 months for 355, 516, and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis, higher age and WFNS scale were associated with an unfavorable outcome as expected. ConclusionThis comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH. RELATED ARTICLE EditorialHaptoglobin and hemoglobin in subarachnoid hemorrhage: A tale of 2 globins Glossary aSAH = aneurysmal subarachnoid hemorrhage; CI = confidence interval; DCI = delayed cerebral ischemia; GOS = Glasgow Outcome Scale; Hb = hemoglobin; Hp = haptoglobin; HP = haptoglobin gene; HWE = Hardy-Weinberg equilibrium; IPLD = individual patient-level data; mRS = modified Rankin Scale; OR = odds ratio; PRISMA-IPD = Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Individual Participant Data; SAH = subarachnoid hemorrhage; TCD = transcranial Doppler; WFNS = World Federation of Neurological Surgeons.Abbreviations: CI = confidence interval; HP = haptoglobin; IPLD = individual patient-level data; OR = odds ratio; TCD = transcranial Doppler. An OR >1 denotes a higher probability of poor outcome.

Haptoglobin genotype predicts severe acute vaso‐occlusive pain episodes in children with sickle cell anemia

“…Individuals with the HP2‐2 genotype have been found to have increased risk for diabetic cardiovascular and renal disease, cognitive decline among those with type 2 diabetes, delayed brain injury after subarachnoid hemorrhage, and development of ARDS in sepsis . Other studies have shown no apparent association between risk for iron accumulation in hereditary hemochromatosis, cardiovascular risks in individuals with elevated HbA1C, or outcomes after subarachnoid hemorrhage . To our knowledge, this is the first study to examine how variations in the haptoglobin genotype may contribute to morbidity in children with SCA.…”

“…The HP2‐2 protein also has a lower circulating concentration and poorer protection against oxidative damage from cell‐free hemoglobin in vitro . The role of HP genotype and its relation to disease severity has been studied in multiple disease states such as epilepsy, cardiovascular disease, hypercholesteremia, diabetes, hemochromatosis, and sub‐arachnoid hemorrhage, with variable results. However, there is little data investigating the role of these genotypes in SCA.…”

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

“…Haptoglobin 2-2 and haptoglobin 2-1 are heterogeneous mixtures of larger polymers. Earlier hypotheses that outcomes of aSAH depended on haptoglobin phenotypes have been refuted (78), and our own studies could not reveal significant biochemical or physiological differences between the binding and detoxifying effects of haptoglobin 1-1 and haptoglobin 2-2 in vitro or in the systemic circulation of guinea pigs (79). In this study, we used a plasma-derived haptoglobin product, which is almost exclusively composed of larger haptoglobin polymers (haptoglobin 2-2 and haptoglobin 2-1).…”

Haptoglobin genotype and outcome after aneurysmal subarachnoid haemorrhage

“…This is the largest study of HP genotype and outcome after SAH and provides a number of novel insights. The HP allele does not associate with outcome after aSAH if this is measured early after aSAH, within the first year 9. We argue that the HP influence on outcome is overshadowed by the effect of early brain injury on outcome in the first year after aSAH, that is, it takes longer than previously thought for early brain injury effect to settle.…”

“…In several small studies, the HP CNV was variably associated with short-term to medium-term outcome after aSAH,3 5–8 but an individual patient level data analysis did not confirm this 9. An important consideration is that these studies looked at outcome mostly within the first 6 months after aSAH, and this may not be early enough to allow early brain injury events other than Hb, to settle.…”