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Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Summary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI‐1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi‐trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9obtained after applying Bonferroni correction for the number of multi‐trait combinations performed (n= 27). Across the 27 multi‐trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

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Both mechanistic target of rapamycin (mTOR) pathway and aldosterone are implicated in the development of cardiovascular and renal disease. However, the interaction between aldosterone and the mTOR pathway is unknown. We hypothesized the following: that (i) increased aldosterone will modulate the activity of the mTORC1 and mTORC2 molecular pathways in the heart and kidney; (ii) a physiologic increase in aldosterone will affect these pathways differently than a pathophysiologic one; and (iii) the changes in the mTOR level/activity will differ between the heart and kidney. In both kidney and heart tissues, phosphorylation of mTOR is significantly decreased when aldosterone levels are physiologically increased (by dietary sodium restriction), followed by a decrease in phosphorylated p70S6K1 in cardiac, but not renal, tissue. Sirtuin 1, an epigenetic modulator, is decreased in the heart but increased in the kidney. Conversely, pathophysiologic aldosterone levels (an infusion for 3 weeks) had divergent effects on phosphorylated mTOR and the downstream substrates of mTORC1 and mTORC2 in cardiac and renal tissues. Increased aldosterone levels significantly alter mTOR activity in the heart and kidney. In the kidney, substantial differences were noted if the increase was produced physiologically vs pathophysiologically, suggesting that mTOR activity, in part, may mediate aldosterone-induced renal damage. Thus, modulating mTOR activity may reduce aldosterone-dependent renal damage similar to mineralocorticoid receptor blockade but potentially with less adverse side effects.

Background and Purpose Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations.Methods Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters.Results We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: −0.88 mm and −1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average.Conclusion Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Introduction:Perivascular spaces visible on brain MRI (PVS) are considered cerebral small vessel disease (CSVD) markers, possibly reflecting impaired brain fluid and metabolite clearance, and could contribute to depression in old age. This study aims to determine the association of PVS with prevalent and incident depression in the community-based Framingham Heart Study (FHS).Methods:FHS participants free of stroke and dementia with available Center for Epidemiological Studies Depression (CES-D) scale and PVS ratings in the basal ganglia (BG) and centrum semiovale (CSO) were included. Depression was defined as CES-D score≥16 or use of antidepressants. PVS were rated on a scale from I-IV in the BG and CSO using a validated method, with grades III-IV representing high PVS burden. A mixed score was created to describe high burden in the BG and/or CSO (0=no high ePVS burden, 1=high burden in the BG, 2=high burden in the CSO, 3=high burden in both regions). Logistic regression analysis was used to assess the association between PVS in the CSO, BG, and mixed regions and prevalent and incident depression. Models adjusted for age, sex, FSH cohort, time interval between CES-D score and MRI measurements, body mass index, smoking status, prevalent hypertension and diabetes.Results:Among 3815 participants included (mean age 57±14, male 47%), incident depression was observed in 19% over the follow up period ranging from 8 to 15 years subsequent to PVS rating. In multivariable adjusted analyses, high burden PVS in the CSO was associated with incident depression (OR 1.75 [1.18, 2.60], p=0.005). In the mixed score, concurrent high burden PVS in both regions (OR 2.10 [1.13, 3.91], p=0.02) and high burden in the CSO only (OR 1.65 [1.05, 2.58], p=0.03) were associated with incident depression. PVS were not associated with prevalent depression.Conclusion:In conclusion, high PVS burden was associated with incident depression in a community-based sample free of stroke and dementia. The association was predominantly driven by high burden of CSO PVS, suggesting that lobar forms of CSVD may play role in late life depression, possibly reflecting disrupted neuroanatomic circuits involved in mood control, and differing from BG PVS.

Objectives:Brain arterial dilation is an increasingly recognized cerebrovascular disease marker. However, demographic and anatomical factors may influence brain arterial diameters within the normal spectrum. We hypothesize that age, sex, height, total cranial volume (TCV) and fetal posterior cerebral arteries (fPCA) presence correlate with brain arterial diameters across diverse populations.Methods:We included participants with available time-of-flight MRA from 9 cohort studies across the United States (4), Ecuador (1), Venezuela (1), South Africa (1) and Singapore (2). Arterial diameters of the basilar artery (BA), cavernous internal carotid arteries (ICAs) and middle cerebral arteries (MCAs) were measured using LKEB Automated Vessel Analysis (LAVA) software. Linear regression models were fitted to assess the association between brain arterial diameters and exposures. The R-squared was calculated to assess the extent of brain arterial diameter variation explained by the variables studied.Results:The sample included 6,269 participants (mean age 68 years; 42% men). Unilateral fPCA was found in 12.6% and bilateral fPCAs in 3.0%. Older age, male sex and TCV were uniformly correlated with larger BA, ICA and MCA diameters (Table). Unilateral and bilateral fPCAs showed a negative correlation with BA diameter and a positive correlation with ICA diameters in a dose-dependent manner. Models fitted for age, sex, TCV, and fPCA presence explained on average 24, 16 and 12 % of the BA, ICAs and MCA diameter interindividual variation, respectively. Using height instead of TCV decreased the R-squared by 2% on average.Conclusions:In this pooled analysis of cohort studies, we found brain arterial diameters consistently correlate with age, sex, TCV and fPCA presence. These factors should be considered to define abnormal arterial diameter cut-offs across populations. If resources are limited or if bedside applicability is desired, height could be used instead of TCV.

Aldosterone's functions and mechanisms of action are different depending on the tissue and the environmental condition. The mineralocorticoid receptor is present in tissues beyond epithelial cells, including the heart and vessels. Furthermore, aldosterone has direct adverse effects by both genomic and rapidnongenomic actions not only through a nuclear receptor but also through caveolae-mediated intracellular events. Also, multiple environmental–genetic interactions play an important role in salt-sensitive hypertension (SSH) and aldosterone modulation. These findings have reshaped our vision of aldosterone's role in cardiovascular pathophysiology. This review describes new mediators of aldosterone's mechanisms of action: lysine-specific demethylase 1 (LSD1), caveolin 1 (cav-1) and striatin.

This study reports the synthesis and characterization of a new ruthenium complex that acts as a molecular catalyst for organic compounds oxidation. The cis-[Ru(BAP)(bpy)(PPh3)(OH2)](ClO4)2 complex, a precursor monomer, was analyzed by UV-Vis and FTIR spectroscopy and used to build new modified electrodes, using carbon rod and carbon felt as substrates. The characterization of these modified electrode surfaces was realized by cyclic voltammetry and the catalytic activity of the films immobilized on the surfaces was tested for the selective oxidation of several organic substrates by heterogeneous electrolysis. The kinetic parameters and yield were better than those obtained by homogeneous catalysis using similar ruthenium complexes. The results allowed to demonstrate the formation of a polymeric film from the ruthenium complex, as well as, to establish the mechanisms for the selective oxidation of the organic species tested.

ABSTRACTNucleic acid amplification tests (NAATs) for enterovirus RNA in cerebrospinal fluid (CSF) have emerged as the new gold standard for diagnosis of enteroviral meningitis, and their use can improve the management and decrease the costs for caring for children with enteroviral meningitis. The Xpert EV assay (Cepheid, Sunnyvale, CA) is a rapid, fully automated real-time PCR test for the detection of enterovirus RNA that was approved by the U.S. Food and Drug Administration for in vitrodiagnostic use in March 2007. In this multicenter trial we established the clinical performance characteristics of the Xpert EV assay in patients presenting with meningitis symptoms relative to clinical truth. Clinical truth for enteroviral meningitis was defined as clinical evidence of meningitis, the absence of another detectable pathogen in CSF, and detection of enterovirus in CSF either by two reference NAATs or by viral culture. A total of 199 prospectively and 235 retrospectively collected specimens were eligible for inclusion in this study. The overall prevalence of enteroviral meningitis was 26.04%. The Xpert EV assay had a sensitivity of 94.69% (90% confidence interval [CI] = 89.79 to 97.66%), specificity of 100% (90% CI = 99.07 to 100%), positive predictive value of 100%, negative predictive value of 98.17, and an accuracy of 98.62% relative to clinical truth. The Xpert EV assay demonstrated a high degree of accuracy for diagnosis of enteroviral meningitis. The simplicity and on-demand capability of the Xpert EV assay should prove to be a valuable adjunct to the evaluation of suspected meningitis cases.

White matter hyperintensities and MRI-defined brain infarcts (BIs) have individually been related to stroke, dementia, and mortality in population-based studies, mainly in older people. Their significance in middle-aged community-dwelling persons and the relative importance of these associations remain unclear. We simultaneously assessed the relation of white matter hyperintensities and BI with incident stroke, mild cognitive impairment, dementia, and mortality in a middle-aged community-based cohort.

Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Recent findings of an association between polymorphisms of advanced glycosylation end product–specific receptor (AGER) and risk of diabetic vasculopathy have generated great interest. However, to date, no genetic–epidemiological data are available on risk of atherothrombotic events among nondiabetic populations.

Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3- and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3- are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+γ, replacement of isotonic Cl- media by hypotonic Cl- resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+γ, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.

Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3-and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3-are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+γ, replacement of isotonic Cl-media by hypotonic Cl-resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+γ, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.

In 1998the Food and Drug Administration approved palivizumab (Synagis) for the prevention of severe lower respiratory tract infection secondary to respiratory syncytial virus (RSV) in pediatric patients at high risk for developing disease that required hospitalization.

ABSTRACTThe enterovirus 5' nontranslated region (NTR) contains an internal ribosome entry site (IRES), which facilitates translation initiation of the viral open reading frame in a 5' (m7GpppN) cap-independent manner, and cis-acting signals for positive-strand RNA replication. For several enteroviruses, the 5' NTR has been shown to determine the virulence phenotype. We have constructed a chimera consisting of the putative IRES element from the Travis strain of echovirus 12 (ECV12), a wild-type, relatively nonvirulent human enterovirus, exchanged with the homologous region of a full-length infectious clone of coxsackievirus B3 (CBV3). The resulting chimera, known as ECV12(5'NTR)CBV3, replicates similarly to CBV3 in human and simian cell lines yet, unlike CBV3, is completely restricted for growth on two primary murine cell lines at 37°C. By utilizing a reverse-genetics approach, the growth restriction phenotype was localized to the predicted stem-loop II within the IRES of ECV12. In addition, a revertant of ECV12(5'NTR)CBV3 was isolated which possessed three transition mutations and had restored capability for replication in the utilized murine cell lines. Assays for cardiovirulence indicated that the ECV12 IRES is responsible for a noncardiovirulent phenotype in a murine model for acute myocarditis. The results indicate that the 5' NTRs of ECV12 and CBV3 exhibit variable intracellular requirements for function and serve as secondary determinants of tissue or species tropism.

Coxsackievirus B3 (CVB3) infections can cause myocarditis in humans and are implicated in the pathogenesis of dilated cardiomyopathy. The natural genetic determinants of cardiovirulence for CVB3 have not been identified, although using strains engineered in the laboratory, cardiovirulence determinants have been identified in the CVB3 5' nontranslated region (5'NTR) and capsid. The myocarditic phenotypes of two CVB3 clinical isolates were determined using an established murine model of inflammatory heart disease. The 5'NTRs and capsid proteins of the noncardiovirulent CVB3/CO strain and cardiovirulent CVB3/AS strain were examined to determine their influence on the cardiovirulence phenotype. Six intratypic chimeric viruses were constructed in which 5'NTR and capsid sequences of the infectious cDNA copy of the cardiovirulent CVB3/20 genome were replaced by homologous sequences from CVB3/CO or CVB3/AS. Chimeric strains were tested for cardiovirulence by inoculation of C3H/HeJ mice. Sections of hearts removed at 10 days postinoculation were examined for evidence of myocarditis by light microscopy and assayed for the presence of virus. Replacement of the CVB3/20 capsid coding region by that from the homologous region of CVB3/CO resulted in no change in the cardiovirulent CVB3/20 phenotype, with virus recoverable from the heart at 10 days postinoculation. However, recombinant virus containing the CVB3/CO 5'NTR alone or the 5'NTR and capsid sequences together were not myocarditic, and infectious virus was not recovered from the myocardium. Chimeric viruses containing the CVB3/AS 5'NTR alone, capsid sequence alone, or both together preserved the myocarditic phenotype. These data support the 5'NTR as the primary site in the determination of the natural cardiovirulence phenotype of CVB3.

Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and fibrotic disorders; however, little is known about its role in fibrogenesis. We examined human embryonic lung fibroblasts that constitutively express the B1 receptor and report that engagement of the B1 receptor by des-Arg10-kallidin stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in α1(I) collagen mRNA, and stimulated type I collagen production. These events were not observed in B2 receptor-activated fibroblasts. In addition, B1 receptor activation by des-Arg10-kallidin induced a rise in cytosolic Ca2+that is consistent with B1 receptor pharmacology. Our results show that the des-Arg10-kallidin-stimulated increase in α1(I) collagen mRNA was time- and dose-dependent, with a peak response observed at 20 h with 100 nmdes-Arg10-kallidin. The increase in CTGF mRNA was also time- and dose-dependent, with a peak response observed at 4 h with 100 nmdes-Arg10-kallidin. The increase in CTGF mRNA was blocked by the B1 receptor antagonist des-Arg10,Leu9-kallidin. Inhibition of protein synthesis by cycloheximide did not block the des-Arg10-kallidin-induced increase in CTGF mRNA. These results suggest that engagement of the kinin B1 receptor contributes to fibrogenesis through increased expression of CTGF.

Introduction:Larger brain arterial diameters, which may be a consequence of connective tissue disorders or hypertension, are associated with mortality, cognitive decline and risk of dementia. Whether there may be genetic determinants of large brain arterial diameters is unknown, but identifying such traits may shed light into possible mechanistic links between large brain arterial diameters and the observed outcomes.Methods:We studied 3654 participants from four ethnically diverse population-based cohorts: The Atherosclerosis Risk in Communities study (n=1565: 74.3% white, 25.7% black), The Northern Manhattan Study (n=1092: 13.8% white, 16.6% black, 69.6% Hispanic), Epidemiology of Dementia in Singapore (n=647: 31.7% Chinese, 35.7% Malay, 32.6% Indian), and Memory Clinic Cohort in Singapore (n=350: 84.9% Chinese, 7.8% Malay, 7.3% Indian). We measured brain arterial diameters for 13 segments and normalized the averaged diameter per participant to obtain global brain arterial diameter as dependent variable. Genome-wide association studies (GWAS) was performed in each study using linear regression, adjusted for sex, age, head size, number of missing arteries and population substructure. Meta-analysis of association statistics was performed using the METAL to generate combined trait-specific effect estimates. We also performed trans-ethnic meta-regression by MR-MEGA to account for the heterogeneity in allelic effect that is correlated with ancestry.Results:Genome-wide significant (P<5x10-8) associations were observed for global brain arterial diameter with three SNPs: rs7921574(P=1.2x10-8) mapping to an intron of CNNM2; rs2075858(P=2.47x10-8) and rs2075857 (P=2.37x10-8) mapping to introns of MUC5B. MR-MEGA analysis showed suggestive evidence of association (P=5.05x10-8) for rs7921574. These loci comprise genes involved in response to magnesium transport, neuronal transmission, hypertension, mucociliary clearance and host defense.Conclusion:Our study reveals two novel risk loci for large brain arterial diameters. We have begun to replicate these associations and to identify functional causal variants in independent studies. Identifying these loci may help us to elucidate underlying disease mechanisms.

Introduction:Time-limited dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has emerged as an important treatment modality for secondary stroke prevention in patients with symptomatic intracranial atherosclerotic disease, minor stroke, or high-risk transient ischemic attack. However, continuation beyond the indicated treatment period may expose patients to bleeding risk without additional benefit.Methods:We conducted a retrospective study of a prospectively maintained registry (the Get-With-The-Guidelines database at our hospital) evaluating patients discharged on time-limited DAPT for secondary stroke prevention between January 1st, 2019 and July 31st, 2020. Intended and actual duration of therapy were extracted from clinical notes and prescription records. We assessed the frequency of inappropriate continuation within the entire cohort and performed univariate analyses to assess for differences in outcome with respect to clinical and demographic characteristics, including social determinants of health (such as race and primary spoken language).Results:Of the 127 patients included, 17 (13%) had inappropriately prolonged treatment with DAPT. Black patients had a significantly higher incidence of inappropriate continuation than non-Black patients and individuals speaking languages other than English or Spanish exhibited a trend toward more frequent occurrence. Patients intended to transition to monotherapy with clopidogrel and those initially presenting with stroke (rather than transient ischemic attack) had similar trends toward more frequent occurrence.Conclusions:Our study represents the first attempt to approximate the incidence of inappropriate prolongation of time-limited DAPT for secondary stroke prevention at a hospital caring for a large underserved population. Our results suggest that social determinants of health may contribute to this phenomenon, but further studies are required to replicate our observations in larger multicenter cohorts. Systems-based interventions should be aimed at ensuring proper duration of therapy to minimize bleeding risk and other side effects.

We have previously demonstrated that young normal (AA) and sickle cell anemia (SS) red blood cells are capable of a volume regulatory decrease response (VRD) driven by a K:CI cotransporter that is activated by low pH or hypotonic conditions. We now report on the characteristics of young SS cells (SS2, discocytes) capable of rapid increase in density in response to swelling. We have isolated cells with high VRD response (H-VRD) and low VRD response (L-VRD) cells by incubation and density-gradient centrifugation under hypotonic conditions. Comparison of these cells in patients homozygous for hemoglobin (Hb)S indicated that H-VRD cells have 91% more reticulocytes (P ≪ 9 × 10-9) than L-VRD cells, 25% less HbF (P ≪ 5.5 × 105), 106% more NEM (N-methylmaleimide)-stimulated K:CI cotransport activity (P <2 × 104), and 86% more volume-stimulated K:CI cotransport activity (P ≪ 1.8 × 10-3). H-VRD and L-VRD cells have similar G-6-PD and Na7H+antiport activity. In agreement with the reduced percent HbF in H-VRD cells, F cells (red blood cells that contain fetal Hb) are depleted from the H-VRD population; however, F reticulocytes are enriched in the H-VRD population to the same extent as non-F reticulocytes, which suggests that both F and non-F reticulocytes have a similar initial distribution of volume-sensitive K:CI cotransport activity but that it may be more rapidly inactivated in F than in S reticulocytes. We find that H-VRD cells consist of 20% reticulocytes (or 79% of all reticulocytes in SS2) and 80% more mature cells. This study demonstrates the role of K:CI cotransport in determining red blood cell density, the heterogeneity of K:CI cotransport activity in reticulocytes, and the capacity for rapid change in the density of reticulocytes with high K:CI cotransport activity. We speculate that the H-VRD population may be more susceptible to generation of dense and irreversibly sickled cells. © 1991 by The American Society of Hematology.

Hemoglobin (Hb) S-Oman has two mutations in the ß-chains. In addition to the classic ßS mutation (ß6 Glu ? Val), it contains a second mutation in the same chain (ß121 Glu ? Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant -?/?? thalassemia and those with about 14% of HbS-Oman and concomitant -?/-? thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a “yarn and knitting needle” shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT’s, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos’ channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide–stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the ß6 Val mutation which are enhanced by the second mutation at ß121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at ß121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.