Individuals Of African Descent Research Articles

NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Review: Genetic research on alcohol use outcomes in African American populations: A review of the literature, associated challenges, and implications.

There have been remarkable advances in understanding genetic influences on complex traits; however, individuals of African descent have been underrepresented in genetic research. We review the limitations of existing genetic research on alcohol phenotypes in African Americans (AA) including both twin and gene identification studies, possible reasons for underrepresentation of AAs in genetic research, the implications of the lack of racially diverse samples, and special considerations regarding conducting genetic research in AA populations. There is a marked absence of large-scale AA twin studies so little is known about the genetic epidemiology of alcohol use and problems among AAs. Individuals of African descent have also been underrepresented in gene identification efforts; however, there have been recent efforts to enhance representation. It remains unknown the extent to which genetic variants associated with alcohol use outcomes in individuals of European and African descent will be shared. Efforts to increase representation must be accompanied by careful attention to the ethical, legal, and social implications of genetic research. This is particularly true for AAs due to the history of abuse by the biomedical community and the persistent racial discrimination targeting this population. Lack of representation in genetic studies limits our understanding of the etiological factors that contribute to substance use and psychiatric outcomes in populations of African descent and has the potential to further perpetuate health disparities. Involving individuals of diverse ancestry in discussions about genetic research will be critical to ensure that all populations benefit equally from genetic advances. (Am J Addict 2017;26:486-493).

A functionally significant SNP in TP53 and breast cancer risk in African-American women

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08–2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

Sickle Cell Trait and Renal Function in Hispanics in the United States: The Northern Manhattan Study.

Sickle cell anemia (SCA) is a common hematological disorder among individuals of African descent in the United States; the disorder results in the production of abnormal hemoglobin. It is caused by homozygosity for a genetic mutation in HBB; rs334. While the presence of a single mutation (sickle cell trait, SCT) has long been considered a benign trait, recent research suggests that SCT is associated with renal dysfunction, including a decrease in estimated glomerular filtration rate (eGFR) and increased risk of chronic kidney disease (CKD) in African Americans. It is currently unknown whether similar associations are observed in Hispanics. Therefore, our study aimed to determine if SCT is associated with mean eGFR and CKD in a sample of 340 Dominican Hispanics from the Northern Manhattan Study. Using regression analyses, we tested rs334 for association with eGFR and CKD, adjusting for age and sex. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and CKD was defined as eGFR < 60 mL/min/1.73 m2. Within our sample, there were 16 individuals with SCT (SCT carriers). We found that SCT carriers had a mean eGFR that was 12.12 mL/min/1.73m2 lower than non-carriers (P=.002). Additionally, SCT carriers had 2.72 times higher odds of CKD compared with non-carriers (P=.09). Taken together, these novel results show that Hispanics with SCT, as found among African Americans with SCT, may also be at increased risk for kidney disease.

Role of cyclooxygenase in the vascular response to locally delivered acetylcholine in Caucasian and African descent individuals

IntroductionIndividuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) compared with Caucasian individuals (CAU). Vasodilatation to acetylcholine (ACh) is lower in AFD compared with CAU in the non-glabrous foot and finger skin sites; the reason for this is unknown. Prostanoids are responsible, in part, for the vasodilator response to ACh, however it is not known whether the contribution differs between ethnicities. Methods12 CAU and 12 AFD males received iontophoresis of ACh (1 w/v%) on non-glabrous foot and finger skin sites following placebo and then aspirin (600mg, single blinded). Aspirin was utilised to inhibit prostanoid production by inhibiting the cyclooxygenase (COX) enzyme. Laser Doppler flowmetry was utilised to measure changes in skin blood flow. ResultsNot all participants could receive iontophoresis charge due to high skin resistance; these participants were therefore excluded from the analyses.Foot: ACh elicited greater maximal vasodilatation in CAU than AFD following placebo (P=0.003) and COX inhibition (COXib) (P<0.001). COXib did not affect blood flow responses in AFD, but caused a reduction in the area under the curve for CAU (P=0.031).Finger: ACh elicited a greater maximal vasodilatation in CAU than AFD following placebo (P=0.013) and COXib (P=0.001). COXib tended to reduce the area under the curve in AFD (P=0.053), but did not affect CAU. ConclusionsCAU have a greater endothelial reactivity than AFD in both foot and finger skin sites irrespective of COXib. It is concluded that the lower ACh-induced vasodilatation in AFD is not due to a compromised COX pathway.

Glaucoma and cigarette smoking: a review of narrative reviews

Background: Glaucoma is an optic neuropathy associated with visual field changes for which high intra-ocular pressure is a majorrisk factor. Emerging research indicates that modifiable factors, among which the cigarette smoke, besides IOP may be associated withthe presence of glaucoma.Objective: The objective of the study was to perform a review of narrative reviews to examine on the relationship between cigarettesmoking and glaucoma.Methods: The results of all narrative reviews in the scientific literature about glaucoma and tobacco smoking were analyzed. Aquality assessment was performed according to an easy and convenient tool for the quality assessment of narrative reviews forsystematic reviews (International Narrative Systematic assessment) the INSA tool. Literature searches were performed usingPubMed.Results: 20 studies about relation between glaucoma and smoke were collected, no restriction language was applied. 15 of thesestudies have been excluded. We selected among them 5 reviews. With the INSA tool we measured the quality of the 5 selectednarrative reviews. Studies that had a highest score with the INSA tool were two: A. Coleman et al. “Risk Factors for GlaucomaNeeding More Attention” and R. Salowe et al. “Primary Open-Angle Glaucoma in Individuals of African Descent: A Review of RiskFactors”.Conclusion: The narrative reviews analyzed underline that there is no definitive association between cigarette smoking.

Blood Group Genotyping to Prevent Alloimmunization in Children with Sickle Cell Disease

Introduction:Sickle cell disease (SCD) patients can suffer from devastating complications of their disease as a result of chronic hemolysis and vasculopathy. Chronic blood transfusion can effectively prevent some of the most severe organ damage such as cerebral vasculopathy. However, alloimmunization remains a major concern for chronically transfused patients, even if prophylactic antigen matching is performed for C, E and Kell antigens. Variants in the Rh blood group have been well described in people of African descent and must be considered when transfusing patients with SCD. The main objectives of this study were to determine the frequency of variants in the Rh and Duffy blood groups and to identify compatible blood donors presenting similar Rh variantsMethods: Extended erythrocyte phenotypes were routinely done at diagnosis for every SCD patient followed at the SCD clinic of CHU Sainte-Justine. Serologic testing was performed by standard methods. Upon informed consent, genotyping for Rh and Fy blood groups was also proposed to all SCD patients. DNA analyses were used to predict D phenotype (including RHD pseudogene), C, c, E, e antigen profile, FY phenotype with GATA-1 status, and to confirm critical position in the RHD (DAU cluster, zygosity) and RHCEgenes (position 48, 254, 733, 1006). The study was approved by the local Research Ethics Board (REB).Results: 203 SCD patients were evaluated: HbSS 64.3%, HbSC 29.6%, HbSb0 3.1%, HbSb+ 2.5% and HbSDIran 0.5%. ABO blood groups followed published prevalence: Group O 48.7%, A 26.2%, B 20.4%and AB 4.7%. 90.2% of patients had either a normal RHD*01 or RHD*10.00 gene which would predict a normal D+ phenotype. Twenty patients would require D− units (9.8%) to reduce their alloimmunization risk (D−, weak partial D and partial D). The RHCE genotyping results were as followed: normal c allele 61.2%, normal e allele 39.3%, partial e allele 34.1% and weak e allele 17.6%. Most RHCE alleles present in the cohort reflected variants previously reported in individuals of African descent. Most patients were compound heterozygotes. 45.8% of RHCE alleles were considered normal: RHCE*ce, RHCE*Ce and RHCE*cE. Fy(a-b-) phenotype was found in 91.6% of patients (186/203).The list of RHCE variant alleles observed in the cohort was compared to Héma-Québec’s (blood supplier for the province of Quebec) African descent blood donor database. For partial e, weak partial e and rare hrB− phenotypes, only D+ donors are available whereas some of the patients are D−. The same is true for one Sec− (RH46, high-prevalence antigen) patient for which no donor is available. As for CEAG− recipients (partial ce-phenotype), two compatible blood donors were identified by screening O− units from donors of African descent. Overall, five patients (2.4%) may not have suitable donors in our blood bank based upon genotype compatibility. Twenty other patients could be added to this calculation because of a variant e allele in trans to a normal E allele.Conclusions: The RH and FY results indicate that very few patients require rare blood units. More than 90% present a normal D antigen and are Fy(a−b−), similar to most blood donors of African ancestry. However, RHCE variants could be more problematic in terms of finding compatible units. This study showed a large array of RH variants, although most are present in heterozygous form accompanied by a normal allele. This could explain the low alloimmunization rate of 3% for Rh antigens observed in this cohort (overall alloimmunization rate of 18.9%). However, as all patients were younger than 18 years old, they will probably be exposed to more blood transfusion during their adult life. Having their RH and FY genotype readily available should make the blood donors’ selection easier. Further prospective studies are needed to evaluate if such an approach will lower the alloimmunization rate. DisclosuresNo relevant conflicts of interest to declare.

Journeys of the Slave Narrative in the Early Americas

With this collection of eight essays (plus an introduction and coda), the editors Nicole N. Aljoe and Ian Finseth seek to reconceptualize the slave narrative genre in multiple ways—by extending its periodization back to the early eighteenth century, incorporating transnational and transcultural narratives, and including texts not actually written by enslaved people. Aljoe and Finseth make a compelling case to expand the traditional slave narrative canon to include lesser-known works that do not always adhere strictly to convention. Those narratives reveal meaningful experiences among black actors and authors operating within the Atlantic world during the eighteenth and early nineteenth centuries. The essays in this volume demonstrate that in this time period individuals of African descent could assume a host of identities over their lifetimes, often due to voluntary or involuntary transnational geographic movement. The cohort of black men that José Guadalupe Ortega discusses shifted from slaves terrorized by Bahamian masters to critical agents in the transformation of the Cuban sugar economy to litigants who used Spanish law to gain their freedom. As Keith Michael Green highlights, Briton Hammon maintained multiple identities representing various states of unfreedom common in the Americas during the eighteenth century—slavery, naval impressment, captivity by American Indians, incarceration, and indentured servitude. The collection reveals a population of black men who were intensely mobile, shifting from one culture, one form of captivity, or one economic state to another, sometimes multiple times during their lives.

Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (∼30%-40%). Health disparities exist with African descent (AD) subjects exhibiting greater mortality than European descent (ED) individuals. Myosin light chain kinase is encoded by MYLK, whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, that is, cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK cytosine-guanine dinucleotides (CpGs) between ARDS patients and intensive care unit (ICU) controls overall and by ethnicity in a nested case-control study of 39 ARDS cases and 75 non-ARDS ICU controls. Two MYLK CpG sites (cg03892735 and cg23344121) were differentially modified between ARDS subjects and controls (P<0.05; q<0.25) in a logistic regression model, where no effect modification by ethnicity or age was found. One CpG site was associated with ARDS in patients aged <58years, cg19611163 (intron 19, 20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2, 3) and CpG (cg16212219, intron 31, 32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting modified cytosine quantitative trait loci (mQTL) were identified using linear regression between local genetic variants and modification levels for 2 ARDS-associated CpGs (cg23344121 and cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS.

Displacement of the Lamina Cribrosa in Response to Acute Intraocular Pressure Elevation in Normal Individuals of African and European Descent.

PurposeTo assess if the in vivo mechanical displacement of the anterior laminar cribrosa surface (ALCS) as a response of an acute elevation in intraocular pressure (IOP) differs in individuals of European (ED) and African descent (AD).MethodsSpectral-domain optical coherence tomography (SDOCT) scans were obtained from 24 eyes of 12 individuals of AD and 18 eyes of 9 individuals of ED at their normal baseline IOP and after 60 seconds IOP elevation using ophthalmodynamometry. Change in depth (displacement) of the LC and to the prelaminar tissue (PLT) were computed in association with the change (delta) in IOP (Δ IOP), race, age, corneal thickness, corneal rigidity (ocular response analyzer [ORA]), and axial.ResultsIn the ED group for small IOP elevations (Δ IOP < 12 mm Hg), the ALCS initially displaced posteriorly but for larger increase of IOP an anterior displacement of the lamina followed. Inversely, in the AD group the ALCS did not show a significant posterior displacement for small Δ IOP, while for larger IOP increases the ALCS significantly displaced posteriorly. Posterior displacement of the lamina cribrosa (LC) was also significantly correlated with longer axial length, higher corneal thickness, and ORA parameters. Prelaminar tissue posteriorly displaced for any magnitude of Δ IOP, in both groups.ConclusionsThe African descent group demonstrated a greater acute posterior bowing of the LC after adjustment for age, axial length, Bruch's membrane opening (BMO) area, and ORA parameters. Greater PLT posterior displacement was also seen in the AD group with increasing IOP, which was tightly correlated with the displacement of the LC.

Changing Racial Bias by Transfer of Functions in Equivalence Classes

Several studies used the stimulus equivalence paradigm to investigate attitudes toward socially relevant stimuli. In one of these studies, de Carvalho and de Rose (The Psychological Record 64: 527–536, 2014) used matching-to-sample (MTS) training to establish equivalence relations between a positive symbol and faces of individuals of African descent (toward which children showed negative bias prior to the research). Only one of four children showed the intended classes. The present study manipulated training parameters to increase the yield of equivalence classes comprising relations contrary to children’s previous racial bias. Thirteen children learned matching tasks that would potentially establish equivalence relations between Black faces and positive symbols, contrary to their preexperimental bias. All 13 children showed equivalence class formation, and nine of them maintained relations between Black faces and positive symbols in a different and more stringent test. Children’s evaluations of the faces with the Self-Assessment Manikin (SAM) showed a pronounced negative bias toward Black faces before training. After class formation, however, the difference between evaluations of Black and White faces was no longer statistically significant. These results showed that procedures based on equivalence and transfer of functions may contribute to educational programs designed to decrease racial biases, a significant challenge for our increasingly multicultural and multiracial societies.

African Descent and Glaucoma Evaluation Study (ADAGES): Racial Differences in Optic Disc Hemorrhage and Beta-Zone Parapapillary Atrophy

To investigate the differences in the frequency of optic disc hemorrhage (DH) and prevalence of beta-zone parapapillary atrophy (βPPA) between individuals of African descent (AD) and European descent (ED). Prospective, multicenter, observational cohort. A total of 1950 eyes of 1172 participants of the African Descent and Glaucoma Evaluation Study (ADAGES). Stereoscopic disc photographs of subjects with and without glaucomatous optic neuropathy (GON) followed during the first 13 years of the ADAGES underwent masked review searching for DH and βPPA. A total of 928 eyes (non-GON, 581; GON, 347) of 551 AD patients (non-GON, 334; GON, 217) and 1022 eyes (non-GON, 568; GON, 454) of 611 ED patients (non-GON, 334; GON, 277) were included. We compared the number of eyes with detected DH at any time during follow-up and eyes with βPPA between the AD and ED groups. The analyses were then adjusted for clinical parameters using multivariable logistic regression. Differences in frequency of DH and prevalence of βPPA. A total of 9395 stereoscopic disc photographs were reviewed. More ED eyes experience DH than AD eyes (49/1022 [4.8%] vs. 10/928 eyes [1.1%], respectively; P < 0.001), whereas βPPA had higher prevalence in AD eyes (675 eyes [72%] vs. 659 eyes [64%]; P < 0.001). In the final multivariable model, after controlling for confounders, AD eyes were less likely to have at least 1 detected DH than ED eyes (odds ratio [OR], 0.21; 95% CI, 0.10-0.45; P < 0.001) but were more likely to have βPPA than ED eyes (OR, 1.55; 95% CI, 1.12-2.14; P= 0.008). Subjects of ED are at higher risk for developing DH compared with AD subjects, whereas ADsubjects have greater prevalence of βPPA. These findings suggest that there are structural differences withinthe optic nerve complex between these groups. Further research is needed to determine whether racial differences in the frequency of DH and prevalence of βPPA affect the likelihood of glaucomatous progression.

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

"Sickle cell anemia: tracking down a mutation": an interactive learning laboratory that communicates basic principles of genetics and cellular biology.

"Sickle cell anemia: tracking down a mutation" is a full-day, inquiry-based, biology experience for high school students enrolled in genetics or advanced biology courses. In the experience, students use restriction endonuclease digestion, cellulose acetate gel electrophoresis, and microscopy to discover which of three putative patients have the sickle cell genotype/phenotype using DNA and blood samples from wild-type and transgenic mice that carry a sickle cell mutation. The inquiry-based, problem-solving approach facilitates the students' understanding of the basic concepts of genetics and cellular and molecular biology and provides experience with contemporary tools of biotechnology. It also leads to students' appreciation of the causes and consequences of this genetic disease, which is relatively common in individuals of African descent, and increases their understanding of the first principles of genetics. This protocol provides optimal learning when led by well-trained facilitators (including the classroom teacher) and carried out in small groups (6:1 student-to-teacher ratio). This high-quality experience can be offered to a large number of students at a relatively low cost, and it is especially effective in collaboration with a local science museum and/or university. Over the past 15 yr, >12,000 students have completed this inquiry-based learning experience and demonstrated a consistent, substantial increase in their understanding of the disease and genetics in general.

Navigating in murky waters: How multiracial Black individuals cope with racism.

Multiracial people are often lauded as evidence of the waning significance of race and racism in the United States. In reality, the experiences of multiracial people illuminate the ways that racism still exists and efforts to classify people based on assumed racial characteristics for the purposes of inclusion and exclusion are alive and well. Multiracial individuals experience racism from multiple sources and in various forms, which has the potential to negatively impact their development and well-being. Thus, scholars and practitioners must better understand how the growing population of multiracial individuals learns to cope with such racism. The central aim of this qualitative interview study was to shed light on the ways in which multiracial individuals of African descent in the United States cope with and respond to racism. Findings are organized around 5 broad conceptual themes for coping with and addressing racism: avoidance and internalization, anger and violence, education and advocacy, seeking culture and community, and chameleon identities. Findings of this study speak to the dynamic nature of strategies used to cope with racism and hold implications for practices and programs designed to support positive racial identity development among multiracial individuals of African descent. (PsycINFO Database Record

High prevalence of haemoglobin S in the closed Egyptian community of Siwa Oasis

BackgroundSickle cell haemoglobinopathy, the most frequent of the hereditary anomalies of haemoglobin, occurs most commonly in individuals of African descent. With a population of about 23 000, Siwa Oasis is...

Increasing Incidence of Chronic Lymphocytic Leukemia in Korea, 1999-2010: Comparison to Plasma Cell Myeloma

Introduction: Chronic lymphocytic leukemia (CLL) and plasma cell myeloma (PCM) have markedly higher incidences in Western compared with Asian countries. In Asian countries, both CLL and PCM have increased over the previous few decades. However, the epidemiologic characteristics of CLL have not been previously studied in Korea. To track the changing trends in the incidence of CLL and PCM, we investigated epidemiologic data in Korea from 1999 to 2010 and compared it with data regarding Taiwanese and Caucasian Americans. We specifically addressed the differences in the trends of CLL and PCM.Methods: We included patients diagnosed with CLL or PCM between 1999 and 2010 from the KCCR and between 1992 and 2010 from the SEER database. We utilized the International Classification of Diseases for Oncology 3rd edition (ICD-O-3) codes for CLL (9823/3) and PCM (9732/3). The age at diagnosis was classified into 18 age groups by 5-year intervals. The data of Taiwan was obtained by personal communication.Results: The ASR of CLL from 1999 to 2010 in Korea was 0.13/100,000 person-years (0.17/100,000 for men and 0.09/100,000 for women). The APC in the CLL incidence in Korea was 4.17% (95% CI: 0.77-7.68%) (Table 1). For comparison, the ASR of the CLL in the US from 1999 to 2010 was 3.21/100,000, and CLL exhibited an APC of 0.68% (95% CI: -0.39 to 1.77%). The APC of CLL over the previous 12 years in Korea (4.17%) was markedly higher (i.e., 6.1-fold) compared with the US (0.68%). In a comparison of different ethnic groups, the ASR in Caucasians was 3.57/100,000; this incidence was the highest rate observed (Figure 1). The ASRs in individuals of African descent and Asians/Pacific Islanders were 2.41/100,000 and 0.74/100,000, respectively. The temporal trends in the ASRs in all races remained stable.The ASR of PCM for the period from 1999 to 2010 in Korea was 1.23/100,000 person-years (1.51/100,100 for men and 1.04/100,000 for women). The APC in the PCM incidence rates was 4.68% (95% CI: 4.12-5.24%) (Table 1). The ASR of PCM in the US from 1999 to 2010 was 3.97/100,000, which was 3.2-fold higher compared with Korea. The incidence of PCM in the US increased, with an APC of 0.50% (95% CI: 0.11-0.88%). The APC in Korea during the same period was 9.4-fold higher compared with the US. In the US, differences in the incidence were observed among ethnic groups, including Caucasians, African Americans and Asians or Pacific Islanders (Figure 1). African Americans constituted the group most susceptible to PCM, with an ASR of 8.42/100,000. The ASRs for Caucasian and Asians/Pacific Islanders were 3.67/100,000 and 2.37/100,000, respectively. The ASRs for the all races remained stable.Conclusion: In conclusion, the incidence rates of CLL have gradually increased from 1999 to 2010, while those of PCM have increased steeply. Both of them still show prominent lower incidences compared to US, but the incidence rates of CLL and PCM appears to be stable in the US. Though genetic background is the key factor for ethnic difference in the incidence, further study will be needed to elucidate the reason for recent differential increasing trends between CLL and PCM incidence in Korea.Table 1Comparison of incidence and trend in CLL and PCM during 1999-2010 between US and Korea°°°°USKoreaComparison (US/Korea)CLLASR*3.210.1324.69APC (95% CI)0.68(-0.39 to 1.77)4.17(0.77 to 7.68)¢"0.16PCMASR*3.971.233.23°°APC (95% CI)0.50(0.11 to 0.88)¢"4.68(4.12 to 5.24)¢"0.11* ASR are expressed per 100,000 person-years¢" APC is statistically significantly different from zeroAbbreviation: CLL, chronic lymphocytic leukemia; PCM, plasma cell myeloma; ASR, age-standardized rate; APC, annual percentage change; CI, confidence interval. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genetic Modifiers Influencing the Development of Albuminuria in Children with Sickle Cell Anemia

Background: Nephropathy in sickle cell anemia (SCA) begins in childhood and portends chronic kidney disease, renal failure, and early mortality among affected adults. Individuals of African descent have disproportionately higher rates of developing non-diabetic renal disease. Several candidate genetic variants have been identified, including some specific to African Americans, which are associated with the development of albuminuria and renal disease. The influence of genetic polymorphisms on albuminuria and elevated glomerular filtration rate (GFR) in children with SCA, both early signs of sickle nephropathy, has not been investigated.Objectives: To determine the influence of selected single nucleotide polymorphisms (SNPs) on the development of albuminuria and elevated GFR in children with SCA; to identify novel genetic variants influencing albuminuria and GFR by whole exome sequencing (WES).Design/Methods: Genomic DNA was collected on children with SCA enrolled in two prospective studies with pre-hydroxyurea renal assessments (n=185): (1) Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175, n=79) with no prior disease-modifying therapy; and (2) Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH, NCT 01425307, n=106) on chronic transfusions for abnormal TCD velocities. Albuminuria was defined as ≥30mg albumin/gm creatinine on the pre-hydroxyurea urine specimen. GFR was measured in HUSTLE using plasma DTPA (technetium 99m-labeled diethylenetriaminepentaacetic acid) clearance, and estimated GFR (eGFR) in TWiTCH based on serum creatinine. DNA samples were genotyped for 8 candidate SNPs previously associated with renal disease, using PCR-based allelic discrimination, bidirectional Sanger sequencing, and analysis of variable number tandem repeats (VNTR). Associations between albuminuria and genetic polymorphisms were tested using an additive model and correlation trend test. Linked WES data from the same patients were analyzed to identify other variants associated with albuminuria and GFR.Results: Albuminuria was present in 13.1% of patients, including 16.3% in HUSTLE and 11.0% in TWiTCH. APOL1 genetic variants were common (G1 allele frequency = 21.9%, G2 allele = 16.0%, Table) and similar to published cohorts. Children with two APOL1 G1 alleles had an increased risk of albuminuria that approached statistical significance (p=0.053). Conversely, the presence of the DARC SNP that confers Duffy antigen expression had a protective effect (p=.038). WES analysis did not identify additional non-synonymous APOL1 variants linked with albuminuria. However, 93 non-synonymous variants were associated with DTPA GFR (p<0.001). Using patients with eGFR as a validation cohort, 7 variants in FUBP1, ZFAND4, CD163, GMFG and HLA-E maintained their association with kidney filtrative function (p<0.05). In particular, two variants in CD163, which is a macrophage scavenger receptor for hemoglobin-haptoglobin complexes, were strongly associated with increased GFR in both patient cohorts.Table 1Candidate genes associated with microalbuminuria. All SNPs were tested with either an additive or recessive genetic model. *The eNOS VNTR was analyzed by the chi-square method.GeneSNPLocationMAFAlbuminuria (Additive)Variant frequencyCasesControlsAPOL1 G1rs7388531922q1221.9%0.05332.0%20.3%APOL1 G2rs7178531322q1216.0%0.44510.0%16.0%DARCrs28147781q2313.6%0.0384.2%15.7%eNOS 4aVNTR7q3531.2%0.333*31.5%22.7%eNOSrs17999837q3512.5%0.66314.6%12.2%eNOSrs20707447q3515.6%0.29910.4%16.3%CUBNrs791897210p1216.2%0.45712.5%16.8%CUBNrs180123910p122.7%0.1990.0%3.1%Conclusion: Genetic polymorphisms associated with chronic kidney disease in African American adults may influence the development of early-onset albuminuria among children with SCA, including an increased risk among children with ≥1 APOL1 G1 alleles and a decreased risk associated with the DARC SNP. Previously published eNOS and CUBN variants had no measureable effects. WES analysis suggests novel genetic variants including CD163 SNPs may influence the development of elevated GFR in children with SCA, and provide candidate genes for future research. DisclosuresOff Label Use: Hydroxyurea is FDA approved for the treatment of sickle cell anemia in adults, but has not yet been approved in children. . Nottage:Janssen Pharmaceuticals: Employment. Ware:Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Bayer Pharmaceuticals: Consultancy; Eli Lilly: Other: DSMB membership.

GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation.

Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.

African Ancestry Is Associated with Higher Intraocular Pressure in Latinos

Intraocular pressure (IOP) is a major risk factor, as well as the only modifiable risk factor, for glaucoma. Racial differences have been observed in IOP measurements with individuals of African descent experiencing the highest IOP when compared with other ethnic groups. The purpose of this study was to examine the relationship between genetic ancestry and IOP in Latinos. Population-based genetic association study. A total of 3541 participants recruited from the Los Angeles Latino Eye Study. Study participants were genotyped using the Illumina OmniExpress BeadChip (∼730K markers). We used STRUCTURE to estimate individual genetic ancestry. Simple and multiple linear regression, as well as quantile regression, analyses were performed to investigate the relationship between genetic ancestry and IOP. The relationship between genetic ancestry and IOP in Latinos. African ancestry was significantly associated with higher IOP in Latinos in our simple linear regression analysis (P= 0.002). After adjusting for age, gender, body mass index, systolic blood pressure, central corneal thickness, and type 2 diabetes, this association remained significant (P= 0.0005). The main association was modified by a significant interaction between African ancestry and hypertension (P= 0.037), with hypertensive individuals experiencing a greater increase in IOP with increasing African ancestry. To our knowledge, we demonstrate for the first time that African ancestry and its interaction with hypertension are associated with higher IOP in Latinos.