Resting Energy Expenditure in Obese African American and Caucasian Women

The prevalence of obesity among African American women approaches 50% and greatly exceeds rates for Caucasian women. In addition, black women lose less weight than white during obesity treatment and gain more weight when untreated. This study assessed resting energy expenditure (REE) and body composition in obese white (n=122) and black (n=44) women to explore the relationship between biological variables and these observed differences. REE and body composition were assessed by indirect calorimetry and densitometry, respectively, before weight loss. REE was significantly lower in black subjects (1637.6 ± 236.9 kcal/d) than in white (1731.4 ± 262.0) (p=0.04). REE remained significantly lower in blacks than whites after adjusting for body weight (p=0.02). REE, adjusted for fat-free mass, was also significantly lower in blacks than whites (p<0.0001), although the overestimation of fat-free mass by densitometry in blacks may have contributed to this finding. There were no differences between the groups in respiratory quotient. These results suggest that a decreased REE may exist in obese black women, and it may be related to the observed differences between black and white women in the prevalence of obesity and in the response to weight loss treatment. These crosssectional findings await confirmation in longitudinal studies.     

HCV Genome-Wide Genetic Analyses in Context of Disease Progression and Hepatocellular Carcinoma

Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.     

Interferon-Based Therapy Decreases Risks of Hepatocellular Carcinoma and Complications of Cirrhosis in Chronic Hepatitis C Patients

Background

Interferon-based therapy (IBT) has been the standard of care for hepatitis C virus (HCV) infection. However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular carcinoma (HCC) and cirrhosis-associated complications, and most included highly selected patients.

Methods

This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000) consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 (>23.7 million). Patients with newly detected HCV infections (n = 11,264) were classified based on treatment and clinical outcomes. IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months. The Cox proportional hazards models were used to estimate the hazard ratio (HR) and associated confidence interval (CI) of HCC and cirrhosis-associated complications for IBT.

Results

The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.31–0.81; P = .004). Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22–0.91; P = .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21–0.69; P = .001), ascites (adjusted HR, 0.28; 95% CI, 0.14–0.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44–0.91; P = .013) were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors.

Conclusion

Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications in patients with chronic HCV infection.     

Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors

Background  

Epidemiological and genetic studies indicate that ethnic/genetic background plays an important role in susceptibility to primary open angle glaucoma (POAG). POAG is more prevalent among the African-descent population compared to the Caucasian population. Damage in POAG occurs at the level of the optic nerve head (ONH) and is mediated by astrocytes. Here we investigated differences in gene expression in primary cultures of ONH astrocytes obtained from age-matched normal and glaucomatous donors of Caucasian American (CA) and African American (AA) populations using oligonucleotide microarrays.     

Patterns and Processes of Genome-Wide Divergence Between North American and African Drosophila melanogaster

Genomic tools and analyses are now being widely used to understand genome-wide patterns and processes associated with speciation and adaptation. In this article, we apply a genomics approach to the model organism Drosophila melanogaster. This species originated in Africa and subsequently spread and adapted to temperate environments of Eurasia and the New World, leading some populations to evolve reproductive isolation, especially between cosmopolitan and Zimbabwean populations. We used tiling arrays to identify highly differentiated regions within and between North America (the United States and Caribbean) and Africa (Cameroon and Zimbabwe) across 63% of the D. melanogaster genome and then sequenced representative fragments to study their genetic divergence. Consistent with previous findings, our results showed that most differentiation was between populations living in Africa vs. outside of Africa (i.e., “out-of-Africa” divergence), with all other geographic differences being less substantial (e.g., between cosmopolitan and Zimbabwean races). The X chromosome was much more strongly differentiated than the autosomes between North American and African populations (i.e., greater X divergence). Overall differentiation was positively associated with recombination rates across chromosomes, with a sharp reduction in regions near centromeres. Fragments surrounding these high F_ST sites showed reduced haplotype diversity and increased frequency of rare and derived alleles in North American populations compared to African populations. Nevertheless, despite sharp deviation from neutrality in North American strains, a small set of bottleneck/expansion demographic models was consistent with patterns of variation at the majority of our high F_ST fragments. Although North American populations were more genetically variable compared to Europe, our simulation results were generally consistent with those previously based on European samples. These findings support the hypothesis that most differentiation between North America and Africa was likely driven by the sorting of African standing genetic variation into the New World via Europe. Finally, a few exceptional loci were identified, highlighting the need to use an appropriate demographic null model to identify possible cases of selective sweeps in species with complex demographic histories.THE study of genetic differentiation between populations and species has recently been empowered by the use of genomic techniques and analysis (e.g., Noor and Feder 2006; Stinchcombe and Hoekstra 2008). In the past decade, genetic studies of adaptation and speciation have taken advantage of emerging molecular techniques to scan the genomes of diverging populations for highly differentiated genetic regions (e.g., Wilding et al. 2001; Emelianov et al. 2003; Beaumont and Balding 2004; Campbell and Bernatchez 2004; Scotti-Saintagne et al. 2004; Achere et al. 2005; Turner et al. 2005; Vasemagi et al. 2005; Bonin et al. 2006, 2007; Murray and Hare 2006; Savolainen et al. 2006; Yatabe et al. 2007; Nosil et al. 2008, 2009; Turner et al. 2008a,b; Kulathinal et al. 2009). As a result, genome scans can identify candidate regions that may be associated with adaptive evolution between diverging populations and, more broadly, are able to describe genome-wide patterns and processes of population differentiation (Begun et al. 2007; Stinchcombe and Hoekstra 2008).Genome scans in well-studied genetic model species such as Drosophila melanogaster gain particular power because differentiated loci are mapped to a well-annotated genome. Moreover, the evolutionary history of D. melanogaster is rich with adaptive and demographic events with many parallels to human evolution. Most notable is the historical out-of-Africa migration and subsequent adaptation to temperate ecological environments of Europe, Asia, North America, and Australia. This has resulted in widespread genetic and phenotypic divergence between African and non-African populations (e.g., David and Capy 1988; Begun and Aquadro 1993; Capy et al. 1994; Colegrave et al. 2000; Rouault et al. 2001; Takahashi et al. 2001; Caracristi and Schlötterer 2003; Baudry et al. 2004; Pool and Aquadro 2006; Schmidt et al. 2008; Yukilevich and True 2008a,b). Further, certain populations in Africa and in the Caribbean vary in their degree of reproductive isolation from populations in more temperate regions (Wu et al. 1995; Hollocher et al. 1997; Yukilevich and True 2008a,b). In particular, the Zimbabwe and nearby populations of southern Africa are strongly sexually isolated from all other populations, designating them as a distinct behavioral race (Wu et al. 1995).D. melanogaster has received a great deal of attention from the population geneticists in studying patterns of sequence variation across African and non-African populations. Many snapshots have been taken of random microsatellite and SNP variants spread across X and autosomes, and these have generated several important conclusions. Polymorphism patterns in European populations are characterized by reduced levels of nucleotide and haplotype diversity, an excess of high frequency-derived polymorphisms, and elevated levels of linkage disequilibrium relative to African populations (e.g., Begun and Aquadro 1993; Andolfatto 2001; Glinka et al. 2003; Haddrill et al. 2005; Ometto et al. 2005; Thornton and Andolfatto 2006; Hutter et al. 2007; Singh et al. 2007). These results have been generally interpreted as compatible with population size reduction/bottlenecks followed by recent population expansions. On the other hand, African populations are generally assumed either to have been relatively constant in size over time or to have experienced population size expansions. They generally show higher levels of nucleotide and haplotype diversity, an excess of rare variants, and a deficit of high frequency-derived alleles (Glinka et al. 2003; Ometto et al. 2005; Pool and Aquadro 2006; Hutter et al. 2007; but see Haddrill et al. 2005 for evidence of bottlenecks in Africa).Previous work also shows that the ratio of X-linked to autosomal polymorphism deviates from neutral expectations in opposite directions in African and European populations with more variation on the X than expected in Africa and less variation on the X than expected in Europe (Andolfatto 2001; Kauer et al. 2002; Hutter et al. 2007; Singh et al. 2007). The deviation from neutrality in the ratio of X-autosome polymorphism may be explained by positive selection being more prevalent on the X in Europe and/or by a combination of bottlenecks and male-biased sex ratios in Europe and female-biased sex ratios in Africa (Charlesworth 2001; Hutter et al. 2007; Singh et al. 2007). The selective explanation stems from the argument that, under the hitchhiking selection model, X-linked loci are likely to be more affected by selective sweeps than autosomal loci (Maynard Smith and Haigh 1974; Charlesworth et al. 1987; Vicoso and Charlesworth 2006, 2009).The relative contribution of selective and demographic processes in shaping patterns of genomic variation and differentiation is highly debated (Wall et al. 2002; Glinka et al. 2003; Haddrill et al. 2005; Ometto et al. 2005; Schöfl and Schlötterer 2004; Thornton and Andolfatto 2006; Hutter et al. 2007; Singh et al. 2007; Shapiro et al. 2007; Stephan and Li 2007; Hahn 2008; Macpherson et al. 2008; Noor and Bennett 2009; Sella et al. 2009). This is especially the case in D. melanogaster because derived non-African populations have likely experienced a complex set of demographic events during their migration out of Africa (e.g., Thornton and Andolfatto 2006; Singh et al. 2007; Stephan and Li 2007), making population genetics signatures of demography and selection difficult to tease apart (e.g., Macpherson et al. 2008). Thus it is still unclear what role selection has played in shaping overall patterns of genomic variation and differentiation relative to demographic processes in this species.While there is a long tradition in studying arbitrarily or opportunistically chosen sequences in D. melanogaster, genomic scans that focus particularly on highly differentiated sites across the genome have received much less attention. Such sites are arguably the best candidates to resolve the debate on which processes have shaped genomic differentiation within species (e.g., Przeworski 2002). Recently, a genome-wide scan of cosmopolitan populations in the United States and in Australia was performed to investigate clinal genomic differentiation on the two continents (Turner et al. 2008a). Many single feature polymorphisms differentiating Northern and Southern Hemisphere populations were identified. Among the most differentiated loci in common between continents, 80% were differentiated in the same orientation relative to the Equator, implicating selection as the likely explanation (Turner et al. 2008a). Larger regions of genomic differentiation within and between African and non-African populations have also been discovered, some of them possibly being driven by divergent selection (e.g., Dopman and Hartl 2007; Emerson et al. 2008; Turner et al. 2008a, Aguade 2009). Despite this recent progress, we still know relatively little about large-scale patterns of genomic differentiation in this species, especially between African and non-African populations, and whether most of this differentiation is consistent with demographic processes alone or if it requires selective explanations.In this work, we explicitly focus on identifying differentiated sites across the genome between U.S., Caribbean, West African, and Zimbabwean populations. This allows us to address several fundamental questions related to genomic evolution in D. melanogaster, such as the following: (1) Do genome-wide patterns of differentiation reflect patterns of reproductive isolation? (2) Is genomic differentiation random across and within chromosomes or are some regions overrepresented? (3) What are the population genetics properties of differentiated sites and their surrounding sequences? (4) Can demographic historical processes alone explain most of the observed differentiation on a genome-wide level or is it necessary to involve selection in their explanation?In general, our findings revealed that most genomic differentiation within D. melanogaster shows an out-of-Africa genetic signature. These results are inconsistent with the notion that most genomic differentiation occurs between cosmopolitan and Zimbabwean reproductively isolated races. Further, we found that the X is more differentiated between North American and African populations and more strongly deviates from pure neutrality in North American populations relative to autosomes. Nevertheless, our article shows that much of this deviation from neutrality is broadly consistent with several demographic null models, with a few notable exceptions. Athough this does not exclude selection as a possible alternative mechanism for the observed patterns, it supports the idea that most differentiation in D. melanogaster was likely driven by the sorting of African standing genetic variation into the New World.     

A Genome-Wide Methylation Study on Essential Hypertension in Young African American Males

Objective

There is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.

Method & Results

We conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14–23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14–30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8–40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10⁻⁵), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095).

Conclusion

The identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.     

Subcellular localization of total and activated Src kinase in African American and Caucasian breast cancer

Background

Src, a non-receptor tyrosine kinase is elevated in cancer with expression and activity correlated with cell proliferation, adhesion, survival, motility, metastasis and angiogenesis. There is limited data on Src expression and subcellular localization in breast cancer and no information about expression in racial/ethnic groups.

Methodology/Principal Findings

The present study evaluated Src expression, activity, and subcellular localization in triple negative breast cancer (TNBC) and ERα positive breast cancer (ER+BC), cancer tissue and adjacent normal epithelial ducts, and Caucasian and African American cases. 79 paraffin embedded breast carcinoma cases were obtained from Tulane University Hospital between 2007–2009. 39 cases represented TNBC (33-African Americans, 4-Caucasians, 2-unknowns) and 40 cases represented ER+BC (21-African Americans, 16-Caucasians, 3-unknowns). Immunohistochemistry was used to measure staining distribution and intensity of total Src and activated phospho-SrcY416 (p-Y416Src) in carcinoma tissue and adjacent normal mammary ducts. In TNBC and ER+BC, total Src was significantly higher in cancer compared to adjacent normal ducts (P<0.0001) in both cell membrane and cytoplasm. In membranes, p-Y416Src was elevated in cancer compared to normal ducts. Total Src in the tumor cytoplasm was significantly higher in TNBC compared to ER+BC (P = 0.0028); conversely, p-Y416Src in the tumor cell membranes was higher in TNBC compared to ER+BC (P = 0.0106). Comparison between African American (n = 21) and Caucasian ER+BC (n = 16) revealed no significant difference in expression and localization of total Src and p-Y416Src. TNBC cases positive for lymph node metastasis showed elevated membrane p-Y416Src compared to lymph node negative TNBC (P = 0.027).

Conclusion/Significance

Total Src and p-Y416Src were expressed higher in cancer compared to adjacent normal ducts. Cytoplasmic total Src and membrane p-Y416Src were significantly higher in TNBC compared to ER+BC. TNBC cases with lymph node metastasis showed elevated membrane p-Y416Src. Taken together, Src was elevated in the membrane and cytoplasm of more aggressive TNBC.     

Serum Leptin and Weight Gain Over 8 Years in African American and Caucasian Young Adults

FOLSOM, AARON R., MICHAEL D. JENSEN, DAVID R. JACOBS, JR., JOAN E. HILNER, ALBERT W. TSAI, AND PAMELA J. SCHREINER. Serum leptin and weight gain over 8 years in African American and Caucasian young adults. Obes Res. 1999;7:1–8. Objective : There is considerable interest in how to prevent weight gain in adulthood. Leptin, a peptide hormone expressed in adipose tissue, is believed to signal the central nervous system about the level of body fat stores, and thereby may control appetite. Little information exists on whether the serum leptin concentration influences long-term weight changes in the free-living population. Research Methods and Procedures : From an ongoing cohort study of young African American and white adults, we selected a sample of participants (n=492), stratified on sex, race, and weight changes over 8 years. Serum leptin was measured on stored specimens using a radioimmunoassay. Weight change was modeled in relation to baseline leptin concentrations. Results : Cross-sectionally, leptin concentration was associated positively with body mass index, negatively with physical activity level, and was higher in women than men. These variables explained 72% of the variance in serum leptin. Over the 8 years, the sample gained an average of 7.8 kg (standard deviation = 10.8). There was no evidence that 8-year weight change was associated with initial leptin concentration: 8-year weight change was only 0.5 kg less (95% confidence interval = ?1.8 to 0.8, p = 0.47) per each 10 ng/ mL increment (approximately one standard deviation) of baseline leptin. In contrast, leptin change correlated highly (r = 0.62) with weight change. Discussion : Our data corroborate evidence that adiposity determines leptin levels but do not support the hypothesis that leptin deficiency plays an important role in obesity in the general population.     

Immune Biomarker Differences and Changes Comparing HCV Mono-Infected,HIV/HCV Co-Infected,and HCV Spontaneously Cleared Patients

Background

Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response

Methods

Fifty immune biomarkers were analyzed at baseline(BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error

Results

Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment

Conclusions

Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets     

Relationship Between Glycated Hemoglobin and Circulating 25-Hydroxyvitamin D Concentration In African American And Caucasian American Men

ObjectiveTo examine whether (1) serum 25-hydroxy- vitamin D level (25[OH]D) is a risk factor for hyperglycemia, as assessed by glycated hemoglobin (HbA1c), in African American men (AAM) and (2) 25(OH)D is a predictor of HbA1c in AAM and Caucasian American men (CAM).MethodsWe prospectively assessed 25(OH)D and HbA1c in 1,074 men, outpatients with and without diabetes, at an urban Veteran Administration Medical Center (66.8% AAM, 26.4% CAM, 6% Hispanic, 0.4% Asian, and 0.4% Native American men). Multivariate regression analyzed the determinants of HbA1c after accounting for potential confounders.ResultsWe found high prevalence of low (< 30 ng/mL) 25(OH)D (81%) and elevated (≥5.7%) HbAlc (53.5%). The 25(OH)D was inversely associated with HbA1c in all men (r = −0.12, P<.001), in AAM (r = −0.11, P = .003), and in CAM (r = −0.15, P = .01). In the entire group the independent determinants of HbA1c included body mass index (BMI), age, 25(OH)D levels, systolic blood pressure (BP), triglycerides, high-density lipoprotein (HDL), and current alcohol use (P<.0001, .013, .009, .01, .008, .034, and .048, respectively) while glomerular filtration rate (GFR) and marital status showed borderline significance (P = .08 and .09, respectively). In AAM these determinants included BMI, 25(OH)D levels, systolic BP, and current alcohol use (P<.0001, .01, .02, and .03, respectively), while age had borderline significance (P = .06). In CAM, these included BMI, age, and triglycerides (P = .01, .03, and .004, respectively) but not 25(OH)D levels (P = .50).ConclusionCirculating low 25(OH)D is a risk factor for hyperglycemia, as assessed by HbA1c, in AAM. The 25(OH)D level is an independent determinant of HbA1c in AAM, but not in CAM, including men with and without diabetes. (Endocr Pract. 2013;19:73-80)     

Pretreatment Predictors of Response to PegIFN-RBV Therapy in Egyptian Patients with HCV Genotype 4

BackgroundEgypt has the highest prevalence of a difficult to treat chronic hepatitis C virus (HCV), genotype 4. Pretreatment factors could guide individualization of therapy which aids in treatment optimization and interleukin IL28B gene polymorphism has been shown to closely relate to HCV treatment response. Polymorphisms in genes encoding inhibitors of T-cell response, which have role in disease progression as Programmed Cell Death 1 (PD-1), and Cytotoxic T-Lymphocytes Antigen-4 (CTLA-4), could be candidate markers predicting treatment response.MethodsThis cohort study consisted of 200 chronic HCV genotype 4 infected patients treated with PegIFN α-2a and RBV in 2 hepatology centers. Genotyping of the polymorphisms in the IL28B gene region (rs12979860), PD1.3 (rs11568821) and CTLA-4 (rs231775) was performed on DNA collected from each patient using TaqMan^® genotyping assay. Groups were classified according to response into sustained virological responders (SVR), or non-responders (NR). A multivariate logistic regression analysis was used to identify potential markers, host pretreatment clinical and viral predictive factors including viral load, insulin resistance, and alpha fetoprotein (AFP) related to treatment response.ResultsOur results showed that in a multivariate analyses IL28B C/C genotype was the most significant predictor for SVR (OR = 10.86; p<0.0001) followed by AFP (OR = 0.915; p = 0.001) then CTLA-4/G genotypes (OR = 1.948; p = 0.022). However, PD-1.3/A genotypes and platelets count were significantly related to response in univariate analysis only (OR = 1.973; p = 0.023; OR = 1.007; p = 0.009 respectively).ConclusionIL28B SNP, AFP level, and CTLA-4 SNP could be used in conjunction to predict treatment response in HCV genotype 4 infected Egyptian patients.     

Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease

Triglyceride content in the liver is regulated by the uptake, production and elimination of lipoproteins, and derangements in these processes contribute to nonalcoholic fatty liver disease (NAFLD). Previous studies show a direct relationship between intrahepatic fat and production of apolipoprotein B100 (apoB100) containing particles, VLDL and LDL, but little consensus exists regarding changes in lipoprotein production in the development of simple steatosis (SS) versus nonalcoholic steatohepatitis (NASH). Further, ethnic variations in lipoproteins among SS and NASH are unknown as is how such variations might contribute to the differential prevalence of disease among Caucasians versus African Americans. In this study, we assessed plasma lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy in 70 non-diabetic class III obese females recruited from the surgical weight loss clinic. Of these, 51 females were stratified by biopsy-staged NAFLD severity (histologically normal, SS, or NASH). NASH females displayed increased circulating triglycerides and increased VLDL particle number and size relative to those with histologically normal livers, while total and large LDL concentration decreased in SS versus NASH and correlated with increased insulin resistance (via HOMA2-IR). When Caucasian women were examined alone (n = 41), VLDL and triglycerides increased between normal and SS, while total LDL and apoB100 decreased between SS and NASH along with increased insulin resistance. Compared to Caucasians with SS, African American women with SS displayed reduced triglycerides, VLDL, and small LDL and a more favorable small to large HDL ratio despite having increased BMI and HOMA2-IR. These findings suggest that ApoB100 and lipoprotein subclass particle number and size can delineate steatosis from NASH in obese Caucasian females, but should be interpreted with caution in other ethnicities as African Americans with SS display relatively improved lipoprotein profiles. This may reflect variation in the relationship between dyslipidemia and NAFLD progression across gender and ethnicity.     

Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy

Background & Aims

The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.

Methods

Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.

Results

By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%– 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).

Conclusion

Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.     

HIV/HCV共感染者抗逆转录病毒治疗后免疫恢复情况

由于具有相同的传播途径,人类免疫缺陷病毒(Human immunodeficiency virus,HIV)和丙型肝炎病毒(Hepatitis C virus,HCV)共感染非常普遍,但是关于合并感染的程度,两种病毒之间的相互关系,在艾滋病抗逆转录病毒治疗(Antiretroviral therapy,ART)前后,HCV合并感染对HIV患者免疫细胞恢复的影响仍不明确。为了通过分析CD4⁺和CD8⁺T淋巴细胞数的变化,以了解辽宁省HIV/HCV共感染者ART后免疫恢复的情况,本研究从辽宁省艾滋病抗病毒治疗数据库中筛选符合要求的HIV感染者和HIV/HCV共感染者,收集感染者基本人口学资料及HCV抗体检测结果、HIV/HCV共感染途径等资料。采用t检验或卡方检验进行组间比较,采用Kaplan-Meier乘积极限法绘制生存分析函数图。结果显示,本研究共纳入HIV感染者12742人,HIV/HCV共感染者340人。HIV感染者和HIV/HCV共感染者的不同人口学特征均差异显著(P<0.001)。HIV感染和HIV/HCV共感染者ART治疗后CD4⁺细胞数和CD4⁺/CD8⁺比值显著升高(P<0.05),CD8⁺细胞数比ART前显著下降(P<0.05)。HIV/HCV共感染者随着ART时长,CD4⁺T淋巴细胞数恢复情况始终显著低于HIV感染者(P<0.05)。生存分析曲线表明,HCV/HIV共感染者从艾滋病诊断开始随着ART的治疗CD4⁺细胞恢复情况显著低于HIV感染者,Log-Rank检验统计量为4.483(P=0.034)。本研究揭示,HCV感染对ART患者CD4⁺和CD8⁺T淋巴细胞的恢复有影响。ART后HIV/HCV共感染者中CD4⁺T淋巴细胞计数的改善低于HIV单一感染者,并且单一感染患者对ART的反应比合并感染患者更好。因此,建议在启动ART之前,对每个感染HIV的患者进行HCV抗体筛查。     

Molecular subtypes of ductal carcinoma in situ in African American and Caucasian American Women: Distribution and correlation with pathological features and outcome

Background: Molecular subtypes of breast cancer have been extensively studied in invasive carcinoma. They were shown to have a different distribution within the various ethnic populations. Few studies have applied the same classification to Ductal Carcinoma in Situ (DCIS). We report the distribution of the molecular breast cancer subtypes in DCIS between African American (AA) and Caucasian American (CA) women, their association with pathological features and outcome. Materials and methods: Tissue microarrays were constructed from paraffin blocks of 94 DCIS cases (67 AA and 27 CA) selected from a cohort of AA and CA patients diagnosed with DCIS between 1996 and 2000; mean age at diagnosis was 61 ± 12 for the AA and 58 ± 11 years for the CA group. TMA blocks were labeled with antibodies for ER, PR, HER2, Ki-67, and CK5/6. The cases were subtyped as Luminal A (ER+ and/or PR+; HER2?), Luminal B (ER+ and/or PR+; HER2+), HER2+ (ER?, PR?; HER2+), basal-like (BL) (ER?, PR?, HER2?; CK5/6+) or unclassified triple negative (UTN) (ER?, PR?, HER2?, CK5/6?). Information on grade, size and follow-up were obtained. Results: (1) Most DCIS cases were Luminal A, comprising 80% of the DCIS cases in AA and 92.6% in CA patients. (2) HER2+, BL and UTN DCIS subtypes were not seen in the CA population, and formed 9% of the DCIS cases in the AA population; these cases were all high grade. (3) In the cases with recurrence (8 AA and 1 CA patients), DCIS was Luminal A in 6 AA and 1 CA and Luminal B in 2 AA patients. Conclusion: The distribution of the molecular subtypes of DCIS did not show a significant difference between the two ethnic groups in our study. In addition, the risk of recurrence might not be higher in the non-luminal subtypes than in Luminal A and B.     

Genome-wide Association and Population Genetic Analysis of C-Reactive Protein in African American and Hispanic American Women

C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women''s Health Initiative SNP Health Association Resource. We discovered and validated a CRP-associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10⁻¹⁰). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10⁻¹⁷), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, we have identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific to populations of African descent.