The frequency of allelic polymorphism of genes encoding immunoproteasome catalytic subunits in acute coronary syndrome patients

Large multifunctional protease LMP2 (Arg60-->His) and LMP7 (Lys145-->Gln) gene allelic polymorphism in 200 patients with acute coronary syndrome and in 80 practically healthy people was determinated. It was shown that interrelation of genotypes Arg/Arg, Arg/His and His/His in LMP2 gene polymorphism is 52, 40.5 and 7.5 % correspondingly (in control group 53.8, 38.7, 7.5 %; P > 0.05 by chi2-test). Analysis of LMP7 gene polymorphism has shown that Lys/Lys - 89.5 %, Lys/Gln - 10.5 %, Gin/Gin - 0 % (in control group 93.8, 6.2, 0 % correspondingly; P > 0.05). The data show that LMP2 and LMP7 gene polymorphism is not a risk factor of acute coronary syndrome in Ukrainian population.     

A genome-wide association search for type 2 diabetes genes in African Americans

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10⁻⁸). SNP rs7560163 (P = 7.0×10⁻⁹, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10⁻⁵) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.     

Characterizing the admixed African ancestry of African Americans

Background

Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.

Results

From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.

Conclusions

These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.     

BRCA1 mutations in African Americans

The breast cancer predisposing gene, BRCA1, was analyzed for germline mutations in 45 African American families at high-risk for hereditary breast cancer. Patients were considered high-risk if they had a family history of the disease, early onset breast cancer, bilateral breast cancer, or breast and ovarian cancer. The entire BRCA1 coding and flanking intron regions have been examined by single stranded conformation polymorphism analysis followed by sequencing of variant bands. Eleven different BRCA1 germline mutations/variations were identified in 7 patients from the 45 high-risk families. Two pathogenic, protein-truncating mutations were detected in exon 11. A ten base pair tandem duplication, 943ins10, was present in a woman with breast and ovarian cancer whose first-degree relatives had prostate cancer. A four base pair deletion, 3450del4, was detected in a breast cancer patient with five cases of breast cancer in the family; two of the proband's sisters with breast cancer also carried the same mutation. Four amino acid substitutions (Lys1183Arg, Leu1564Pro, Gln1785His, and Glu1794Asp) and four nucleotide substitutions in intron 22 (IVS22+78 C/A, IVS22+67 T/C, IVS22+8 T/A and IVS22+7 T/C) were observed in patients and not in control subjects. One early onset breast cancer patient carried five distinct BRCA1 variations, two amino acid substitutions and three substitutions in intron 22. An amino acid substitution in exon 11, Ser1140Gly, was identified in 3 different unrelated patients and in 6 of 92 control samples. The latter probably represents a benign polymorphism. Electronic Publication     

The Quality of Mental Health Care for African Americans

In response to the Surgeon General's request for more research on racial disparities in mental health care, especially research that includes high-need populations (e.g., the homeless, incarcerated, children in foster care, and substance abusers), we examined racial disparities in the provision of mental health counseling, psychotherapy, and pharmacotherapy in hospital outpatient settings using nationally representative data from the 1997 National Hospital Ambulatory Medical Care Survey (NHAMCS). After controlling for diagnosis and other factors, we found that African Americans were less likely than whites to receive mental health counseling and psychotherapy, but more likely than whites to receive pharmacotherapy. We also found that substance abuse clinics were more likely than primary care and specialty mental health clinics to provide mental health counseling and psychotherapy. However, specialty mental health clinics were the only clinics to provide pharmacotherapy. Future research should examine racial disparities in a variety of settings, controlling for diagnosis as well as other factors.     

Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.     

African ancestry is associated with asthma risk in African Americans

Background

Asthma is a common complex condition with clear racial and ethnic differences in both prevalence and severity. Asthma consultation rates, mortality, and severe symptoms are greatly increased in African descent populations of developed countries. African ancestry has been associated with asthma, total serum IgE and lower pulmonary function in African-admixed populations. To replicate previous findings, here we aimed to examine whether African ancestry was associated with asthma susceptibility in African Americans. In addition, we examined for the first time whether African ancestry was associated with asthma exacerbations.

Methodology/Principal Findings

After filtering for self-reported ancestry and genotype data quality, samples from 1,117 self-reported African-American individuals from New York and Baltimore (394 cases, 481 controls), and Chicago (321 cases followed for asthma exacerbations) were analyzed. Genetic ancestry was estimated based on ancestry informative markers (AIMs) selected for being highly divergent among European and West African populations (95 AIMs for New York and Baltimore, and 66 independent AIMs for Chicago). Among case-control samples, the mean African ancestry was significantly higher in asthmatics than in non-asthmatics (82.0±14.0% vs. 77.8±18.1%, mean difference 4.2% [95% confidence interval (CI):2.0–6.4], p<0.0001). This association remained significant after adjusting for potential confounders (odds ratio: 4.55, 95% CI: 1.69–12.29, p = 0.003). African ancestry failed to show an association with asthma exacerbations (p = 0.965) using a model based on longitudinal data of the number of exacerbations followed over 1.5 years.

Conclusions/Significance

These data replicate previous findings indicating that African ancestry constitutes a risk factor for asthma and suggest that elevated asthma rates in African Americans can be partially attributed to African genetic ancestry.     

Charting the ancestry of African Americans

The Atlantic slave trade promoted by West European empires (15th-19th centuries) forcibly moved at least 11 million people from Africa, including about one-third from west-central Africa, to European and American destinations. The mitochondrial DNA (mtDNA) genome has retained an imprint of this process, but previous analyses lacked west-central African data. Here, we make use of an African database of 4,860 mtDNAs, which include 948 mtDNA sequences from west-central Africa and a further 154 from the southwest, and compare these for the first time with a publicly available database of 1,148 African Americans from the United States that contains 1,053 mtDNAs of sub-Saharan ancestry. We show that >55% of the U.S. lineages have a West African ancestry, with <41% coming from west-central or southwestern Africa. These results are remarkably similar to the most up-to-date analyses of the historical record.     

Obesity and Pulmonary Function in African Americans

BackgroundObesity prevalence in United States (US) adults exceeds 30% with highest prevalence being among blacks. Obesity is known to have significant effects on respiratory function and obese patients commonly report respiratory complaints requiring pulmonary function tests (PFTs). However, there is no large study showing the relationship between body mass index (BMI) and PFTs in healthy African Americans (AA).ObjectiveTo determine the effect of BMI on PFTs in AA patients who did not have evidence of underlying diseases of the respiratory system.MethodsWe reviewed PFTs of 339 individuals sent for lung function testing who had normal spirometry and lung diffusion capacity for carbon monoxide (DLCO) with wide range of BMI.ResultsFunctional residual capacity (FRC) and expiratory reserve volume (ERV) decreased exponentially with increasing BMI, such that morbid obesity resulted in patients breathing near their residual volume (RV). However, the effects on the extremes of lung volumes, at total lung capacity (TLC) and residual volume (RV) were modest. There was a significant linear inverse relationship between BMI and DLCO, but the group means values remained within the normal ranges even for morbidly obese patients.ConclusionsWe showed that BMI has significant effects on lung function in AA adults and the greatest effects were on FRC and ERV, which occurred at BMI values < 30 kg/m2. These physiological effects of weight gain should be considered when interpreting PFTs and their effects on respiratory symptoms even in the absence of disease and may also exaggerate existing lung diseases.     

Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D Levels among African Americans

Vitamin D is implicated in a wide range of health outcomes, and although environmental predictors of vitamin D levels are known, the genetic drivers of vitamin D status remain to be clarified. African Americans are a group at particularly high risk for vitamin D insufficiency but to date have been virtually absent from studies of genetic predictors of circulating vitamin D levels. Within the Southern Community Cohort Study, we investigated the association between 94 single nucleotide polymorphisms (SNPs) in five vitamin D pathway genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1) and serum 25-hydroxyvitamin D (25(OH)D) levels among 379 African American and 379 Caucasian participants. We found statistically significant associations with three SNPs (rs2298849 and rs2282679 in the GC gene, and rs10877012 in the CYP27B1 gene), although only for African Americans. A genotype score, representing the number of risk alleles across the three SNPs, alone accounted for 4.6% of the variation in serum vitamin D among African Americans. A genotype score of 5 (vs. 1) was also associated with a 7.1 ng/mL reduction in serum 25(OH)D levels and a six-fold risk of vitamin D insufficiency (<20 ng/mL) (odds ratio 6.0, p = 0.01) among African Americans. With African ancestry determined from a panel of 276 ancestry informative SNPs, we found that high risk genotypes did not cluster among those with higher African ancestry. This study is one of the first to investigate common genetic variation in relation to vitamin D levels in African Americans, and the first to evaluate how vitamin D-associated genotypes vary in relation to African ancestry. These results suggest that further evaluation of genetic contributors to vitamin D status among African Americans may help provide insights regarding racial health disparities or enable the identification of subgroups especially in need of vitamin D-related interventions.     

Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA

African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA pools were genotyped in duplicate on the Illumina HumanHap550-Duo BeadChip. Normalization methods were developed and applied to array intensity values to reduce inter-array variance. Allele frequencies were calculated from normalized channel intensities and compared between case and control pools. Three SNPs had p values of <1.0E−6: rs4462445 (ch 13), rs4821469 (ch 22) and rs8077346 (ch 17). After normalization, top scoring SNPs (n = 65) were genotyped individually in 464 of the original cases and 478 of the controls, with replication in 336 non-DM ESRD cases and 363 non-nephropathy controls. Sixteen SNPs were associated with non-DM ESRD (p < 7.7E−4, Bonferroni corrected). Twelve of these SNPs are in or near the MYH9 gene. The four non-MYH9 SNPs that were associated with non-DM ESRD in the pooled samples were not associated in the replication set. Five SNPs that were modestly associated in the pooled samples were more strongly associated in the replication and/or combined samples. This is the first GWAS for non-DM ESRD in African Americans using pooled DNA. We demonstrate strong association between non-DM ESRD in African Americans with MYH9, and have identified additional candidate loci.     

High allelic polymorphism,moderate sequence diversity and diversifying selection for B-NK but not B-lec,the pair of lectin-like receptor genes in the chicken MHC

We previously characterised the C-type lectin-like receptor genes B-NK and B-lec, located next to each other in opposite orientations in the chicken major histocompatibility complex (MHC). We showed that B-NK is an inhibitory receptor expressed on natural killer cells, whereas B-lec is an activation-induced receptor with a broader expression pattern. It is interesting to note that the chicken MHC has been linked with resistance or susceptibility to Marek's disease virus (MDV), an oncogenic herpes virus. Recent reports show that the C-type lectin-like receptors in mouse and rat (Ly49H, NKR-P1 and Clr) are associated with resistance to another herpesvirus, cytomegalovirus (CMV). Therefore, B-NK and B-lec are potential candidate genes for the MHC-mediated resistance to MDV. In this paper, we report that both genes encode glycosylated type II membrane proteins that form disulphide-linked homodimers. The gene sequences from nine lines of domestic chicken representing seven haplotypes show that B-lec is well conserved between the different haplotypes, apparently under purifying selection. In contrast, B-NK has high allelic polymorphism and moderate sequence diversity, with 21 nucleotide changes in the complementary deoxyribonucleic acids (cDNAs) resulting in 20 amino acid substitutions. The allelic variations include substitutions, an indel and loss/gain of three predicted N-linked glycosylation sites. Strikingly, there is as much as 7% divergence between protein sequences of B-NK from different haplotypes, greater than the difference observed between the highly polymorphic human KIR NK receptors. Analysis of ds and dn reveal evidence of strong positive selection for B-NK to be polymorphic at the protein level, and modelling demonstrates significant variation between haplotypes in the predicted ligand binding face of B-NK.     

The Genetic Ancestry of African Americans,Latinos, and European Americans across the United States

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry.     

Equine plasminogen polymorphism: allelic frequencies in 23 breeds

A modified procedure for detection of the two alleles of equine plasminogen using Western blotting methods following polyacrylamide gel isoelectric focusing is described. Gene frequencies in 23 breeds and Equus przewalskii are provided.     

Atrial Fibrillation and Colonic Neoplasia in African Americans

Background

Colorectal cancer (CRC) and atrial fibrillation/flutter (AF) share several risk factors including increasing age and obesity. However, the association between CRC and AF has not been thoroughly examined, especially in African Americans. In this study we aimed to assess the prevalence of AF and its risk factors in colorectal neoplasia in an African American.

Methods

We reviewed records of 527 African American patients diagnosed with CRC and 1008 patients diagnosed with benign colonic lesions at Howard University Hospital from January 2000 to December 2012. A control group of 731 hospitalized patients without any cancer or colonic lesion were randomly selected from the same time and age range, excluding patients who had diagnosis of both CRC and/or adenoma. The presence or absence of AF was based upon ICD-9 code documentation. The prevalence of AF in these three groups was compared by multivariate logistic regression.

Results

The prevalence of AF was highest among CRC patients (10%) followed by adenoma patients (7.2%) then the control group (5.4%, P for trend = 0.002). In the three groups of participants, older age (P<0.008) and heart failure (P<0.001) were significantly associated with higher risk of AF. After adjusting for these risk factors, CRC (OR: 1.4(95%CI):0.9–2.2, P = 0.2) and adenoma (OR: 1.1(95%CI):0.7–1.6, P = 0.7) were not significantly associated AF compared to control group.

Conclusions

AF is highly prevalent among CRC patients; 1 in 10 patients had AF in our study. The predictors of AF in CRC was similar to that in adenoma and other patients after adjustment for potential confounders suggesting that the increased AF risk in CRC is explained by higher prevalence of AF risk factors.