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author:("kosov, Roman")
1.  Relationship between Hysterectomy and Admixture in African American Women 
Objective
Most studies suggest that hysterectomies are more common in African Americans than in other ethnic groups. To assess this ethnic surgical disparity in a novel way, our main goal was to determine whether admixture (the proportion of sub-Saharan African or European origin in individuals) is associated with hysterectomy frequency in African American women in the Women’s Health Initiative (WHI).
Study Design
In this retrospective study, we used ancestry informative single nucleotide polymorphisms (SNPs) to estimate admixture proportions in >10,000 African American women from the WHI. Logistic regression models were used to assess the association between admixture and self-reported history of hysterectomy with and without controlling for relevant covariates. Multinomial logistic regression models were used to assess the association between admixture and self-reported age of hysterectomy. We also considered other potential risk factors (adiposity, hypertension, and education) for hysterectomy accounting for admixture.
Results
African admixture was a strong risk factor after adjusting for multiple covariates (OR 1.85, P<.0001). The admixture risk for hysterectomy was highest for those performed in the 35–39 age range (OR 3.08, P<.0001) and least evident in oldest ages (45 or older). Our analyses also suggest that adiposity, hypertension and education were independently associated with hysterectomy in this population group.
Conclusion
These results suggest that higher African admixture is associated with higher frequencies of hysterectomy and that genetic studies specifically targeting African American women and diseases associated with hysterectomy may be especially useful in understanding the pathogenesis and underlying cause of this disparity in health outcome.
doi:10.1016/j.ajog.2013.01.027
PMCID: PMC3613241  PMID: 23333549
ancestry; ancestry informative markers; fibroid tumors; Women’s Health Initiative
2.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
doi:10.1038/gene.2009.80
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
3.  Risk for Myasthenia Gravis maps to 151Pro→ Ala change in TNIP1 and to HLA-B*08 
Annals of neurology  2012;72(6):927-935.
Objective
The objective of this study is to comprehensively define the genetic basis of Early Onset Myasthenia Gravis.
Methods
We have carried out a two-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the HLA region.
Results
We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10−92, OR = 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10−113, OR = 6.41). In addition to the expected association with PTPN22 (rs2476601, OR =1.71, p = 8.2 ×10−10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR = 1.91, p = 3.2 × 10−10).
Interpretation
The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8+ T-cells may play a key role in disease initiation or pathogenesis.
doi:10.1002/ana.23691
PMCID: PMC3535539  PMID: 23055271
4.  Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants 
Human Molecular Genetics  2012;21(23):5209-5221.
To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
doi:10.1093/hmg/dds359
PMCID: PMC3490520  PMID: 22936693
5.  Classical HLA-DRB1 and DPB1 Alleles Account for HLA Associations with Primary Biliary Cirrhosis 
Genes and immunity  2012;13(6):461-468.
Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with HLA region polymorphisms. To determine if associations can be explained by classical HLA determinants we studied Italian 676 cases and 1440 controls with genotyped with dense single nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (p = 1.59 × 10−11) was the strongest predisposing allele where as DRB1*11 (p = 1.42 × 10−10) was protective. Additionally DRB1*14 and the DPB1 association (DPB1*03:01) (p = 9.18 × 10−7) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.
doi:10.1038/gene.2012.17
PMCID: PMC3423484  PMID: 22573116
genetic risk; risk allele; imputation; antigen binding pocket; autoimmune disease
6.  Genome-wide association study identifies novel loci predisposing to cutaneous melanoma† 
Human Molecular Genetics  2011;20(24):5012-5023.
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10−10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
doi:10.1093/hmg/ddr415
PMCID: PMC3298855  PMID: 21926416
7.  Relationship between Adiposity and Admixture in African American and Hispanic American Women 
Objective
To investigate whether differences in admixture in African American (AFA) and Hispanic American (HA) adult women are associated with adiposity and adipose distribution.
Design
The proportion of European, sub– Saharan African and Amerindian admixture was estimated for AFA and HA women in the Women's Heath Initiative using 92 ancestry informative markers. Analyses assessed the relationship between admixture and adiposity indices.
Subjects
11712 AFA and 5088 HA self– identified post– menopausal women.
Results
There was a significant positive association between body mass index (BMI) and African admixture when BMI was considered as a continuous variable, and age, education, physical activity, parity, family income and smoking were included covariates (p < 10− 4). A dichotomous model (upper and lower BMI quartiles) showed that African admixture was associated with a high odds ratio [OR = 3.27 (for 100% admixture compared to 0% admixture), 95% confidence interval (CI) 2.08 – 5.15]. For HA there was no association between BMI and admixture. In contrast, when waist to hip ratio (WHR) was used as a measure of adipose distribution, there was no significant association between WHR and admixture in AFA but there was a strong association in HA (p<10− 4; OR Amerindian admixture = 5.93, CI = 3.52 – 9.97).
Conclusion
These studies show that 1) African admixture is associated with BMI in AFA women; 2) Amerindian admixture is associated with WHR but not BMI in HA women; and 3) it may be important to consider different measurements of adiposity and adipose distribution in different ethnic population groups.
doi:10.1038/ijo.2011.84
PMCID: PMC3137678  PMID: 21487399
European admixture; African admixture; Amerindian admixture; post–menopausal women; waist to hip ratio; body mass index
8.  Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis 
Nature genetics  2010;42(8):658-660.
A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38).
doi:10.1038/ng.627
PMCID: PMC3150510  PMID: 20639880
9.  Ancestry Informative Marker Sets for Determining Continental Origin and Admixture Proportions in Common Populations in America 
Human mutation  2009;30(1):69-78.
To provide a resource for assessing continental ancestry in a wide variety of genetic studies we identified, validated and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan® assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.
doi:10.1002/humu.20822
PMCID: PMC3073397  PMID: 18683858
population structure; continental ancestry; population stratification; ancestry informative markers
10.  A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus 
Nature genetics  2009;41(11):1228-1233.
Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P ≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
doi:10.1038/ng.468
PMCID: PMC2925843  PMID: 19838195
11.  European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups 
Molecular Medicine  2009;15(11-12):371-383.
The definition of European population genetic substructure and its application to understanding complex phenotypes is becoming increasingly important. In the current study using over 4,000 subjects genotyped for 300,000 single-nucleotide polymorphisms (SNPs), we provide further insight into relationships among European population groups and identify sets of SNP ancestry informative markers (AIMs) for application in genetic studies. In general, the graphical description of these principal components analyses (PCA) of diverse European subjects showed a strong correspondence to the geographical relationships of specific countries or regions of origin. Clearer separation of different ethnic and regional populations was observed when northern and southern European groups were considered separately and the PCA results were influenced by the inclusion or exclusion of different self-identified population groups including Ashkenazi Jewish, Sardinian, and Orcadian ethnic groups. SNP AIM sets were identified that could distinguish the regional and ethnic population groups. Moreover, the studies demonstrated that most allele frequency differences between different European groups could be controlled effectively in analyses using these AIM sets. The European substructure AIMs should be widely applicable to ongoing studies to confirm and delineate specific disease susceptibility candidate regions without the necessity of performing additional genome-wide SNP studies in additional subject sets.
doi:10.2119/molmed.2009.00094
PMCID: PMC2730349  PMID: 19707526
12.  An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels 
BMC Genetics  2009;10:39.
Background
Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia.
Results
In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups.
Conclusion
These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.
doi:10.1186/1471-2156-10-39
PMCID: PMC2728728  PMID: 19630973
13.  Analysis of East Asia Genetic Substructure Using Genome-Wide SNP Arrays 
PLoS ONE  2008;3(12):e3862.
Accounting for population genetic substructure is important in reducing type 1 errors in genetic studies of complex disease. As efforts to understand complex genetic disease are expanded to different continental populations the understanding of genetic substructure within these continents will be useful in design and execution of association tests. In this study, population differentiation (Fst) and Principal Components Analyses (PCA) are examined using >200 K genotypes from multiple populations of East Asian ancestry. The population groups included those from the Human Genome Diversity Panel [Cambodian, Yi, Daur, Mongolian, Lahu, Dai, Hezhen, Miaozu, Naxi, Oroqen, She, Tu, Tujia, Naxi, Xibo, and Yakut], HapMap [ Han Chinese (CHB) and Japanese (JPT)], and East Asian or East Asian American subjects of Vietnamese, Korean, Filipino and Chinese ancestry. Paired Fst (Wei and Cockerham) showed close relationships between CHB and several large East Asian population groups (CHB/Korean, 0.0019; CHB/JPT, 00651; CHB/Vietnamese, 0.0065) with larger separation with Filipino (CHB/Filipino, 0.014). Low levels of differentiation were also observed between Dai and Vietnamese (0.0045) and between Vietnamese and Cambodian (0.0062). Similarly, small Fst's were observed among different presumed Han Chinese populations originating in different regions of mainland of China and Taiwan (Fst's <0.0025 with CHB). For PCA, the first two PC's showed a pattern of relationships that closely followed the geographic distribution of the different East Asian populations. PCA showed substructure both between different East Asian groups and within the Han Chinese population. These studies have also identified a subset of East Asian substructure ancestry informative markers (EASTASAIMS) that may be useful for future complex genetic disease association studies in reducing type 1 errors and in identifying homogeneous groups that may increase the power of such studies.
doi:10.1371/journal.pone.0003862
PMCID: PMC2587696  PMID: 19057645
14.  Kinesin-II Is Preferentially Targeted to Assembling Cilia and Is Required for Ciliogenesis and Normal Cytokinesis in TetrahymenaV⃞ 
Molecular Biology of the Cell  1999;10(10):3081-3096.
We cloned two genes, KIN1 and KIN2, encoding kinesin-II homologues from the ciliate Tetrahymena thermophila and constructed strains lacking either KIN1 or KIN2 or both genes. Cells with a single disruption of either gene showed partly overlapping sets of defects in cell growth, motility, ciliary assembly, and thermoresistance. Deletion of both genes resulted in loss of cilia and arrests in cytokinesis. Mutant cells were unable to assemble new cilia or to maintain preexisting cilia. Double knockout cells were not viable on a standard medium but could be grown on a modified medium on which growth does not depend on phagocytosis. Double knockout cells could be rescued by transformation with a gene encoding an epitope-tagged Kin1p. In growing cells, epitope-tagged Kin1p preferentially accumulated in cilia undergoing active assembly. Kin1p was also detected in the cell body but did not show any association with the cleavage furrow. The cell division arrests observed in kinesin-II knockout cells appear to be induced by the loss of cilia and resulting cell paralysis.
PMCID: PMC25561  PMID: 10512852

Results 1-14 (14)