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1.  Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts 
Human genetics  2012;131(9):1453-1466.
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5′UTR and exons 1–2 of the MSMB pre-mRNA, with exons 2–10 of the NCOA4 premRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between –27 and –236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
doi:10.1007/s00439-012-1182-2
PMCID: PMC3956317  PMID: 22661295
2.  Association Assessment of Copy Number Polymorphism and Risk of Age-Related Macular Degeneration 
Ophthalmology  2011;118(12):2442-2446.
Purpose
We previously identified a genetic copy number polymorphism (CNP147) that was statistically associated with age-related macular degeneration (AMD), and which resides downstream of the complement factor H (CFH) gene. Factor H protein is polymorphic at amino acid 402 in which the resulting histidine containing moiety has been established to impart significant risk of AMD. Here we present a method to precisely determine the exact copy number of CNP147 and examine in more detail the association with AMD.
Design
Case-control Study
Participants
421 AREDS (Age-related Eye Disease cohort Study) subjects of whom approximately 35% were diagnosed with neovascular disease, 19% with geographic atrophy, 16% with both, 30% with large drusen and 215 controls.
Methods
Using copy number assays available from Applied Biosystems Inc., we examined four loci spanning CNP147 and neighboring CNP148 in an AREDS matched case-control sample set. We analyzed these data by copy number while controlling for two high-risk CFH variants, rs1061170 (Y402H) and rs1410996. We phased the high risk CFH variants with CNP147 and analyzed haplotype frequencies in cases and controls. To further validate copy numbers, six Utah CEPH families (Centre D’etude du Polymorphism Humaine) were typed for CNP147 and the segregation assessed.
Main Outcome Measures
Increased or decreased risk of AMD from genetic loci.
Results
Having fewer than 2 copies of CNP147 is associated with an estimated 43% reduction in odds of having AMD in this sample set (adjusted odds ratio=0.57, P=0.006). CNP148 variation is rare in Caucasians and it was not statistically significant. Common haplotypes reveal that the risk alleles for rs1061170 and rs1410996 most frequently segregate with higher copy numbers for CNP147; but not exclusively, and that one haplotype that carried a deletion of CNP147 was highly protective (odds ratio=0.25 P=1.3×10−13) when compared to the reference.
Conclusions
In this matched subset of AREDS subjects, after adjusting for two known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD.
doi:10.1016/j.ophtha.2011.05.027
PMCID: PMC3223559  PMID: 21856016
Copy number polymorphism; age-related macular degeneration; HapMap 3; TaqMan Copy Number Assays; qPCR
3.  Genome-Wide Association Studies of Cancer 
Journal of Clinical Oncology  2010;28(27):4255-4267.
Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.
doi:10.1200/JCO.2009.25.7816
PMCID: PMC2953976  PMID: 20585100
4.  Molecular Evolutionary Analysis of ABCB5: The Ancestral Gene Is a Full Transporter with Potentially Deleterious Single Nucleotide Polymorphisms 
PLoS ONE  2011;6(1):e16318.
Background
ABCB5 is a member of the ABC protein superfamily, which includes the transporters ABCB1, ABCC1 and ABCG2 responsible for causing drug resistance in cancer patients and also several other transporters that have been linked to human disease. The ABCB5 full transporter (ABCB5.ts) is expressed in human testis and its functional significance is presently unknown. Another variant of this transporter, ABCB5 beta posses a “half-transporter-like” structure and is expressed in melanoma stem cells, normal melanocytes, and other types of pigment cells. ABCB5 beta has important clinical implications, as it may be involved with multidrug resistance in melanoma stem cells, allowing these stem cells to survive chemotherapeutic regimes.
Methodology/Principal Findings
We constructed and examined in detail topological structures of the human ABCB5 protein and determined in-silico the cSNPs (coding single nucleotide polymorphisms) that may affect its function. Evolutionary analysis of ABCB5 indicated that ABCB5, ABCB1, ABCB4, and ABCB11 share a common ancestor, which began duplicating early in the evolutionary history of chordates. This suggests that ABCB5 has evolved as a full transporter throughout its evolutionary history.
Conclusions/Significance
From our in-silco analysis of cSNPs we found that a large number of non-synonymous cSNPs map to important functional regions of the protein suggesting that these SNPs if present in human populations may play a role in diseases associated with ABCB5. From phylogenetic analyses, we have shown that ABCB5 evolved as a full transporter throughout its evolutionary history with an absence of any major shifts in selection between the various lineages suggesting that the function of ABCB5 has been maintained during mammalian evolution. This finding would suggest that ABCB5 beta may have evolved to play a specific role in human pigment cells and/or melanoma cells where it is predominantly expressed.
doi:10.1371/journal.pone.0016318
PMCID: PMC3029322  PMID: 21298007
5.  Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration 
Nature genetics  2006;38(4):458-462.
Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries1,2. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD3–8. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.
doi:10.1038/ng1750
PMCID: PMC2921703  PMID: 16518403
6.  UBIAD1 Mutation Alters a Mitochondrial Prenyltransferase to Cause Schnyder Corneal Dystrophy 
PLoS ONE  2010;5(5):e10760.
Background
Mutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure.
Methodology/Principal Findings
We characterized five novel mutations in the UBIAD1 gene in ten SCD families, including a first SCD family of Native American ethnicity. Examination of protein homology revealed that SCD altered amino acids which were highly conserved across species. Cell lines were established from patients including keratocytes obtained after corneal transplant surgery and lymphoblastoid cell lines from Epstein-Barr virus immortalized peripheral blood mononuclear cells. These were used to determine the subcellular localization of mutant and wild type protein, and to examine cholesterol metabolite ratios. Immunohistochemistry using antibodies specific for UBIAD1 protein in keratocytes revealed that both wild type and N102S protein were localized sub-cellularly to mitochondria. Analysis of cholesterol metabolites in patient cell line extracts showed no significant alteration in the presence of mutant protein indicating a potentially novel function of the UBIAD1 protein in cholesterol biochemistry. Molecular modeling was used to develop a model of human UBIAD1 protein in a membrane and revealed potentially critical roles for amino acids mutated in SCD. Potential primary and secondary substrate binding sites were identified and docking simulations indicated likely substrates including prenyl and phenolic molecules.
Conclusions/Significance
Accumulating evidence from the SCD familial mutation spectrum, protein homology across species, and molecular modeling suggest that protein function is likely down-regulated by SCD mutations. Mitochondrial UBIAD1 protein appears to have a highly conserved function that, at least in humans, is involved in cholesterol metabolism in a novel manner.
doi:10.1371/journal.pone.0010760
PMCID: PMC2874009  PMID: 20505825
8.  Multilocus analysis of age-related macular degeneration 
Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case–control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4–4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5–4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway’s involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.
doi:10.1038/ejhg.2009.23
PMCID: PMC2729805  PMID: 19259132
age-related macular degeneration; complement; ARMS2; HTRA1
9.  Multilocus analysis of age-related macular degeneration 
European Journal of Human Genetics  2009;17(9):1190-1199.
Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case–control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4–4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5–4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.
doi:10.1038/ejhg.2009.23
PMCID: PMC2729805  PMID: 19259132
age-related macular degeneration; complement; ARMS2; HTRA1
10.  An Analysis Pipeline for Genome-wide Association Studies 
Cancer informatics  2008;6:455-461.
We developed an efficient pipeline to analyze genome-wide association study single nucleotide polymorphism scan results. Perl scripts were used to convert genotypes called using the BRLMM algorithm into a modified PB format. We computed summary statistics characteristic of our case and control populations including allele counts, missing values, heterozygosity, measures of compliance with Hardy-Weinberg equilibrium, and several population difference statistics. In addition, we computed association tests, including exact tests of association for genotypes, alleles, the Cochran-Armitage linear trend test, and dominant, recessive, and overdominant models at every single nucleotide polymorphism (SNP). In addition, pairwise linkage disequilbrium statistics were elaborated, using the command line version of HaploView, which was possible by writing a reformatting script. Additional Perl scripts permit loading the results into a MySQL database conjoined with a Generic Genome Browser (gbrowse) for comprehensive visualization. This browser incorporates a download feature that provides actual case and control genotypes to users in associated genomic regions. Thus, re-analysis “on the fly” is possible for casual browser users from anywhere on the Internet.
PMCID: PMC2603547  PMID: 19096721
single nucleotide polymorphism; SNP; genetic association; GWAS; genetic epidemiology
11.  An Analysis Pipeline for Genome-wide Association Studies 
Cancer Informatics  2008;6:455-461.
We developed an efficient pipeline to analyze genome-wide association study single nucleotide polymorphism scan results. Purl scripts were used to convert genotypes called using the BRLMM algorithm into a modified PB format. We computed summary statistics characteristic of our case and control populations including allele counts, missing values, heterozygosity, measures of compliance with Hardy-Weinberg equilibrium, and several population difference statistics. In addition, we computed association tests, including exact tests of association for genotypes, alleles, the Cochran-Armitage linear trend test, and dominant, recessive, and overdominant models at every single nucleotide polymorphism (SNP). In addition, pairwise linkage disequilbrium statistics were elaborated, using the command line version of HaploView, which was possible by writing a reformatting script. Additional Perl scripts permit loading the results into a MySQL database conjoined with a Generic Genome Browser (gbrowse) for comprehensive visualization. This browser incorporates a download feature that provides actual case and control genotypes to users in associated genomic regions. Thus, re-analysis “on the fly” is possible for casual browser users from anywhere on the Internet.
PMCID: PMC2603547  PMID: 19096721
single nucleotide polymorphism; SNP; genetic association; GWAS; genetic epidemiology
12.  Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping 
BMC Genetics  2008;9:14.
Background
Genetic isolates such as the Ashkenazi Jews (AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap (CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups.
Results
A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean FST of 0.009 (P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium (LD) statistics (Haploview) as well as by expectation-maximization haplotype phase inference (HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview (50,397 vs. 44,169) or by HAP (59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU (e.g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ.
Conclusion
LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure.
doi:10.1186/1471-2156-9-14
PMCID: PMC2259380  PMID: 18251999
13.  Risk for HIV-1 Infection Associated With a Common CXCL12 (SDF1) Polymorphism and CXCR4 Variation in an African Population 
Summary
CXC chemokine ligand 12 (CXCL12), or stromal cell–derived factor 1 (SDF1), is the only known natural ligand for the HIV-1 coreceptor, CXC chemokine receptor 4 (CXCR4). A single nucleotide polymorphism (SNP) in the CXCL12 gene (SDF1-3′A) has been associated with disease progression to AIDS in some studies, but not others. Mutations in the CXCR4 gene are generally rare and have not been implicated in HIV-1/AIDS pathogenesis. This study analyzed the SDF1-3′A SNP and performed mutation screening for polymorphic markers in the CXCR4 gene to determine the presence or absence of significant associations with susceptibility to HIV-1 infection. The study consisted of 257 HIV-1–seropositive patients and 113 HIV-1–seronegative controls representing a sub-Saharan African population belonging to the Xhosa ethnic group of South Africa. The SDF1-3′A SNP was associated with an increased risk for HIV-1 infection (P = 0.0319) whereas no significant association was observed between the occurrence of the SDF1-3′A SNP and increased or decreased plasma levels of CXCL12. Comprehensive mutation analysis of the CXCR4 gene confirmed a high degree of genetic conservation within the coding region of this ancient population.
PMCID: PMC1369993  PMID: 16284526
CXC chemokine ligand 12 (CXCL12); CXC chemokine receptor 4 (CXCR4); SDF1-3′A single-nucleotide polymorphism; HIV-1 infection risk; African population
14.  Extended Haplotypes in the Complement Factor H (CFH) and CFH-related (CFHR) Family of Genes that Protect against Age-related Macular Degeneration: Identification, Ethnic Distribution and Evolutionary Implications 
Annals of medicine  2006;38(8):592-604.
Background
Variants in the complement factor H gene (CFH) are associated with age-related macular degeneration (AMD). CFH and five CFH-related genes (CFHR1-5) lie within the regulators of complement activation (RCA) locus on chromosome 1q32.
Aims and Methods
In this study, we refined the structural and evolutionary relationships between these genes and AMD using a combined molecular and immunohistochemical approach.
Results
We identify and characterize a large, common deletion that encompasses both the CFHR1 and CFHR3 genes. CFHR1, an abundant serum protein, is absent in subjects homozygous for the deletion. Analysis of AMD cases and controls from two cohorts demonstrates that deletion homozygotes comprise 1.1% of cases and 5.7% of the controls ( 2=32.8; P=1.6 E-09). CFHR1 and CFHR3 transcripts are abundant in liver, but undetectable in the ocular RPE/choroid complex. AMD-associated CFH/CFHR1/CFHR3 haplotypes are widespread in human populations.
Conclusion
The absence of CFHR1 and/or CFHR3 may account for the protective effects conferred by some CFH haplotypes. Moreover, the high frequencies of the 402H allele and the delCFHR1/CFHR3 alleles in African populations suggest an ancient origin for these alleles. The considerable diversity accumulated at this locus may be due to selection, which is consistent with an important role for the CFHR genes in innate immunity.
PMCID: PMC1905836  PMID: 17438673
Age-related macular degeneration; vision; Factor H; Factor H-related; complement; alternative pathway; deletion; haplotype; evolution
15.  Long homopurine•homopyrimidine sequences are characteristic of genes expressed in brain and the pseudoautosomal region 
Nucleic Acids Research  2006;34(9):2663-2675.
Homo(purine•pyrimidine) sequences (R•Y tracts) with mirror repeat symmetries form stable triplexes that block replication and transcription and promote genetic rearrangements. A systematic search was conducted to map the location of the longest R•Y tracts in the human genome in order to assess their potential function(s). The 814 R•Y tracts with ≥250 uninterrupted base pairs were preferentially clustered in the pseudoautosomal region of the sex chromosomes and located in the introns of 228 annotated genes whose protein products were associated with functions at the cell membrane. These genes were highly expressed in the brain and particularly in genes associated with susceptibility to mental disorders, such as schizophrenia. The set of 1957 genes harboring the 2886 R•Y tracts with ≥100 uninterrupted base pairs was additionally enriched in proteins associated with phosphorylation, signal transduction, development and morphogenesis. Comparisons of the ≥250 bp R•Y tracts in the mouse and chimpanzee genomes indicated that these sequences have mutated faster than the surrounding regions and are longer in humans than in chimpanzees. These results support a role for long R•Y tracts in promoting recombination and genome diversity during evolution through destabilization of chromosomal DNA, thereby inducing repair and mutation.
doi:10.1093/nar/gkl354
PMCID: PMC1464109  PMID: 16714445
16.  The B30.2(SPRY) Domain of the Retroviral Restriction Factor TRIM5α Exhibits Lineage-Specific Length and Sequence Variation in Primates 
Journal of Virology  2005;79(10):6111-6121.
Tripartite motif (TRIM) proteins are composed of RING, B-box 2, and coiled coil domains. Some TRIM proteins, such as TRIM5α, also possess a carboxy-terminal B30.2(SPRY) domain and localize to cytoplasmic bodies. TRIM5α has recently been shown to mediate innate intracellular resistance to retroviruses, an activity dependent on the integrity of the B30.2 domain, in particular primate species. An examination of the sequences of several TRIM proteins related to TRIM5 revealed the existence of four variable regions (v1, v2, v3, and v4) in the B30.2 domain. Species-specific variation in TRIM5α was analyzed by amplifying, cloning, and sequencing nonhuman primate TRIM5 orthologs. Lineage-specific expansion and sequential duplication occurred in the TRIM5α B30.2 v1 region in Old World primates and in v3 in New World monkeys. We observed substitution patterns indicative of selection bordering these particular B30.2 domain variable elements. These results suggest that occasional, complex changes were incorporated into the TRIM5α B30.2 domain at discrete time points during the evolution of primates. Some of these time points correspond to periods during which primates were exposed to retroviral infections, based on the appearance of particular endogenous retroviruses in primate genomes. The results are consistent with a role for TRIM5α in innate immunity against retroviruses.
doi:10.1128/JVI.79.10.6111-6121.2005
PMCID: PMC1091705  PMID: 15857996

Results 1-16 (16)