Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
The expense of human leukocyte antigen (HLA) allele genotyping has motivated the development of imputation methods that use dense single nucleotide polymorphism (SNP) genotype data and the region’s haplotype structure, but the performance of these methods in admixed populations (such as African Americans) has not been adequately evaluated. We compared genotype-based—derived from both genome-wide genotyping and targeted sequencing—imputation results to existing allele data for HLA–DRB1, −DQB1, and –DPB1.
In European Americans, the newly-developed HLA Genotype Imputation with Attribute Bagging (HIBAG) method outperformed HLA*IMP:02. In African Americans, HLA*IMP:02 performed marginally better than HIBAG pre-built models, but HIBAG models constructed using a portion of our African American sample with both SNP genotyping and four-digit HLA class II allele typing had consistently higher accuracy than HLA*IMP:02. However, HIBAG was significantly less accurate in individuals heterozygous for local ancestry (p ≤0.04). Accuracy improved in models with equal numbers of African and European chromosomes. Variants added by targeted sequencing and SNP imputation further improved both imputation accuracy and the proportion of high quality calls.
Combining the HIBAG approach with local ancestry and dense variant data can produce highly-accurate HLA class II allele imputation in African Americans.
HLA; African American; Single nucleotide polymorphisms; Imputation; Admixture
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
To identify the genetic predictors of serum total IgE levels.
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions—6p24.3–p12.1, 17p13.3–13.1, 2p13.3–q12.1, and 6q23.3–q25.2—in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3–p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10−11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3–13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10−6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.
Matrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A Threonine to Alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction (MI) and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a non-invasive measure of subclinical coronary atherosclerosis.
Methods and Results
In 605 Epidemiology of Coronary Artery Calcification Study participants, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relationship between MGP Thr83Ala and CAC progression (P=0.001). In the fully-adjusted model, every one Ala83 allele increase was associated with an estimated 1.9% (95% CI: 0.7%, 3.0%) per one-year since baseline larger increase in CAC quantity. A proxy SNP for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) Study.
Increased risk of MI associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.
Population; Genetics; Atherosclerosis; Calcium; Imaging
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American individuals are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care, or whether there is a predisposing genetic component.
To assess the relationship between genetic ancestry and severe exacerbations among African American individuals with asthma.
Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These individuals were 12–56 years of age; received care from a single, large health system; and had a physician diagnosis of asthma. Genetic ancestry was estimated using a set of validated ancestry informative markers. Severe exacerbations (i.e., asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.
We assessed genetic ancestry in 392 African American individuals with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among males but not among females. The association among males persisted after adjusting for potential confounders (relative risk of 4.30 for every 20% increase in African ancestry; P-value 0.029).
African ancestry was a significantly and positively associated with severe exacerbations among African American males. These findings suggest that a portion of the risk of asthma exacerbations in this high risk group is attributable to a genetic risk factor which partitions with ancestry.
asthma; continental population groups; African continental ancestry group; genetic association study; health status disparities; minority health
Genome-wide association studies of asthma have implicated many genetic risk factors, with
well-replicated associations at approximately 10 loci that account for only a small proportion of
the genetic risk.
We aimed to identify additional asthma risk loci by performing an extensive replication
study of the results from the EVE Consortium meta-analysis.
We selected 3186 SNPs for replication based on the p-values from the EVE Consortium
meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine
different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association
analyses were conducted within each participating study and the resulting test statistics were
combined in a meta-analysis.
Two novel associations were replicated in European Americans: rs1061477 in the
KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25)
and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not
replicate any additional associations in the African American or Latino individuals.
This extended replication study identified two additional asthma risk loci in populations
of European descent. The absence of additional loci for African Americans and Latino individuals
highlights the difficulty in replicating associations in admixed populations.
Asthma; genetic risk factors; meta-analysis; KLK3
A BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFF expression in vivo increases in natural rhinovirus infection. BAFF may play a role in airway antiviral immunity and impact asthma exacerbation rates.
BAFF; B-cell activating factor; tumor necrosis factor ligand superfamily; asthma; asthma exacerbations; genetics
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome-wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M SNP array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy-neutral) and 6q (copy-loss). Combined loss and copy-neutral events were associated with increasing disease grade (p=0.03), stage (p=0.01), and diagnostic PSA (p=0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The ‘regulation of apoptosis’ pathway was associated with stage of disease (p=0.004), while the ‘reproductive cellular process’ pathway was associated with diagnostic PSA (p=0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (p=0.007). These findings confirm known regions of CNAs in prostate cancer, and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help clarify the genetic basis of prostate cancer aggressiveness.
Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.
In humans, genetic variation and dietary factors may alter the biologic effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP-DNA adduct levels in human prostate. In the present study, we expanded our investigation to estimate the associations between beverage consumption and PhIP-DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP-DNA adduct levels showing an inverse correlation in both tumor (p=0.006) and non-tumor (p=0.002) prostate cells. Red wine consumption differed significantly between African-American and white cases, but PhIP-DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP-DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and non-specific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13-16%) of the variation in PhIP-DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP-DNA adduct variation in African-American cases, while only 19% of the PhIPDNA adduct variation in whites. We conclude that red wine consumption may counteract biologic effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans.
compounds, heterocyclic; resveratrol; UDP-glucuronosyltransferase; sulfotransferases; African Americans; chemoprevention
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies (GWAS) of asthma in 5,416 asthma cases representing European Americans, African Americans/African Caribbeans, and Latinos, and replicated five regions among the most significant signals in 12,649 individuals from the same ethnic groups. Four were at previously reported loci on 17q21, and near the IL1RL1, TSLP, and IL33, genes, but we report for the first time that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a novel association with asthma in the PYHIN1, gene that was specific to individuals of African descent (p=3.9×10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, PAA-meta = 6.51×10−10) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.
Lung cancer continues to be the leading cause of cancer death in the USA and the best example of a cancer with undisputed evidence of environmental risk. However, a genetic contribution to lung cancer has also been demonstrated by studies of familial aggregation, family-based linkage, candidate gene studies and most recently genome-wide association studies (GWAS). The African-American population has been underrepresented in these genetic studies and has patterns of cigarette use and linkage disequilibrium that differ from patterns in other populations. Therefore, studies in African-Americans can provide complementary data to localize lung cancer susceptibility genes and explore smoking dependence-related genes. We used admixture mapping to further characterize genetic risk of lung cancer in a series of 837 African-American lung cancer cases and 975 African-American controls genotyped at 1344 ancestry informative single-nucleotide polymorphisms. Both case-only and case–control analyses were conducted using ADMIXMAP adjusted for age, sex, pack-years of smoking, family history of lung cancer, history of emphysema and study site. In case-only analyses, excess European ancestry was observed over a wide region on chromosome 1 with the largest excess seen at rs6587361 for non-small-cell lung cancer (NSCLC) (Z-score = −4.33; P = 1.5 × 10−5) and for women with NSCLC (Z-score = −4.82; P = 1.4 × 10−6). Excess African ancestry was also observed on chromosome 3q with a peak Z-score of 3.33 (P = 0.0009) at rs181696 among ever smokers with NSCLC. These results add to the findings from the GWAS in Caucasian populations and suggest novel regions of interest.
African American patients suffer disproportionately from uncontrolled asthma. Treatment with an inhaled corticosteroid (ICS) is considered first-line therapy for persistent asthma.
To determine the degree to which African American patients respond to ICS medication and whether the level of response is influenced by other factors, including genetic ancestry.
Patients aged 12-56 years who received care from a large health system in southeast Michigan and who resided in Detroit were recruited to participate if they had a diagnosis of asthma. Patients were treated with 6 weeks of inhaled beclomethasone dipropionate, and pulmonary function was re-measured after treatment. Ancestry was determined by genotyping ancestry informative markers. The main outcome measure was ICS responsiveness defined as the change in pre-bronchodilator FEV1 over the 6-week course of treatment.
Among 147 participating African American patients with asthma, average improvement in FEV1 following 6 weeks of ICS treatment was 11.6%. The mean proportion of African ancestry in this group was 78.4%. The degree of baseline bronchodilator reversibility was the only factor consistently associated ICS responsiveness as measured by both an improvement in FEV1 and in patient reported asthma control (P=0.001 and P=0.021, respectively). The proportion of African ancestry was not significantly associated with ICS responsiveness.
While baseline pulmonary function parameters appear to be associated with the likelihood to respond to ICS treatment, the proportion of genetic African ancestry does not. This study suggests that genetic ancestry may not contribute to differences in ICS controller response among African American patients with asthma.
Although African American patients suffer disproportionately from asthma-related complications, response to ICS controller therapy does not appear to be dependent on an individual’s proportion of African ancestry.
Personalized medicine will be most beneficial to groups disproportionately affected by disease complications. Here we find baseline bronchodilator reversibility but not African ancestry to be associated with ICS responsiveness among African American patients with asthma.
inhaled corticosteroids; asthma; race-ethnicity; continental population groups; ancestry; urban health
Genome-wide linkage and association studies have uncovered variants associated with sarcoidosis, a multi-organ granulomatous inflammatory disease. African ancestry may influence disease pathogenesis since African Americans are more commonly affected by sarcoidosis. Therefore, we conducted the first sarcoidosis genome-wide ancestry scan using a map of 1,384 highly ancestry informative single nucleotide polymorphisms genotyped on 1,357 sarcoidosis cases and 703 unaffected controls self-identified as African American. The most significant ancestry association was at marker rs11966463 on chromosome 6p22.3 (ancestry association risk ratio (aRR)= 1.90; p=0.0002). When we restricted the analysis to biopsy-confirmed cases, the aRR for this marker increased to 2.01; p=0.00007. Among the eight other markers that demonstrated suggestive ancestry associations with sarcoidosis were rs1462906 on chromosome 8p12 which had the most significant association with European ancestry (aRR=0.65; p=0.002), and markers on chromosomes 5p13 (aRR=1.46; p=0.005) and 5q31 (aRR=0.67; p=0.005), which correspond to regions we previously identified through sib pair linkage analyses. Overall, the most significant ancestry association for Scadding stage IV cases was to marker rs7919137 on chromosome 10p11.22 (aRR=0.27; p=2×10−5), a region not associated with disease susceptibility. In summary, through admixture mapping of sarcoidosis we have confirmed previous genetic linkages and identified several novel putative candidate loci for sarcoidosis.
Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma; yet, there is significant variability in treatment response. Dual specificity phosphatase-1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.
To determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.
Study participants with asthma were drawn from the following multi-ethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study, the Study of African Americans, Asthma, Genes & Environments (SAGE), and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICS for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in forced expiratory volume at one second (FEV1) and self-reported asthma control.
DUSP1 polymorphisms, rs881152 and rs34507926, localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA participants. This interaction was also seen for rs881152 among SAPPHIRE, but not SAGE participants. Among the group of SAPPHIRE patients prospectively treated with ICS for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.
DUSP1 polymorphisms were associated with clinical response to ICS therapy, and therefore, may be useful in the future to identify asthma patients more likely to respond to this controller treatment.
These findings further our understanding of ICS pharmacogenetics and will hopefully result in improved tailoring of this controller therapy among individuals with asthma and in better disease control.
We identified genetic variants in DUSP1 which appeared to mediate the clinical response to inhaled corticosteroid (ICS) medication. These findings may eventually assist in identifying individuals with asthma most likely to respond this controller therapy.
Asthma; inhaled corticosteroids; dual specificity phosphatase-1; DUSP1; corticosteroid responsiveness
Rare, inactivating mutations in the BRCA1 gene appear to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations, e.g., missense mutations, in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200 kb-region surrounding (and including) the BRCA1 gene. We also used the Genotype-IBD Sharing Test (GIST) to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln356Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (p=0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval = 1.21 to 4.20). Notably, BRCA1 Gln356Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, GIST results suggest that Gln356Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (p=0.022). Thus, we have identified a common, non-synonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.
prostate; cancer; genetics; BRCA1; risk
There are considerable racial disparities in prostate cancer risk, with a 60% higher incidence rate among African American (AA) men compared with European American (EA) men, and a 2.4 fold higher mortality rate in AA men than in EA men. Recently, studies have implicated several African-ancestry associated prostate cancer susceptibility loci on chromosome 8q24. In the current study, we performed admixture mapping in AA men from two independent case-control studies of prostate cancer to confirm the 8q24 ancestry association and also identify other genomic regions that may harbor prostate cancer susceptibility genes. A total of 482 cases and 261 controls were genotyped for 1,509 ancestry informative markers across the genome. The mean estimated individual admixture proportions were 20% European and 80% African. The most significant observed increase in European ancestry occurred at rs2141360 on chromosome 7q31 in both the case-only (p=0.0000035) and case-control analyses. The most significant observed increase in African ancestry across the genome occurred at a locus on chromosome 5q35 identified by SNPs rs7729084 (case-only analysis: p=0.002), and rs12474977 (case-control analysis: p=0.004), which are separated by 646 kb and were adjacent to one another on the panel. On chromosome 8, rs4367565 was associated with the greatest excess African ancestry in both the case-only and case-control analyses (case-only and case-control p=0.02), confirming previously reported African-ancestry associations with chromosome 8q24. In conclusion, we confirmed ancestry associations on 8q24, and identified additional ancestry-associated regions potentially harboring prostate cancer susceptibility loci.
Prostate Cancer; Admixture Mapping; Ancestry; PODXL; DOCK4
Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and U.S. Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02 to 0.09, and for autosomal SNPs 10-20 kb apart with common alleles (minor allele frequency ≥ 0.05), the linkage disequilibrium measure r2 was at least 0.8 for 15% and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA (~88%) at r2≥0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations.
single nucleotide polymorphism; population genetics; human genetics; founder population; linkage disequilibrium; haplotypes
Previous studies have found associations between mitochondrial DNA (mtDNA) mutations and several cancer types. Recently, we found that mutations in the mtDNA gene cytochrome c oxidase subunit 1 (COI) were both linked to and associated with prostate cancer (PCa) in Caucasian men. Here we examine the association between COI mutations and PCa in African American men.
The entire COI gene was directly sequenced in 132 PCa cases and 135 controls from the Flint Men’s Health Study, a community-based sample of African American men with and without PCa. Associations between all variants and PCa were evaluated.
We identified 102 COI single nucleotide polymorphisms (SNPs), including 15 missense variants. Overall, the presence of one or more COI missense variants was not significantly associated with PCa. Individually, two SNPs (T6221C and T7389C) were significantly associated with prostate cancer (P < 0.05) and in strong linkage disequilibrium with each other (r2 > 0.6).
Of the two significantly associated SNPs, one is a synonymous substitution and the other is part of the African-specific mitochondrial haplogroup (L). Additional research will be needed to determine the clinical relevance of these associations in African populations.
prostate cancer; COI; SNP; association
In a recent genome-wide association study by Gudmundsson et al. (2007), two prostate cancer susceptibility loci were identified on chromosome 17q. The first locus, at 17q12, was distinguished by two intronic single nucleotide polymorphisms (SNPs) in the TCF2 gene (rs4430796 and rs7501939). The second locus was in a gene-poor region of 17q24, where the strongest evidence of association was for SNP rs1859962. To determine if these loci were also associated with hereditary prostate cancer, we genotyped them in a family-based association sample of 403 non-Hispanic white families, including 1,015 men with and without prostate cancer. SNPs rs4430796 and rs7501939, which were in strong linkage disequilibrium (r2=0.68), showed the strongest evidence of prostate cancer association. Using a family-based association test, the “A” allele of SNP rs4430796 was over-transmitted to affected men (p=0.006), with an odds ratio of 1.40 (95%CI=1.09–1.81) under an additive genetic model. Notably, rs4430796 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p=0.006 versus p=0.118). Our results confirm the prostate cancer association with SNPs on chromosome 17q12 initially reported by Gudmundsson et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset disease. Importantly, these SNPs do not account for a significant portion of our prior prostate cancer linkage evidence on chromosome 17. Thus, there likely exist one or more additional independent prostate cancer susceptibility loci in this region.
cancer; genetics; prostate; association; chromosome 17