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BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.
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Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Femenino , Humanos , Población Negra/genética , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.
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Melanoma , Neoplasias Cutáneas , Humanos , Alelos , Melanoma/genética , Melanoma/metabolismo , Linfocitos T CD8-positivos/metabolismo , Neoplasias Cutáneas/genética , Histocompatibilidad , Antígenos de Histocompatibilidad Clase I/genéticaRESUMEN
Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature.
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A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Predisposición Genética a la Enfermedad , Genotipo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Mutación , Linaje , Factor 5 de Crecimiento de FibroblastosRESUMEN
INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members. RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91). DISCUSSION: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants.
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Enfermedad de Alzheimer , Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Longevidad , Proteínas de la Membrana/genética , LinajeRESUMEN
Osteoporosis is a common skeletal disorder characterized by deterioration of bone tissue. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative pairs, approximately cousins, from 10 pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently, variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant in MEGF6 (rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genes megf6a and megf6b in zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in silico protein structure modeling, and functional assays support a role for MEGF6 in predisposition to osteoporosis.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intercelular/genética , Osteoporosis/genética , Anciano , Anciano de 80 o más Años , Animales , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/patología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma , Pez CebraRESUMEN
BACKGROUND: The etiology of rotator cuff tearing is likely multifactorial, including a potential genetic predisposition. The purpose of the study was to identify genetic variants associated with rotator cuff tearing utilizing the UK Biobank (UKB) cohort, confirm variants using a separate genetic database, and evaluate tissue expression of genes with associated variants following rotator cuff tearing using RNA sequencing. METHODS: Genome-wide association study (GWAS): A GWAS was performed using data from UKB with 5701 cases of rotator cuff injury. RNA sequencing analyses: rotator cuff biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humerus fracture (controls). Total RNA was extracted and differential gene expression was measured by RNAseq for genes with variants associated with rotator cuff tearing. RESULTS: The results of the UKB GWAS identified 3 loci that reached genome-wide statistical significance: 2 loci on chromosome 7 in GLCCI1 (rs4725069; P = 5.0E-09) and THSD7A (rs575224171; P = 5.3E-09), and 1 locus on chromosome 2 in ZNF804A (rs775583810; P = 3.9E-09). The association with rotator cuff injury of the GLCCI1 single-nucleotide polymorphism (SNP; rs4725069) was confirmed in the Kaiser Permanente Research Bank cohort (P = .008). Twenty previously reported SNPs in 12 genes were evaluated using summary statistics from the UKB GWAS, which confirmed 3 SNPs in TNC with rotator cuff injury (rs1138545, rs72758637, and rs7021589; all P < .0024). Of 17 genes with variants associated with rotator cuff injury (14 previously from literature plus 3 new genes from current UKB GWAS), TIMP2, Col5A1, TGFBR1, and TNC were upregulated (P < .001 for all) and THSD7A was downregulated (P = .005) in tears vs. controls in the RNA sequencing data set. CONCLUSION: The UKB GWAS has identified 3 novel loci associated with rotator cuff tearing (ZNF804A, GLCCI1, THSD7A). Expression of the THSD7A gene was significantly downregulated in rotator cuff tears vs. controls supporting a potential functional role. Three previously reported SNPs in the TNC gene were validated in the UKB GWAS, supporting a role for this gene in rotator cuff tearing. Finally, TIMP2, Col5A1, TGFBR1, and TNC genes were found to have significantly upregulated tissue expression in cases vs. controls supporting a biologic role in tearing for these genes.
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Lesiones del Manguito de los Rotadores , Manguito de los Rotadores , Artroscopía , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Factores de Transcripción de Tipo Kruppel , Polimorfismo de Nucleótido Simple , Lesiones del Manguito de los Rotadores/genéticaRESUMEN
BACKGROUND: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). METHODS: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. RESULTS: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values = .001 and .0001, respectively). DISCUSSION: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.
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Envejecimiento/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Longevidad/genética , Separasa/genética , Anciano , Femenino , Variación Genética , Genotipo , Humanos , Masculino , LinajeRESUMEN
The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10-12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
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Enfermedad/genética , Mutación Missense/genética , Programas Informáticos , Área Bajo la Curva , Análisis Mutacional de ADN , Exoma/genética , Frecuencia de los Genes , Humanos , Curva ROCRESUMEN
Familial recurrence of anorectal malformations (ARMs) has been reported in single institution case series and in two population-based studies. Here, we investigate the familial aggregation of ARMs using well-established, unbiased methods in a population genealogy of Utah. Study subjects included 255 ARM cases identified from among the two largest healthcare providers in Utah with linked genealogy data using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. The genealogical index of familiality (GIF) statistic, which compares the average pair-wise relatedness of cases to sets of matched controls, was used to test excess familial clustering. We also estimated relative risks (RRs) for ARM and associated phenotypes in relatives of cases adjusting for age-, sex-, and birthplace. Significant excess familial clustering was observed for all ARM subjects (GIF p < 1e-3). Significant RR estimates for ARM (RR = 15.6, p = 3.3e-6), and for almost all co-morbid birth defects previously associated with ARM, were observed among first-degree relatives of ARM case subjects. This genealogically-based population survey of familial aggregation of ARMs confirms the presence of a heritable component to ARMs and provides unbiased risk estimates to relatives of cases, which may have clinical utility.
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Malformaciones Anorrectales/genética , Linaje , Malformaciones Anorrectales/epidemiología , Femenino , Humanos , Masculino , Factores de Riesgo , Utah/epidemiologíaRESUMEN
Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Anciano , Frecuencia de los Genes , Genotipo , Haplotipos/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Factores de RiesgoRESUMEN
BACKGROUND: A familial and genetic predisposition for the development of rotator cuff tearing has been identified. The purpose of this study was to determine if a familial predisposition exists for healing after rotator cuff repair and if the reported significant association with a single-nucleotide polymorphism (SNP) in the ESRRB gene is present in patients who fail to heal. MATERIALS AND METHODS: The study recruited 72 patients undergoing arthroscopic rotator cuff repair for a full-thickness posterosuperior tear. Magnetic resonance imaging studies were performed at a minimum of 1 year postoperatively (average, 2.6 years). Healing failures were classified as lateral or medial. Self-reported family history of rotator cuff tearing data and genome-wide genotypes were available. Characteristics of cases with and without a family history of rotator cuff tearing were compared, and a comparison of the frequency of SNP 1758384 (in ESRRB) was performed between patients who healed and those who failed to heal. RESULTS: Of the rotator cuff repairs, 42% failed to heal; 42% of patients reported a family history of rotator cuff tear. Multivariate regression analysis showed a significant association between familiality and overall healing failure (medial and lateral failures) (P = .036) and lateral failures independently (P = .006). An increased risk for the presence of a rare allele for SNP rs17583842 was present in lateral failures compared with those that healed (P = .005). CONCLUSIONS: Individuals with a family history of rotator cuff tearing were more likely to have repair failures. Significant association of a SNP variant in the ESRRB gene was also observed with lateral failure.
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Receptores de Estrógenos/genética , Lesiones del Manguito de los Rotadores/genética , Lesiones del Manguito de los Rotadores/cirugía , Manguito de los Rotadores/cirugía , Cicatrización de Heridas/genética , Adulto , Anciano , Alelos , Artroscopía , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Insuficiencia del Tratamiento , Resultado del Tratamiento , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND: The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. MATERIALS AND METHODS: A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). RESULTS: Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. CONCLUSIONS: This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing.
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Estudio de Asociación del Genoma Completo , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Lesiones del Manguito de los Rotadores , Traumatismos de los Tendones/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 6/genética , Estudios Transversales , HumanosRESUMEN
BACKGROUND: Prostate cancer (PC) relative risks (RRs) are typically estimated based on status of close relatives or presence of any affected relatives. This study provides RR estimates using extensive and specific PC family history. METHODS: A retrospective population-based study was undertaken to estimate RRs for PC based on complete family history of PC. A total of 635,443 males, all with ancestral genealogy data, were analyzed. RRs for PC were determined based upon PC rates estimated from males with no PC family history (without PC in first, second, or third degree relatives). RRs were determined for a variety of constellations, for example, number of first through third degree relatives; named (grandfather, father, uncle, cousins, brothers); maternal, paternal relationships, and age of onset. RESULTS: In the 635,443 males analyzed, 18,105 had PC. First-degree RRs ranged from 2.46 (=1 first-degree relative affected, CI = 2.39-2.53) to 7.65 (=4 first-degree relatives affected, CI = 6.28-9.23). Second-degree RRs for probands with 0 affected first-degree relatives ranged from 1.51 (≥1 second-degree relative affected, CI = 1.47-1.56) to 3.09 (≥5 second-degree relatives affected, CI = 2.32-4.03). Third-degree RRs with 0 affected first- and 0 affected second-degree relatives ranged from 1.15 (≥1 affected third-degree relative, CI = 1.12-1.19) to 1.50 (≥5 affected third-degree relatives, CI = 1.35-1.66). RRs based on age at diagnosis were higher for earlier age at diagnoses; for example, RR = 5.54 for ≥1 first-degree relative diagnosed before age 50 years (CI = 1.12-1.19) and RR = 1.78 for >1 second-degree relative diagnosed before age 50 years, CI = 1.33, 2.33. RRs for equivalent maternal versus paternal family history were not significantly different. CONCLUSIONS: A more complete PC family history using close and distant relatives and age at diagnosis results in a wider range of estimates of individual RR that are potentially more accurate than RRs estimated from summary family history. The presence of PC in second- and even third-degree relatives contributes significantly to risk. Maternal family history is just as significant as paternal family history. PC RRs based on a proband's complete constellation of affected relatives will allow patients and care providers to make more informed screening, monitoring, and treatment decisions.
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Predisposición Genética a la Enfermedad , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Riesgo , Adulto , Anciano , Anciano de 80 o más Años , Familia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Sistema de Registros , Estudios Retrospectivos , Medición de RiesgoRESUMEN
BACKGROUND: The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Variants of estrogen-related receptor-ß (ESRRB) have been previously associated with rotator cuff disease. The purpose of the present study was to confirm the association between multiple candidate genes, including ESRRB, and rotator cuff disease in an independent set of patients with rotator cuff tear. MATERIALS AND METHODS: The Illumina 5M (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) platform was used to genotype 175 patients with rotator cuff tear. Genotypes were used to select a set of 2595 genetically matched Caucasian controls available from the Illumina iControls database. Tests of association were performed with Genome-wide Efficient Mixed Model Association (GEMMA) software at 69 SNPs that fell within 20 kb of 6 candidate genes (DEFB1, DENND2C, ESRRB, FGF3, FGF10, and FGFR1). RESULTS: Tests of association revealed 1 significantly associated SNP occurring in ESRRB (rs17583842; P = 4.4E-4). Another SNP within ESRRB (rs7157192) had a nominal P value of 7.8E-3. FastPHASE software estimated 2 frequent haplotypes among 54 individuals who carried both risk alleles at these 2 SNPs. The first haplotype had a frequency of 13.9% (n = 15) in risk-allele carriers and only 2.2% in controls (odds ratio, 6.9; 95% confidence interval, 3.9-2.2). The second haplotype had a frequency of 12.9% in risk-allele carriers and only 2.7% in controls (odds ratio, 5.3; 95% confidence interval, 3.0-9.5). CONCLUSIONS: The significant association and the presence of high-risk haplotypes identified in the ESRRB gene confirm the association of variants in ESRRB and rotator cuff disease.
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Receptores de Estrógenos/genética , Lesiones del Manguito de los Rotadores , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Haplotipos , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Rotura/genéticaRESUMEN
BACKGROUND: Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists. METHODS: A novel analysis of a computerized population-based resource linking genealogy and cancer data was used to test the hypothesis of a role of the Y chromosome in prostate cancer predisposition. Using a statewide cancer registry from 1966 linked to a computerized genealogy representing over 1.2 million descendants of the Utah pioneers, 1,000 independent sets of males, each set hypothesized to share the same Y chromosome as represented in genealogy data, were tested for a significant excess of prostate cancer. RESULTS: Multiple Y chromosomes representing thousands of potentially at-risk males were identified to have a significant excess risk for prostate cancer. CONCLUSIONS: This powerful and efficient in silico test of an uncommon mode of inheritance has confirmed evidence for Y chromosome involvement in prostate cancer.
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Cromosomas Humanos Y , Neoplasias de la Próstata/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Linaje , Neoplasias de la Próstata/epidemiología , Utah/epidemiologíaRESUMEN
Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.
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Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Alelos , Estudios de Casos y Controles , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Metaanálisis como Asunto , Linaje , Fenotipo , Factores de RiesgoRESUMEN
Background: Common genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears (RCTs). We hypothesize that rare variants contribute to symptomatic RCTs and that they can be identified in related cases with a full-thickness tear requiring surgical management. Methods: We used the Utah Population Database to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full-thickness RCT. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full-thickness RCT (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full-thickness RCTs. Results: A total of 82 rare (minor allele frequency <0.005) coding variants were identified as shared in at least one cousin pair affected with full-thickness rotator cuff tearing belonging to a high-risk pedigree, which included variants in RUNX1, ADAM12, TGFBR2, APBB1, PDLIM7, LTBP1, MAP3K4, and MAP3K1. Analysis of 39 of these variants with data available in the UK Biobank (3899 cases with rotator cuff injury and 11,697 matched controls; mean case age 59.9 years) identified a significant association with the APBB1 gene (OR = 2.37, P = .007, uncorrected). The PDLIM7 allele was found to be in significant excess in RCT cases in a separate cohort of Utah patients with full-thickness RCTs (10 carriers out of 458 independent, unrelated patients; minor allele frequency of 0.022) compared to a minor allele frequency of 0.0058 for the European (non-Finnish) control population rate (749 carriers out of 128612 tested) (chi-square test: 19.3 [P < .001]). Discussion: The analysis of closely related individuals with confirmed full-thickness RCTs from high-risk pedigrees has identified 82 rare, shared candidate genetic predisposition coding variants. Association of the PDLIM7 allele with risk for tear was confirmed in an independent cohort of RCTs. Further analysis of the variant alleles is required for confirmation of these genes in rotator cuff tearing.
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BACKGROUND: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. METHODS: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. RESULTS: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). CONCLUSIONS: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.