RESUMO
We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.
Assuntos
Replicação do DNA , DNA/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Suscetibilidade a Doenças , Humanos , Islândia , Masculino , Neoplasias da Próstata/epidemiologia , Fatores de Risco , População Branca/genéticaRESUMO
In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.
Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Cutâneas/genética , Carcinoma Basocelular/complicações , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Humanos , Queratina-5/genética , Desequilíbrio de Ligação/genética , Melanoma/patologia , Proteínas de Membrana/genética , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Neoplasias Cutâneas/complicaçõesRESUMO
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
Assuntos
Cromossomos Humanos Par 4 , Cromossomos Humanos Par 9 , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Europa (Continente)/epidemiologia , Fatores de Transcrição Forkhead/genética , Humanos , Tireotropina/sangue , Tiroxina/sangue , Fatores de Transcrição , Tri-Iodotironina/sangueRESUMO
The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
Assuntos
Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Idoso , Carcinoma Basocelular/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Locos de Características Quantitativas , Neoplasias Cutâneas/genéticaRESUMO
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.
Assuntos
Carcinoma Basocelular/genética , Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Melanoma/genética , Mutação/genética , Pigmentação/genética , Neoplasias Cutâneas/genética , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Alelos , Carcinoma Basocelular/diagnóstico , Carcinoma de Células Escamosas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , RNA/metabolismo , Neoplasias Cutâneas/diagnósticoRESUMO
We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).
Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença , Mutação/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Estudos de Casos e Controles , Cromossomos Humanos Par 3/genética , Feminino , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-IdadeRESUMO
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Assuntos
Proteína Agouti Sinalizadora/genética , Carcinoma Basocelular/genética , Melanoma/genética , Monofenol Mono-Oxigenase/genética , Pigmentação/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Estudos de Casos e Controles , Europa (Continente) , Cor de Olho/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Melanoma/patologia , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Razão de Chances , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Sistema de Registros , Neoplasias Cutâneas/patologiaRESUMO
Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.
Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Doenças Vasculares Periféricas/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Tabagismo/genética , Europa (Continente) , Feminino , Genótipo , Humanos , Masculino , Família Multigênica/genética , Nova Zelândia , Razão de Chances , Fumar/efeitos adversos , Fumar/genéticaRESUMO
We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Variação Genética , Receptores de Estrogênio/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismoRESUMO
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.
Assuntos
Cromossomos Humanos Par 2 , Cromossomos Humanos X , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Frequência do Gene , Testes Genéticos , Humanos , Islândia , Desequilíbrio de Ligação , Masculino , Países Baixos , Espanha , Suécia , Estados UnidosRESUMO
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
Assuntos
Cromossomos Humanos Par 17 , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença , Variação Genética , Receptores de Estrogênio/biossíntese , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , HumanosRESUMO
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Assuntos
Cromossomos Humanos Par 8/genética , Ligação Genética , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Próstata/genética , Negro ou Afro-Americano , Europa (Continente) , Genômica/métodos , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estados Unidos , População BrancaRESUMO
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.