19 research outputs found
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
Genome-wide association study of germline variants and breast cancer-specific mortality
BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis
of women of European ancestry.
METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe
HNA-1d: a new human neutrophil antigen located on Fc gamma receptor IIIb associated with neonatal immune neutropenia
BackgroundNeonatal immune neutropenia (NIN) is a rare, but potentially
life-threatening, disorder caused by maternal alloantibodies recognizing
paternal neutrophil antigens on fetal cells. Alloantibodies directed
against the human neutrophil alloantigen system (HNA)-1 located on Fc
receptor IIIb (FcRIIIb) are most frequently implicated in NIN. In this
report, we describe two cases of NIN with alloantibodies against
FcRIIIb, which did not match one of the known HNA-1a, -1b, or -1c
specificities, but define a new antigen, HNA-1d.
Study Design and MethodsNeutrophil-reactive antibodies were detected by
agglutination, microscopic immunofluorescence, and monoclonal antibody
(MoAb)-specific immobilization of neutrophil antigens (MAIGA) assay. For
epitope mapping of FcRIIIb-reactive antibodies, recombinant chimeric
variants of FcRIIIb were used in the MAIGA assay. Genotyping of FCGR3B
was performed by allele-specific polymerase chain reaction.
ResultsBoth mothers were typed FCGR3B*01+, *02-, *03+. Antibody
screening revealed the presence of alloantibodies reactive with FcRIIIb
encoded by FCGR3B*02, but not with FcRIIIb encoded by FCGR3B*03.
MAIGA with recombinant, partly chimeric FcRIIIb variants demonstrated
that the antigen recognized by maternal antibodies is characterized by
two amino acids, Ala78 and Asp82. Among the FCGR3B alleles, the sequence
Ala78—Asn82 is exclusively encoded by FCGR3B *02.
ConclusionA previously unrecognized second antigen, HNA-1d, is present
on FcRIIIb encoded by FCGR3B*02. This antigen is characterized by the
sequence Ala78—Asn82. It appears that only individuals carrying the
HNA-1c phenotype can form anti-HNA-1d alloantibodies. The HNA-1 system
now consists of four antigens encoded by three alleles
Transfusion-related acute lung injury caused by human leucocyte antigen class II antibody
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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction
Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
In a genome-wide scan, we show that 30 variants in 25 genomic regions
are associated with risk of TN breast cancer. Women carrying many of the
risk variants may have 4-fold increased risk relative to women with few
variants.Triple-negative (TN) breast cancer is an aggressive subtype of
breast cancer associated with a unique set of epidemiologic and genetic
risk factors. We conducted a two-stage genome-wide association study of
TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148
cases, 1309 controls) to identify loci that influence TN breast cancer
risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide
significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined.
Results also suggested a substantial enrichment of significantly
associated variants among the single nucleotide polymorphisms (SNPs)
analyzed in stage 2. Variants from 25 of 74 known breast cancer
susceptibility loci were also associated with risk of TN breast cancer
(P < 0.05). Associations with TN breast cancer were confirmed for 10
loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3,
19p13.1, RALY), and we identified associations with TN breast cancer for
15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1,
ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24,
BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of
previously reported signals in ESR1 [rs12525163 odds ratio (OR) =
1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x
10(-) (9)) were associated with TN breast cancer. A polygenic risk score
(PRS) for TN breast cancer based on known breast cancer risk variants
showed a 4-fold difference in risk between the highest and lowest PRS
quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x
10(-) (69)). This translates to an absolute risk for TN breast cancer
ranging from 0.8% to 3.4%, suggesting that genetic variation may be
used for TN breast cancer risk prediction
Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10-8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10-4 and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10-9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10-69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction