Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.
Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.
Mayo Clinic College of Medicine, Rochester, MN 55905, USA. slager@mayo.edu
Susan L
SL
Slager
Kari G
KG
Rabe
Sara J
SJ
Achenbach
Celine M
CM
Vachon
Lynn R
LR
Goldin
Sara S
SS
Strom
Mark C
MC
Lanasa
Logan G
LG
Spector
Laura Z
LZ
Rassenti
Jose F
JF
Leis
Nicola J
NJ
Camp
Martha
M
Glenn
Neil E
NE
Kay
Julie M
JM
Cunningham
Curtis A
CA
Hanson
Gerald E
GE
Marti
J Brice
JB
Weinberg
Vicki A
VA
Morrison
Brian K
BK
Link
Timothy G
TG
Call
Neil E
NE
Caporaso
James R
JR
Cerhan
D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059847:HLA-DRB5 Chains; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000099185:Interferon Regulatory Factor-8
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens; D059847:HLA-DRB5 Chains; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C069050:HLA-DQA1 antigen