A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia

被引:53
作者
Sellick, Gabrielle S.
Goldin, Lynn R.
Wild, Ruth W.
Slager, Susan L.
Ressenti, Laura
Strom, Sara S.
Dyer, Martin J. S.
Mauro, Francesca R.
Marti, Gerald E.
Fuller, Stephen
Lyttelton, Matthew
Kipps, Thomas J.
Keating, Michael J.
Call, Timothy G.
Catovsky, Daniel
Caporaso, Neil
Houlston, Richard S.
机构
[1] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England
[2] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA
[3] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Biostat, Rochester, MN USA
[4] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA
[5] Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA
[6] Univ Leicester, MRC, Toxicol Unit, Leicester, Leics, England
[7] Univ Roma La Sapienza, Dipartimento Biotecnol Cellulari & Ematol, Div Hematol, Rome, Italy
[8] US FDA, Ctr Biol Evaluat & Res, Div Cell Therapy, Flow & Image Cytometry Sect, Bethesda, MD USA
[9] US FDA, Ctr Biol Evaluat & Res, Div Gene Therapy, Flow & Image Cytometry Sect, Bethesda, MD USA
[10] Univ Sydney, Nepean Hosp, Dept Med, Penrith, Australia
[11] Gen Hosp Kettering, Kettering, England
[12] Univ Calif San Diego, Moores Canc Ctr, Div Hematol Oncol, San Diego, CA 92103 USA
[13] Univ Texas, MD Anderson Canc Ctr, Div Hematol, Houston, TX 77030 USA
[14] Mayo Clin, Coll Med, Dept Med, Div Hematol, Rochester, MN USA
[15] Inst Canc Res, Sect Hematooncol, Sutton, Surrey, England
基金
英国医学研究理事会;
关键词
D O I
10.1182/blood-2007-05-091561
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders display familial aggregation. To identify a susceptibility gene for CLL, we assembled families from the major European (ICLLC) and American (GEC) consortia to conduct a genome-wide linkage analysis of 101 new CLL pedigrees using a high-density single nucleotide polymorphism (SNP) array and combined the results with data from our previously reported analysis of 105 families. Here, we report on the combined analysis of the 206 families. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. After the removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage (NPL) score of 3.02 (P =.001) on chromosome 2q21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a common recessive model of disease susceptibility (HLOD = 3.11; P = 7.7 x 10(-5)), which was significant at the genome-wide level. In addition, 2 other chromosomal positions, 6p22.1 (corresponding to the major histocompatibility locus) and 18q21.1, displayed HLOD scores higher than 2.1 (P <.002). None of the regions coincided with areas of common chromosomal abnormalities frequently observed in CLL. These findings provide direct evidence for Mendelian predisposition to CLL and evidence for the location of disease loci.
引用
收藏
页码:3326 / 3333
页数:8
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