Slager, Susan L.

Abstract 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 × 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.

AbstractA role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.

Purpose Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease. Patients and Methods Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis. Results We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, −871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position −871, we found that the reporter construct containing a T at −871 had a 2.6-fold increase in activity (P = .004). Conclusion Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at −871 in the BLyS promoter.