Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18 control variation in levels of T and B lymphocyte subpopulations

Abstract

Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped.

Figure 1

Chromosome 4 multipoint linkage map for six phenotypes under investigation. CD4:CD8 ratio was strongly linked, peaking at 58 cM (P<.0001). A less significant but coincident linkage was seen for CD8 and CD4:CD8 ratio in the p telomeric region (P<.01). QTL analysis was performed with the W2 method in SIBPAL2, using all 15 families (excluding any grandparents who were available). Marker distances were based on the Marshfield Clinic map. P values for linkage were derived empirically, using a Monte Carlo permutation method, and are given as negative logs to base 10 on the abscissa.

Figure 2

Chromosome 18 multipoint linkage map for six phenotypes under investigation. CD4 and CD19 achieved nominal P values of ⩽.01 for at least one point on the chromosome. CD4, CD19, and lymphocyte counts are distinguished by an apparent region of coincident linkage between 89 and 107 cM. QTL analysis was performed as described in the legend of figure 1.

Figure 3

Chromosome 1 multipoint map for six phenotypes under investigation. CD8, CD4, CD19, and lymphocyte counts achieved nominal P values of ⩽.01 for at least one point on the chromosome. CD8, CD19, and lymphocyte counts are distinguished by an apparent region of coincident linkage between 193 and 215 cM. QTL analysis was performed as described in the legend of figure 1.

Figure 4

Chromosome 2 multipoint map for six phenotypes under investigation. CD4, CD19, CD4:CD8 ratio, and lymphocyte count all achieved nominal P values of ⩽.01 for at least one point on the chromosome. CD4 and lymphocyte count are distinguished by an apparent region of coincident linkage around 32 cM. QTL analysis was performed as described in the legend of figure 1.