Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia

Abstract

Hemolytic anemia is a forme fruste of systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (alpha = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene, SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.

Figures

Figure 1

Multipoint effect on chromosome 1 at D1S1589. Dashed horizontal lines, threshold for significant and suggestive linkage (LOD = 3.3 and 1.9); dashed line, European-American pedigrees; thick solid line, African-American pedigrees; thin solid line, all pedigrees. Approximate marker placements are represented as vertical bars along the x axis.

Figure 2

Pedigree diagrams of the 16 African-American pedigree subset with their contribution to linkage in 11q14 at D11S2002.

Figure 3

Chromosome 11 showing maximum two-point LOD at D11S2002. Dashed horizontal lines, threshold for significant and suggestive linkage (LOD = 3.3 and 1.9); dashed line, European-American pedigrees; thick solid line, African-American pedigrees; thin solid line, all pedigrees. Approximate marker placements are represented as vertical bars along the x axis.

Figure 4

Fine mapping on chromosome 11. Dashed horizontal lines, threshold for significant and suggestive linkage (LOD = 3.3 and 1.9); thick sold line, the screening dominant model with penetrance values of 92 and 49% in females and males, respectively; thin double lines, the maximized dominant model with penetrance values of 99 and 35% in females and males, respectively. Only those markers used for fine mapping were maximized by using this model. Approximate marker placements are represented as vertical bars along the x axis.

Figure 5

Multipoint HLOD scores on chromosome 11 within the 16 African-American pedigrees (HLOD = 3.56). Thick solid line, the screening dominant model with penetrance values of 92 and 49% in females and males, respectively; thick dashed line, the maximized dominant model with penetrance values of 99 and 35% in females and males, respectively. Approximate marker placements are represented as vertical bars along the x axis.