Genome-wide linkage scan for familial IgA nephropathy among southeast Asian Chinese: evidence for a suggestive novel susceptibility locus on chromosome 8p23

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a high incidence and prevalence among Asians. Three genome-wide studies of familial IgAN among Caucasians have identified two major susceptibility loci on chromosomes 6q22 and 2q36, and two additional loci with suggestive linkage to IgAN on chromosomes 4q26-31 and 17q12-22. We report the preliminary results of a genome-wide scan of a large 4-generation Singaporean Chinese family (F66) for which we ascertained DNA samples for 66 members, including 9 affected members. Linkage analysis at 10 cM resolution was performed using the ABI PRISM Linkage Mapping Set Ver 2.5. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a region of suggestive linkage (maximum multipoint logarithm of odds [LOD] score of 2.23) was identified on chromosomes 8p23. By non-parametric analysis, a significant linkage to chromosome 8p23 (maximum multipoint LOD score 3.89, p-value 0.004) was found. Two additional microsatellite markers were genotyped in F66 along with 6 additional Chinese IgAN families from Hong Kong. Parametric analysis of all 7 families generated a maximum heterogeneous LOD score of 2.77 (α=1.0) over a region of 9.9 cM. The α score of 1.0 indicates genetic homogeneity at the 8p23 locus, suggestive of an “Asian-specific” susceptibility locus for IgAN. We are currently genotyping additional markers in F66 and a total of 23 Hong Kong families in order to conduct an “affected only” analysis to provide definitive evidence for linkage of familial IgAN among Southeast Asian Chinese to a novel susceptibility locus on chromosome 8p23.