Parallel genotyping of 10,204 single nucleotide polymorphisms to screen for susceptible genes for IgA nephropathy.
BACKGROUND
IgA nephritis (IgAN) is the most common glomerulonephritis worldwide. We aim to genotype SNPs (single nucleotide polymorphisms) genomewide in patients with IgAN to search for genetic clues to its aetiology.


METHODS
Genotyping for 10,204 SNPs genomewide was done with the Gene Chip Human Mapping 10K Microarray (Affymetrix). Twenty-eight patients with IgAN and 30 normal subjects were screened and analysed for differences in genotype frequency, allele frequency and heterozygosity reduction.


RESULTS
Among the most significantly associated SNPs, 48 SNPs were found mapping directly to the intron of 42 genes that localised in 13 somatic chromosomes and chromosome X. Genotype distribution of these SNPs did not deviate from the Hardy-Weinberg equilibrium in normal subjects. The most significantly associated gene, glial cells missing homolog 1 (GCM, 2 =13.05, P = 0.000) is a transcription factor mapped to 6p12.2. GCM1 reported decreased in placenta of patients with pre-eclampsia. The second gene, Tenascin-R (TNR, 2 = 9.85, P = 0.002) is a glycoprotein and extra-cellular matrix component mapped to 1q25.1. Tenascin-R was associated with motor coordination impairment and enhanced anxiety profile in deficient mice. Interestingly, Triadin (TRDN, 2 = 9.16, P = 0.01) is an integral membrane protein mapped to 6q22.31 within the IgAN1 locus. Triadin was shown to participate in cardiac myocyte arrhythemia. However, there is no published study of these genes in IgAN.


CONCLUSIONS
Forty-two associated genes (particularly GCM1, TNR and TRDN) are identified as possible susceptibility or marker genes for IgAN. Knowledge of their mesangial expression and binding capacity for IgA-containing complexes may help elucidate the pathogenesis of IgAN.
Woo
Keng Thye
KT
Renal Medicine Department, Singapore General Hospital, Singapore. woo.keng.thye@sgh.com.sg
Lau
Yeow Kok
YK
Wong
Kok Seng
KS
Zhao
Yi
Y
Chan
Choong Meng
CM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D004268:DNA-Binding Proteins; D004198:Disease Susceptibility; D005819:Genetic Markers; D005820:Genetic Testing; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D009124:Muscle Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012846:Singapore / Q000453:epidemiology; D013223:Statistics as Topic; D019063:Tenascin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; D005819:Genetic Markers; D009124:Muscle Proteins; D009687:Nuclear Proteins; C498269:TRDN protein, human; D019063:Tenascin; D014157:Transcription Factors; C074638:tenascin R