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Abstract
Acute myelogenous leukemia (AML) is caused by dysregulation of oncogenes, tumor suppressor genes, and DNA mismatch repair genes. Accumulating evidence has shown that genetic differences in mismatch repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. In AML and lymphoma, the promoter of hMLH1 is frequently hypermethylated. The purpose of this study is to investigate the association of hMLH1 gene polymorphisms with the susceptability to AML in Korean people. Allelic frequency of rs9311149, rs1800734, rs3774343, rs4647215, rs3774341, rs3774335, rs748766, D376D, V384D SNPs of hMLH1 was determined in 32 normal subjects by sequencing analysis. Haplotype frequency and linkage disequilibrium coefficiency of nine SNPs were estimated. The author selected and genotyped six SNPS for full-scale association study, they include one tagging SNP from neighboring six SNPs and five SNPs including two novel SNPs. One hundred and sixty eight AML cases and 255 unrelated healthy controls were used for the study. V384D was associated with increased risk of AML both in genotypes (OR=2.335; 95% CI: 1.056∼5.165, p=0.032) and in allele frequency (OR=2.417; 95% CI: 1.118∼5.228, p=0.021). Other SNPs except V384D were not associated with AML. The allele frequency of the SNPs between Asians, European descendants, and Africans was very significantly different (p<0.01), respectively. Among Asians, that of Koreans and Japanese was similar (p>0.05), while that between Korean and Chinese, and that between Japanese and Chinese were significantly different (p<0.05). The data uggests that V384D polymorphism of hMLH1 might be associated with AML.
Figures and Tables
Fig. 1
(A) Partial sequence of the hMLH1 exon10 around rs4986984. Genomic DNA from normal individual was sequenced. The arrow indicates the C/T heterozygosity of rs4986984 at position +18524 from the start of the translation site. (B) Partial sequence of the hMLH1 exon14 around CNUH-GRCHD03-209. Genomic DNA from normal individual was sequenced. The arrow indicates the A/G heterozygosity of CNUH-GRCHD03-209 at position +32178 from the start of the translation site.
Table 1
Characteristics of the study population
FAB classification: M0 (undifferntiated AML), M1 (myeloblastic, without maturation), M2 (myeloblastic, with maturation), M3 (promyelocytic), M4 (myelomonocytic), M5 (monoblastic leukemia or monocytic leukemia), M6 (erythrocytic), M7 (megakaryoblastic). Others: 2nd leukemia (10), biphenotype etc (2).
Table 3
SNPs of hMLH1 genotype distributions of controls and AML cases, with Ors and 95% CIs
Numbers in the n column indicate the number of individuals. In the genotypes frequency column, number of individuals with a given genotype and parentheses show percentages. p-value was calculated by Hardy-Weinberg equilibrium. Odds ratios are given with 95% confidence intervals (95% CI). Normal, healthy korean normal population; AML, Acute myelogenous leukemia patients. aCalculated from the translation start site. bAmino acid: Amino acids change; cNA: not applicable.
Table 4
Comparison allele frequency of the SNPs in the hMLH1 gene in different population
Parentheses show the number of chromosomes. Different population data were obtained from the International Hapmap projects (http://hapmap.org/index.html.en). Population descriptors: KOR: Korean normal population; JPT: Japanese in Tokyo, Japan; CHB: Han Chinese in Beijing, China; CEU: CEPH (Utah residents with ancestry from northern and western Europe); YRI: Yoruba in Ibadan, Nigeria. *ED (Ethnic difference) in allele frequency was calculated by subtracting the korean allele frequency from the highest allele frequency of minor allele among ethnic groups at each SNP site. †frequency data from Wang Y et al.23
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