Genetic variation in SULT1A1
is associated with functional effects on enzymatic activity, thermal stability, cellular phenotype, and protein degradation.7
Associations of genotype with phenotype have only been reported for Caucasian and African-American populations, with the magnitude of effect varying by ethnicity.8
For this reason, we sought to determine the impact of these genetic variants on enzymatic activity in an Asian population. We genotyped two SNPs in the SULT1A1
distal promoter, four SNPs in the proximal promoter, two SNPs in the 3′-UTR, one SNP in the 3′ flanking region, and SULT1A1*1/2
in the coding region. The correlation of SNPs, as well as copy number variation, with variation of SULT1A1 platelet enzymatic activity in Japanese subjects was investigated.
has been reported to have frequencies of 0.332, 0.294, and 0.080 in Caucasian, African-American, and Han Chinese subjects, respectively.25
In this study, the allele frequency for SULT1A1*1/2
in Japanese subjects was 0.109, which is consistent with previous reports.13
Further, genotype–phenotype analysis indicated that SULT1A1*1/2
was only marginally associated with SULT1A1 activity in Japanese subjects, accounting for only 4% of the observed inter-individual variability.
While promoter SNPs have been demonstrated to be significantly associated with enzymatic activity in Caucasians and African-Americans,19
we found no significant associations in Japanese subjects. We further identified two common SNPs in the distal promoter; similarly, these SNPs were not associated with platelet SULT1A1 activity.
We have reported that 3′-UTR SNPs play a central role in the regulation of SULT1A1 activity in both Caucasians and African-Americans and, combined with CNV, they account for the largest percentage of variability in enzymatic activity.20
In this study, the allele frequencies of SNPs in the 3′-UTR were substantially lower than the allele frequencies in Caucasians and African-Americans and no influence on enzymatic activity was evident. Since the allele frequencies were low in Japanese subjects, it is possible that a larger study population could identify significant associations.
CNVs also display ethnic differences, with 5% of Caucasian subjects possessing a single copy of the gene, 61% with two copies, and 26% with three or more copies, while 63% of African-American subjects had three or more copies.28
This study further documented that the variability in the level of the SULT1A1 enzyme in platelet and liver samples was best explained by gene copy-number differences. In the present study, 65% of the Japanese subjects had two copies of SULT1A1
, which was similar to the distribution in Caucasians. Of all the genetic variants examined in the study, copy number variation has the greatest impact on SULT1A1 enzymatic activity in Japanese people, accounting for 10% of the observed inter-individual variability. Although the effects of copy number variation are statistically significant, the overall impact is small, leading to the speculation that environmental influences could be the greatest determinant of variability in SULT1A1 activity. Indeed, some dietary chemicals and environmental phenolic contaminants have been shown to be potent inhibitors of SULT1A1.29
Thus, studies of gene–environment interactions in determining SULT1A1 activity warrant further study in all ethnicities.