Effect of C/T −13910 cis-acting regulatory variant on expression and activity of lactase in Indian children and its implication for early genetic screening of adult-type hypolactasia

Absorption of milk sugar (lactose) is regulated by the activity of lactase enzyme in gut wall. Intestinal lactase activity declines during childhood in majority of human populations leading to adult-type hypolactasia (primary lactose malabsorption), limiting the use of fresh milk due to lactose intolerance. Aim of this study was to correlate lactase expression and activity with C/T −13910 variant in Indian children, determine the age of onset of down-regulation of lactase activity and assess the applicability of the C/T −13910 variant as a diagnostic marker for identifying children genetically inclined to develop adult-type hypolactasia. Intestinal biopsies were obtained from 176 children aged 1–16 years undergoing routine endoscopy for various abdominal complaints. The biopsies were assayed for lactase, sucrase and maltase activities and genotyped for C/T 13910 variant using PCR-RFLP analysis. The functional effect of the C/T − 13910 variant on expression of lactase mRNA and protein in these children was examined using reverse-transcription PCR and western blotting. Among the 176 children investigated in our study, 56.8% (100/176) carried the C/C − 13910 genotype, which has been associated with the onset of adult-type hypolactasia, while 40.9% (72/176) carried the C/T − 13910 genotype and 2.3% (4/176) the T/T − 13910 genotype. There was a significant correlation between lactase activity and C/T − 13910 variant ( P < 0.001). The mean level of lactase activity among children with C/C − 13910 genotype was 15.9 U/g protein and with C/T and T/T − 13910 genotypes was 30.9 U/g protein. The age of onset of down-regulation of lactase activity in children with C/C − 13910 genotype was between 3 and 5 years and keeping 10 U/g protein lactase activity as cut off, adult-type hypolactasia was evident in all the individuals > 8 years of age for this genotype. C/C − 13910 genotype was associated with low expression of lactase mRNA and protein compared with C/T genotype. Considering lactase activity of 10 U/g protein as gold standard, predictive value of genetic test based on C/T − 13910 variant for adult-type hypolactasia was 100% in children > 8 years of age. C/T − 13910 cis-acting regulatory variant located ≈ 14 kb upstream of lactase gene (LCT) completely correlates with lactase phenotype in Indian children. The genetic testing for the C/T − 13910 variant may be helpful in the diagnosis of adult-type hypolactasia in Indian children. ► Our research is the first to corr