Several Different Lactase Persistence Associated Alleles and High Diversity of the Lactase Gene in the Admixed Brazilian Population

Abstract

Adult-type hypolactasia is a common phenotype caused by the lactase enzyme deficiency. The −13910 C>T polymorphism, located 14 Kb upstream of the lactase gene (LCT) in the MCM6 gene was associated with lactase persistence (LP) in Europeans. This polymorphism is rare in Africa but several other variants associated with lactase persistence were observed in Africans. The aims of this study were to identify polymorphisms in the MCM6 region associated with the lactase persistence phenotype and to determine the distribution of LCT gene haplotypes in 981 individuals from North, Northeast and South Brazil. These polymorphisms were genotyped by PCR based methods and sequencing. The −13779*C,−13910*T, −13937*A, −14010*C, −14011*T LP alleles previously described in the MCM6 gene region that acts as an enhancer for the LCT gene were identified in Brazilians. The most common LP allele was −13910*T. Its frequency was highly correlated with European ancestry in the Brazilian populations investigated. The −13910*T was higher (0.295) in southern Brazilians of European ancestry and lower (0.175) in the Northern admixed population. LCT haplotypes were derived from the 10 LCT SNPs genotyped. Overall twenty six haplotypes previously described were identified in the four Brazilian populations studied. The Multidimensional Scaling analysis showed that Belém, in the north, was closer to Amerindians. Northeastern and southern Afro-descendants were more related with Bantu-speaking South Africans whereas the Southern population with European ancestry grouped with Southern and Northern Europeans. This study shows a high variability considering the number of LCT haplotypes observed. Due to the highly admixed nature of the Brazilian populations, the diagnosis of hypolactasia in Brazil, based only in the investigation of the −13910*T allele is an oversimplification.

Functional Significance of Single Nucleotide Polymorphisms in the Lactase Gene in Diverse US Patients and Evidence for a Novel Lactase Persistence Allele at −13909 in Those of European Ancestry

“…These data indicate that in this diverse U.S. population genetic testing alone would mis-classify a large number of screened subjects when using intestinal lactase enzyme levels as a gold standard (5, 6). A similar observation was recently made in a Brazilian population (16). …”

“…We did not identify any of the potential lactase persistence alleles reported to be present in European-ancestry individuals in recent publications (11-13). SNPs associated with lactase persistence in other heterogeneous populations were also absent (16-19). However, we discovered a novel C>A variant at -13909, present in both of the individuals who share a long, novel haplotype in this region (64 and 71).…”

Association of lactase persistence genotype with milk consumption, obesity and blood pressure: a Mendelian randomization study in the 1982 Pelotas (Brazil) Birth Cohort, with a systematic review and meta-analysis

“…This association was corroborated by several functional studies 4 , 6–9 which revealed the causal effect of rs4988235 on LP. Further genetic variability in this region has been described in non-Europeans, including admixed populations such as Brazil 10 . The gastrointestinal symptoms in response to lactose that occur (at varying levels) in individuals with adult-type hypolactasia motivated investigation of the positive association between LP and intake of milk and other dairy products 2 , 11 , 12 .…”

Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population

“…The method of genomic control employed in this study has been used successfully in other publications by this research group. 24,[29][30][31][32][33] The results from the multivariate statistical model used to determine the association between the CYP3A5 gene A6986G polymorphism and the drugs examined did not differ between the patients with and without hepatotoxicity (p = 0.176; OR 0.562, 95% CI 0.255-1.238). The CYP3A5 gene polymorphism results are consistent with data published previously for other populations, because no association was observed between the A6986G polymorphism and drug-induced hepatotoxicity.…”