The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

Abstract

SummaryExpression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cisacting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11-site LCT haplotype known as A (Hollox et al. 2001). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at − 14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA -22 kb) (Enattah et al. 2002). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the -14 kb T allele and the -22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non-persistent individuals who were mainly of non-UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the − 14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the -14 kb SNP and LCT. The combined data shows that although the -14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity. *

Genetic testing improves the diagnosis of adult type hypolactasia in the Mediterranean population of Sardinia

“…As far as the discrepancy observed in one individual (30 years and of Sardinian descent) with a lactose normal absorption carrying a lactose non-persistent genotype is concerned, several explanations may account for this divergence: (a) the genetic switch of adult type hypolactasia in rare individuals might be postponed to later in life; (b) the association of lactase non-persistence with the C/T-13910 variant might be not absolute (Poulter et al, 2003); (c) the breath test could be falsely negative for unexplained reasons in a normal H2 producer. Indeed, it has been reported that two individuals from Naples carrying the C/C-13910 genotype had a high lactase activity determined by enzyme assay (Swallow, 2003).…”

Lactase persistence-related genetic variant: population substructure and health outcomes

“…8 Further to this, extensive linkage disequilibrium for 1 Mb across LCT has been reported in a North European population. 10 This work places the correlated allele on an extended common haplotype background and there is redundancy with respect to the genotyping of further variants associated with lactase persistence. Therefore, genotyping of the putatively causal C/T À13910 variant (rs4988235) will effectively capture the genetic variation highlighted by previous association studies.…”

“…Therefore, genotyping of the putatively causal C/T À13910 variant (rs4988235) will effectively capture the genetic variation highlighted by previous association studies. 8,10 The T allele of this single nucleotide polymorphism (SNP) is associated with lactase persistence and its prevalence has been shown to vary across Europe, being 70-80% in Northern European populations and 5 -10% in Southern European populations. 6 The geographic variation in the prevalence of lactase persistence raises the possibility that C/T À13910 may also vary geographically within a country such as Britain, as part of the north-south gradient seen across much of Europe.…”

Evolutionary Genetics: Genetics of lactase persistence – fresh lessons in the history of milk drinking

“…These may lie, for example, in adjacent noncoding sequence that regulates transcription or translation. This suggestion should find favour among those advocating hunts for causative SNPs within regulatory regions, for example, King and Wilson 7 and Prokunina et al 8 The authors' final explanation is that lack of conservation may not rule out the functional importance of their diseaseassociated SNPs if these functions have been acquired only recently in primate evolution. Comparisons with more distantly related mammals might not show conservation if SNP sites have been evolving rapidly under adaptive pressures in our lineage.…”