UCL Genetics Institute (UGI)

given by Dr Chrissy Roberts (LSHTM)

Venue: LG6, LSHTM

Abstract:

The Killer-cell Immunoglobulin-like Receptor (KIR) and Human Leukocyte Antigen (HLA) genes exemplify features of the genome that will currently not reveal their secrets to even the highest density SNP typing array, yet these most complexly polymorphic gene systems underpin the function of both the innate and adaptive human cellular immune responses. HLA and KIR proteins interact with one another directly and constellations of polymorphisms in the two systems have been shown to influence many facets of human health. HLA/KIR has been associated with a number of communicable (HIV, HCV, HBV, malaria), non-communicable (type I diabetes, prostate cancer) and autoimmune (psoriasis, coeliac disease, Birdshot chorioretinopathy) diseases, along with a number of reproductive disorders (pre-eclampsia, abnormal foetal mass) and also variations in the success of haematopoietic stem cell transplantation. The genetic typing of these systems presents substantial technical challenges. In HLA, it is the density of polymorphism in the regions encoding the peptide binding grooves, with the consequence of several thousand alleles having been identified, that makes their typing a costly, time-consuming and labour intensive process. In KIR, there is a great difficulty in assaying a region of the genome that exhibits haplotypic plasticity in addition to allelic diversity. The genomic architecture of the KIR region comprises at its core some 17 genes of distinct functions, that are nearly sequence identical and which are arranged in a head-to-tail manner, with some genes occupying more than one locus and other genes of distinct function segregating as alleles of a single locus. Both of these problems are exacerbated when working with African populations, where population diversity is less well defined and where there is less linkage disequilibrium than in Caucasian populations. We hypothesised that some proportion of an individual’s genetic risk of developing more severe phenotypic sequelae of ocular Chlamydia trachomatis infections was attributable to that individual’s HLA class I and KIR genotypes. To test this we undertook to perform a family based association analysis in samples collected in The Gambia. This seminar will present our technical and analytic approach to addressing the question, along with the results from the association tests, which indicate that a common HLA-KIR constellation is associated with an up to six-fold increase in an individual’s risk of early onset trachomatous scarring.