HLA predisposition to human papillomavirus induced cervical neoplasia : population based studies from the Västerbotten county in northern Sweden

Infection with human papillomaviruses (HPV) types 16 and 18 is the major cause of cervical neoplasia. Although a high proportion of cervical cancers (CXCA) harbor HPV genomes, only a small number of women infected with high-risk papillomaviruses develop cervical tumors, suggesting that other environmental and/or genetic factors contribute to cervical carcinogenesis. Several studies have identified genes encoding human leukocyte antigens (HLA) associated with cervical intraepithelial neoplasia (CIN) and CXCA.

Many genes encoding the products involved in immune responses are clustered within the human major histocompatibility complex (MHC) on the short arm of chromosome 6 (6p21.3). The human AMC extends over 3500 kilobases and comprises more than 200 genes with known and unknown functions

The HLA class I genes encodes cell surface glycoproteins (HLA-A, -B, -C) that associates in the endoplasmic reticulum with beta32-microglubulin and peptides derived from endogenously processed antigens. HLA class II genes encode cell surface glycoproteins, which bind to peptides that originate mainly from exogenous antigens processed through the endosomal/lysosomal pathway.

In addition to HLA class I and class II molecules, genes that encode the cytokines, tumor necrosis factor (TNF) alpha and beta are located in the class III region. The MHC class I chain related genes (MICA/B) located in the centromeric end of the HLA class I region, have recently been in focus for it can function as a ligand for gamma/delta T cells and NK cell receptors. MICA protein is mainly expressed by epithelial cells and its interaction with NK cells and gamma/delta T cells might have a role in the pathogenesis of CXCA.

The aim of this thesis was to investigate the association of candidate HLA genes with CIN and CXCA. Several different genotyping methods were used to study the polymorphic HLA genes in two different patient groups. Patients and controls from a cohort of Västerbotten were included in this population-based study. Candidate genes in the HLA class I, class II and class III region were analyzed and their association with CXCA and susceptibility to HPV infection was measured using appropriate statistical methods. The strongest association of HLA genes with CXCA was found in the HLA class II locus. The relative risks of CXCA among DR15 and DQ6 (DQB1*0602) positive patients were 3.73 and 4.33, corresponding to population attributable proportions of 27.9% and 30.8%, respectively. MICA was not associated with either CIN or CXCA. The polymorphism of the TNFA gene was associated with susceptibility to HPV 16 infection and increased the risk for CIN and CXCA in patients with the DR15-DQ6 haplotype.

List of scientific papers

I. Ghaderi M, Hjelmstrom P, Hallmans G, Wiklund F, Lenner P, Dillner J, Sanjeevi CB (1999). "MICA gene polymorphism and the risk to develop cervical intraepithelial neoplasia" Hum Immunol 60(10): 970-3
https://pubmed.ncbi.nlm.nih.gov/10566597

II. Ghaderi M, Nikitina L, Peacock CS, Hjelmstrom P, Hallmans G, Wiklund F, Lenner P, Blackwell JM, Dillner J, Sanjeevi CB (2000). "Tumor necrosis factor a-11 and DR15-DQ6 (B*0602) haplotype increase the risk for cervical intraepithelial neoplasia in human papillomavirus 16 seropositive women in Northern Sweden. " Cancer Epidemiol Biomarkers Prev 9(10): 1067-70
https://pubmed.ncbi.nlm.nih.gov/11045789

III. Ghaderi M, Wallin KL, Wiklund F, Nikitina Zake L, Hallmans G, Lenner P, Dillner J, Sanjeevi CB (2001). "Risk of invasive cervical cancer associated with polymorphic HLA DR/DQ haplotypes." (Submitted)

IV. Ghaderi M, Nikitina Zake L, Wallin KL, Wiklund F, Hallmans G, Lenner G, Dillner J, Sanjeevi CB (2001). "Tumor necrosis factor A and MHC class I chain-related gene A (MICA) polymorphisms in Swedish patients with cervical cancer." Hum Immunol (In Print)