title: HLA class II locus and susceptibility to podoconiosis.
abstract: BACKGROUND
  Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%).
  
  
  METHODS
  We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls.
  
  
  RESULTS
  We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis.
  
  
  CONCLUSIONS
  Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-5635, USA. ayeleft@mail.nih.gov
authors.forename: Fasil
authors.initials: F
authors.lastname: Tekola Ayele
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Chris
authors.initials: C
authors.lastname: Finan
authors.forename: Elena
authors.initials: E
authors.lastname: Hailu
authors.forename: Paul
authors.initials: P
authors.lastname: Sinnott
authors.forename: Natalia Diaz
authors.initials: ND
authors.lastname: Burlinson
authors.forename: Abraham
authors.initials: A
authors.lastname: Aseffa
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Newport
authors.forename: Gail
authors.initials: G
authors.lastname: Davey
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D004604:Elephantiasis / Q000453:epidemiology / Q000235:genetics*; D019353:Endemic Diseases; D005002:Ethiopia; D005260:Female; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen