title: Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population.
abstract: OBJECTIVE
  To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa.
  
  
  METHODS
  Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher's exact test.
  
  
  RESULTS
  A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2 x 10(-13) and 1.7 x 10(-5), respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects.
  
  
  CONCLUSIONS
  This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG.
authors.affiliation: Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Susan E I
authors.initials: SE
authors.lastname: Williams
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Whigham
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Carmichael
authors.forename: Xuejun
authors.initials: X
authors.lastname: Qin
authors.forename: Silke
authors.initials: S
authors.lastname: Schmidt
authors.forename: Michele
authors.initials: M
authors.lastname: Ramsay
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
mesh_terms: D000368:Aged; D000483:Alleles; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D017889:Exfoliation Syndrome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005902:Glaucoma, Open-Angle / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D013019:South Africa
chemical_list: D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human