A Single Nucleotide Polymorphism in the Promoter of the LOXL1 Gene and Its Relationship to Pelvic Organ Prolapse and Preterm Premature Rupture of Membranes

Abstract

Pelvic organ prolapse (POP) and preterm premature rupture of the membranes (PPROM), two conditions which have in common weakening of the tensile strength of tissues, are thought to be caused, in part, by abnormal extracellular matrix synthesis and/or catabolism. We identified a new single nucleotide polymorphism (SNP) (NT_010194(LOXL1):g.45008784A>C) in the promoter of the LOXL1 gene, which is essential for elastin synthesis. Promoter studies showed that the minor “C” allele had significantly greater activity than the major “A” allele. Case-control studies examined the association of the alleles of this SNP with POP and PPROM. When comparing allele frequencies and genotypes in POP cases versus controls, no significant associations were found. A case-control study conducted in African-American neonates also found no significant associations between the promoter alleles and PPROM. We conclude that a functional SNP exists in the promoter region of LOXL1. Association studies suggest that the promoter SNP does not contribute significantly to risk of POP or PPROM.

Genetic epidemiology of pelvic organ prolapse: a systematic review

“…Of these articles, 21 pertained to the genetic epidemiology of POP (Figure 1). This included one GWAS(17), two linkage analyses(18,19) and 18 case-control candidate gene association studies(20–37) involving 10 candidate genes (collagen type 1 alpha 1 ( COL1A1 ) (n=5)(26–28,33,35), collagen type 3 alpha 1 ( COL3A1 ) (n=4)(20,30–32), laminin gamma-1 ( LAMC1 ) (n=3) (19,23,36), matrix metalloproteinase 9 ( MMP9 ) (n=3)(24,28,37), matrix metalloproteinases 1 and 3 ( MMP1 & 3 ) (n=2)(28,34), lysyl oxidase-like 1 ( LOXL1 ) (n=1)(29), estrogen receptor alpha ( ER α)(n=1)(21), estrogen receptor beta ( ER β)(n=1)(22), progesterone receptor (PGR) (n=1)(25) (Table 1). All studies were published in 2007 or later.…”

“…All studies were published in 2007 or later. Most had government(17,18,20,21,23,25,29,32–37) and/or university grant funding(20–22,24,25), 71% (15/21).…”

“…The prolapse phenotype was most commonly defined by POP-Q stages II-IV(20–25,28,29,33,37), although some studies were more stringent(17,18,26–28,30,32–36), and two studies did not define the prolapse phenotype(19,31). All of the case-control studies defined the control as POP-Q stage 0 or 0-I.…”

“…All of the case-control studies defined the control as POP-Q stage 0 or 0-I. Many excluded women with connective tissue diseases(17,23,27,29,31,34,36,37). The GWAS(17) and both linkage analyses(18,19) were performed in families with a high rate of POP.…”

LOXL1Promoter Haplotypes Are Associated with Exfoliation Syndrome in a U.S. Caucasian Population

“…3), and has been shown to influence transcriptional activity, the C allele being associated with increased transcription. 37 Among the 13 significant SNPs, only two SNPs, rs12914489 and rs3825942 (G153D), showed an independent effect on ES (P ϭ 0.017 and 0.018, respectively) after adjustment for age and all the other SNPs. After further analysis adjustment for age, and the effects of SNPs rs1048661 and rs3825942, only rs12914489, located in the distal promoter region, remained significantly associated with ES (P ϭ 0.04; Table 1).…”