Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse

Abstract

OBJECTIVE We sought to comprehensively evaluate the association of laminin gamma-1 (LAMC1) and advance pelvic organ prolapse. STUDY DESIGN We conducted a candidate gene association of patients (n =239) with stages III–IV prolapse and controls (n =197) with stages 0–I prolapse. We used a linkage disequilibrium (LD)–tagged approach to identify single-nucleotide polymorphisms (SNPs) in LAMC1 and focused on non-Hispanic white women to minimize population stratification. Additive and dominant multivariable logistic regression models were used to test for association between individual SNPs and advanced prolapse. RESULTS Fourteen SNPs representing 99% coverage of LAMC1 were genotyped. There was no association between SNP rs10911193 and advanced prolapse (P =.34). However, there was a trend toward significance for SNPs rs1413390 (P =.11), rs20563 (P =.11), and rs20558 (P =.12). CONCLUSION Although we found that the previously reported LAMC1 SNP rs10911193 was not associated with nonfamilial prolapse, our results support further investigation of this candidate gene in the pathophysiology of prolapse.

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.…”

“…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.…”

“…The GWAS(17) and both linkage analyses(18,19) were performed in families with a high rate of POP. All other studies were population based(20–25,28,30,31,36,37). Studies looked at Asian (33.3%, 7/21) (20–22,24–26,30), European (23.8%, 5/21) (27,28,31,33,34) and U.S. Caucasian populations (23.8%, 5/21(17–19,36,37); two studies included sub-analyses of African Americans(23,29) and Brazilian white and non-white (9.5%, 2/21)(32,35) populations (Table 1).…”

“…Age was similar between cases and controls for nine studies(17,26–31,33), had a discrepancy of ≥ 5 years for six studies (23,32,34–37), a discrepancy of ≥ 10 years for three studies(21,22,24) and markedly disparate proportions of younger and older women in two studies (study did not report mean or median ages)(20,25). Two studies preferentially recruited controls from an older population(36,37); all other studies with an age discrepancy had controls that were younger than the prolapse cases.…”