Paraoxonase single nucleotide variants show associations with polycystic ovary syndrome: a meta-analysis

Anthicha Kunjantarachot; Noel Pabalan; Hamdi Jarjanazi; Denise Maria Christofolini; Erik Montagna; Caio Parente Barbosa; Bianca Bianco

doi:10.1186/s12958-020-00665-1

Paraoxonase single nucleotide variants show associations with polycystic ovary syndrome: a meta-analysis

Reprod Biol Endocrinol. 2020 Nov 20;18(1):114. doi: 10.1186/s12958-020-00665-1.

Authors

Anthicha Kunjantarachot¹, Noel Pabalan², Hamdi Jarjanazi³, Denise Maria Christofolini⁴, Erik Montagna⁴, Caio Parente Barbosa⁴, Bianca Bianco⁴

Affiliations

¹ Chulabhorn International College of Medicine, Thammasat University, Khlong Luang District, Rangsit, Pathumthani, Thailand.
² Chulabhorn International College of Medicine, Thammasat University, Khlong Luang District, Rangsit, Pathumthani, Thailand. noelpabalan@mail.com.
³ Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment, Conservation and Parks, 125 Resources Road, Toronto, Ontario, Canada.
⁴ Human Reproduction and Genetics Center, Department of Collective Health, Faculdade de Medicina do ABC, Santo André, SP, Brazil.

Abstract

Background: Etiology of polycystic ovary syndrome (PCOS) is attributed to genetic and environmental factors. One environmental factor is oxidative stress. Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-associated enzyme encoded by the PON1 gene. The PON1 gene has been implicated in the risk for PCOS, the influence of which appears to come from single nucleotide variants (SNVs) at multiple genetic loci. However, association study reports have been inconsistent which compels a meta-analysis to obtain more precise estimates.

Methods: From 12 publications, extracted genotype data were used in two genetic procedures. First, linkage disequilibrium (LD) was used to group eight PON SNVs into three: LD1, LD2 and LD3. Second, frequencies of the variant (var), wild-type (wt) and heterozygous (het) genotypes were used for genetic modeling (allele-genotype for LD1 and standard for LD2 and LD3). Risk associations were expressed in terms of pooled odds ratios (ORs), 95% confidence intervals (CIs) and P^a-values. Evidence was considered strong when significance was high (P^a < 0.0001) and heterogeneity absent (I² = 0%). Pooled effects were subjected to modifier (power), subgroup (Asian/Caucasian), outlier, sensitivity and publication bias treatments. Multiple comparisons were Bonferroni-corrected.

Results: This meta-analysis generated 11 significant outcomes, five in LD1, six in LD2 and none in LD3. All six LD2 outcomes did not survive the Bonferroni-correction but two of the five in LD1 did. These two core LD1 findings conferred greater odds of PCOS to the var allele in the highly significant (P^a < 0.0001) overall (OR 1.44, 95% CI 1.24-1.67) and Asian (OR 1.41, 95% CI 1.20-1.65) outcomes. Of these two core outcomes, the Asian effect was homogeneous (I² = 0%) but not the overall (I² = 29%).

Conclusions: Of the eight PON SNVs examined, two (rs854560 and rs662) were associated with PCOS risk. These 1.4-fold increased risk effects rendered Asians susceptible to PCOS. High statistical power, high significance, zero to low-level heterogeneity, robustness and lack of bias in the core outcomes underpinned the strong evidence for association.

Keywords: Meta-analysis; PCOS; PON; Paraoxonase; Single nucleotide variants.

Publication types

Meta-Analysis

MeSH terms

Alleles
Aryldialkylphosphatase / genetics*
Female
Gene Frequency
Genetic Predisposition to Disease / genetics*
Genotype
Humans
Linkage Disequilibrium
Odds Ratio
Polycystic Ovary Syndrome / genetics*
Polymorphism, Single Nucleotide*

Substances

Aryldialkylphosphatase
PON1 protein, human