Noel Pabalan

The multifactorial pathogenesis of severe malaria is partly attributed to host genes, such as those encoding cytokines involved in complex inflammatory reactions, namely tumor necrosis factor-alpha (TNF-α). However, the relationship between TNF-α -308G >A gene polymorphism (rs1800629) and the severity of Plasmodium falciparum (P. falciparum) malaria remains unclear, which prompts a meta-analysis to obtain more precise estimates. The present meta-analysis aimed to better understand this correlation and provide insight into its association in populations with different ethnicities. Literature search outcomes included eight eligible articles in which TNF-α -308G >A polymorphism was determined in uncomplicated malaria (UM) and severe malaria (SM) of P. falciparum as represented in the case and control groups. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated in standard homozygous, recessive, dominant, and codominant genetic models. Subgroup analysis was based on ethnicity, i.e., Africans and Asians. The analyses included overall and the modified outcomes; the latter was obtained without the studies that deviated from the Hardy-Weinberg Equilibrium. The significant data also underwent sensitivity treatment but not publication bias tests because the number of studies was less than ten. Interaction tests were applied to differential outcomes between the subgroups. Overall and HWE-compliant analyses showed no significant association between the TNF-α -308G >A polymorphism and susceptibility to P. falciparum SM (ORs = 1.10–1.52, 95%CIs = 0.68–2.79; P^a = 0.24–0.68). Stratification by ethnicity revealed that two significant associations were found only in the Asians favoring SM for dominant (OR = 1.95, 95% CI = 1.06–3.61, P^a = 0.03) and codominant (OR = 1.83, 95% CI = 1.15–2.92, P^a = 0.01) under the random-effects model, but not among the African populations. The two significant Asian associations were improved with a test of interaction with P-value of0.02–0.03. The significant core outcomes were robust. Results of the meta-analysis suggest that TNF-α -308G >A polymorphism might affect the risk of P. falciparum SM, particularly in individuals of Asian descent. This supports ethnicity as one of the dependent factors of the TNF-α -308G >A association with the clinical severity of malaria. Further large and well-designed genetic studies are needed to confirm this conclusion.

Summary The meta-analysis of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms from genetic association studies and genome-wide association studies was performed in order to test the hypothesis of association between OPG polymorphisms and fracture. The findings showed a significant 13% to 37% protective effect of OPG on fractures in postmenopausal women (PSM) (rs2073618), overall, ≥ 60y and Western subjects (rs3134069 and rs3134070). Purpose Fractures in older people usually result from compromised bone integrity. The multifactorial aetiology of fractures includes both genetic and environmental factors. Inconsistency of reported associations of osteoprotegerin (OPG) (TNFRSF11B) polymorphisms with fracture in the older adult population warranted a meta-analysis to determine more precise estimates. Methods We searched for all available literature on OPG (TNFRSF11B) and fracture. Four polymorphisms were examined, one exonic (rs2073618) and three intronic (rs3134069, rs3134070 and rs3102735). The first two intron polymorphisms were combined (OPGI: osteoprotegerin intron) on account of complete linkage disequilibrium. Risks were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using the allele-genotype model that included variant (var), wild-type (wt) and heterozygote (het). Multiple comparisons were Bonferroni-corrected. We used meta-regression to examine sources of heterogeneity. Zero heterogeneity (homogeneity: I² = 0%) and high significance (P^a < 0.00001) were the criteria for strength of evidence. Significant outcomes were subjected to sensitivity analysis and publication bias assessment. Results From 13 articles (11 genetic association and two genome-wide), this meta-analysis generated five significant pooled ORs, all indicating reduced risks (ORs 0.44–0.87). Of the five, four highly significant comparisons (P^a ≤ 0.00001–0.002) survived the Bonferroni correction, one in rs2073618 het model of the postmenopausal women (OR 0.87, 95% CI 0.81–0.92, I² = 0%) and the other three in OPGI wt model of the overall analysis, ≥ 60 y and Western subjects (ORs 0.63–0.71, 95% CI 0.47–0.86, I² = 97–99%). These findings were consistent, had high significance and high statistical power and were robust and without evidence of publication bias. Four covariates (year of publication, study quality, fracture type/site and sample size) were the sources of heterogeneity in the OPGI overall outcomes (P^a = 0.0001–0.03). Conclusion Evidence showed that the OPG (TNFRSF11B) polymorphisms reduced the risk for fracture in older adults, particularly protective among postmenopausal women, ≥ 60 y and Western subjects.

Objectives: Reported associations of the cannabinoid receptor 1 (CNR1) single nucleotide polymorphisms (SNPs) with alcohol dependence (AD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. Methods: A Boolean search of 4 databases (PubMed, Scopus, Google Scholar, and Mednar) sought articles that evaluated the association between CNR1 polymorphisms and risk of AD. We selected the articles with sufficient genotype frequency data to enable calculation of odds ratios (ORs) and 95% confidence intervals (CIs). Using the Population Intervention Comparators Outcome elements, AD patients (P) were compared by genotype data between AD-participants (I) and non-AD-participants (C) in order to determine the risk of AD (O) attributed to the CNR1 SNPs. Analyzing 4 SNPs (rs1049353, rs1535255, rs2023239, and rs806379) using standard genetic models, we examined associations where multiple comparisons were Holm–Bonferroni corrected. The pooled ORs were assessed for aggregate statistical power and robustness (sensitivity analysis). Subgroups were Caucasians and African-Americans. Results: From 32 comparisons, 14 were significant indicating increased risk, from which 5 outcomes (P-value for association [P ^a] = .003 to <.001) survived the Holm–Bonferroni-correction, which were deemed robust. In the rs1535255 outcomes, the codominant effect (OR = 1.43, 95% CIs = 1.24–1.65, P ^a < .001) had greater statistical power than the dominant effect (OR = 1.30, 95% CI = 1.08–1.57, P ^a = .006). In contrast, the rs2023239 codominant outcome was underpowered. Significance of both rs806379 Caucasian outcomes (ORs = 1.20–1.43, 95% CIs = 1.07–1.57, P ^a = .003) contrasted with the null effects in African-Americans (ORs = 0.98–1.08, 95% CIs = 0.70–1.53). Conclusions: Three CNR1 SNPs (rs1535255, rs2023239, and rs806379) were implicated in their associations with development of AD: based on aggregate statistical power, rs1535255 presented greater evidence for associations than rs2023239; rs806379 implicated the Caucasian subgroup. Multiple statistical and meta-analytical features (consistency, robustness, and high significance) underpinned the strengths of these outcomes. Our findings could render the CNR1 polymorphisms useful in the clinical genetics of AD.

Background: The aim of this study was to investigate associations between polymorphisms in the Lysyl oxidase (LOX) gene with susceptibility to cancer. The role of LOX in carcinogenesis prompted several association studies in various cancer types; however the outcomes of these studies have inconsistent. Thus, we performed a meta-analysis to obtain more precise estimates. Materials and Methods: A literature search yielded 14 articles from which we examined five cancer groups: breast, bone, lung, gastrointestinal, and gynecological cancers. For each cancer group, pooled odds ratios (ORs) and confidence intervals (95% CIs) were calculated using standard genetic models. High significance (p-value for association [p^a] < 0.00001), homogeneity (I² = 0%), and high precision of effects (CI difference [CID] Results: We generated 28 comparisons from which 13 were significant (p^a < 0.05), indicating increased risk, (OR >1.00) found in all cancer groups except breast (p^a = 0.10–0.91). Of the 13, three met all criteria (core) for strength of evidence (p^a < 0.00001, CIDs 0.49–0.56 and I² = 0%), found in dominant/codominant models of gynecological cancers (ORs 1.52–1.62, 95% CIs 1.26–1.88) and codominant model of lung cancer (OR 1.44, 95% CI 1.19–1.74). These three were deemed robust. Conclusion: Based on the three core outcomes, associations of LOX 473G/A with lung, ovarian, and cervical cancers indicate 1.4–1.6-fold increased risks, underpinned by robustness and high statistical power at the aggregate level.

Background: Reported associations of allograft rejection in kidney transplant patients with VEGF single nucleotide polymorphisms (SNPs) have been inconsistent between studies, which prompted a meta-analysis to obtain more precise estimates. Methods: Using the PICO elements, kidney transplant patients (P) were compared by genotype data between rejectors (I) and non-rejectors (C) in order to determine the risk of allograft rejection (O) attributed to the VEGF SNPs. Literature search of four databases yielded seven articles. To calculate risks for allograft rejection, four SNPs were examined. Using the allele-genotype model we compared the variant (var) with the wild-type (wt) and heterozygous (var-wt) alleles. Meta-analysis treatments included outlier and subgroup analyses, the latter was based on ethnicity (Indians/Caucasians) and rejection type (acute/chronic). Multiple comparisons were corrected with the Bonferroni test. Results: Five highly significant outcomes (Pa < 0.01) survived Bonferroni correction, one of which showed reduced risk for the var allele (OR 0.61, 95% CI 0.45-0.82). The remaining four indicated increased risk for the wt allele where the chronic rejection (OR 2.10, 95% CI 1.36-3.24) and Indian (OR 1.44, 95% CI 1.13-1.84) subgroups were accorded susceptibility status. Conclusions: Risk associations for renal allograft rejection were increased and reduced on account of the wt and var alleles, respectively. These findings could render the VEGF polymorphisms useful in the clinical genetics of kidney transplantation.

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. 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. 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%). 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.

The genetics of cancer metastasis is important for designing optimal therapeutic strategies. The lysyl oxidase (LOX) gene has been found important in the metastatic process, with roles in setting the microenvironment for future metastatic sites. Associations between the LOX polymorphisms (473G/A and -22G/C) have been examined in several studies, however, results were inconsistent, prompting a meta-analysis in order to obtain more precise estimates.Searches of six databases yielded 14 articles (15 studies) that examined associations of 473G/A and -22G/C with cancer. We examined five cancer groups: breast, lung, bone (osteosarcoma), GIC (gastrointestinal cancers) and GYC (gynecological cancers). For each cancer group, we calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using standard genetic models. High significance (P^a < 0.00001), homogeneity (I² = 0%) and high precision of effects (CI difference < 1.0 [upper CI-lower CI]) comprised the three criteria for strength of evidence (SOE). Multiple comparisons were Bonferroni-corrected. Sensitivity analysis assessed robustness of the outcomes.Thirteen significant associations indicating increased risk (OR > 1.00) were found in all cancer groups except breast (P^a = 0.10-0.91). Of the 13, two were in osteosarcoma where the -22G/C effects (ORs 4.05-4.07, 95% CIs 1.30-12.70, P^a = 0.02) were homogeneous (I² = 0%) but imprecise (CIDs 11.4) and did not survive the Bonferroni correction. In contrast, the Bonferroni-surviving dominant/codominant outcomes in lung cancer (OR 1.44, 95% CI 1.19-1.74) and GYC (ORs 1.52-1.62, 95% CIs 1.26-1.88) met all three SOE criteria (P^a = 0.00001, I² = 0%, CIDs 0.49-0.56).In summary, associations of LOX 473G/A with lung, ovarian and cervical cancers indicate 1.4-1.6-fold increased risks. These outcomes were underpinned by robustness and high statistical power at the aggregate level.

Aim: Allograft survival post-kidney transplantation (KT) are in large part attributed to genetics, which render the recipient susceptible or protected from allograft rejection. KT studies involving single nucleotide polymorphisms (SNPs) have reported the association of interleukin-18 (IL-18) with KT and its role in allograft rejection. However, the reported outcomes been inconsistent, prompting a meta-analysis to obtain more precise estimates. Methods: We posed two hypotheses about the IL-18 SNPs: their association with KT (H1), and increase or decrease in the risks of allograft rejection (H2). Using standard genetic models, we estimated odds ratios [ORs] and 95% confidence intervals by comparing the IL-18 genotypes between two groups: (i) patients and controls for H1 (GD: genotype distribution analysis); (ii) rejectors and non- rejectors for H2 (allograft analysis). Multiple comparisons were corrected with the Holm-Bonferroni (HB) test. Subgrouping was ethnicity-based (Asians and Caucasians). Heterogeneity was outlier-treated and robustness of outcomes was sensitivity-treated. Results: This meta-analysis generated eight significant outcomes, which HB filtered into four core outcomes, found in the dominant/codominant models. Two of the four were in GD, indicating associations of the IL-18 SNPs with KT (ORs 1.34 to 1.39, 95% CIs 1.13-1.70, PHB = .0007-.004). The other two were in allograft analysis indicating reduced risk with HB P-values of .03 for overall (OR 0.74, 95% CI 0.56-0.93) and Asian (OR 0.70, 95% CI 0.53-0.92). In contrast to the protected Asian subgroup, Caucasians showed non-significant increased risk (OR 1.20. 95% CI .82-1.75, Pa = .35). Sensitivity treatment conferred robustness to all the core outcomes. Conclusions: Overall association of IL-18 SNPs with KT was significant (up to 1.4-fold) and Asians KT recipients were protected (up to 30%). Enabled by outlier treatment, these findings were supported by non-heterogeneity and robustness. More studies may confirm or modify our findings.

The genetics of cancer progression is important for the design of optimal therapeutic strategies. Lysyl oxidase (LOX) is a cancer progression gene that has been studied enough to warrant a synthesis of its primary data from association studies. However, reported associations between the LOX G473A (rs1800449) gene polymorphism and cancer have been inconsistent, prompting a meta-analysis so that we could obtain more precise estimates. Database searches of the published literature yielded seven case-control studies. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using four genetic models: homozygous (H), recessive (R), dominant (D) and codominant (C). Subgroup analysis was based on ethnicity and cancer type. Outlier analysis was used to examine sources of heterogeneity. The strength of evidence was based on the magnitude of effects, high associative significance, consistency and homogeneity. H/R outcomes exerted more associative effects than D/C results. Two reasons for this are as follows: (i) H/R analyses precluded outlier treatment; and (ii) the magnitude of H/R (ORs of > 2.0) was twice that of D/C (ORs > 1.0). All else being equal, significant pooled ORs in all genetic models had high significance (Pa < 10-5). Strong evidence for associations was found in the outcomes for Asian and gastrointestinal (GI) cancers. In summary, the LOX rs1800449 polymorphism confers significant overall susceptibility, particularly in GI cancers, and places Asians at risk.