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Higher iron stores and the HFE 187C>G variant delay onset of peripheral neuropathy during combination antiretroviral therapy.
Kallianpur, AR, Wen, W, Erwin, AL, Clifford, DB, Hulgan, T, Robbins, GK
PloS one. 2020;(10):e0239758
Abstract
OBJECTIVE People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.
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Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response.
Lewis, JP, Fisch, AS, Ryan, K, O'Connell, JR, Gibson, Q, Mitchell, BD, Shen, H, Tanner, K, Horenstein, RB, Pakzy, R, et al
Clinical pharmacology and therapeutics. 2011;(4):568-74
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Abstract
A common functional variant in paraoxonase 1 (PON1), Q192R, was recently reported to be a major determinant of clopidogrel response. This variant was genotyped in 566 participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) study and in 227 percutaneous coronary intervention (PCI) patients. Serum paraoxonase activity was measured in a subset of 79 PAPI participants. PON1 Q192R was not associated with pre- or post-clopidogrel platelet aggregation in the PAPI study (P = 0.16 and P = 0.21, respectively) or the PCI cohort (P = 0.47 and P = 0.91, respectively). The Q192 allele was not associated with cardiovascular events (hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.20-1.06; P = 0.07). No correlation was observed between paraoxonase activity and post-clopidogrel platelet aggregation (r(2) < 0.01, P = 0.78). None of 49 additional PON1 variants evaluated was associated with post-clopidogrel platelet aggregation. These findings do not support a role for PON1 as a determinant of clopidogrel response.
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Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study.
Siitonen, N, Pulkkinen, L, Lindström, J, Kolehmainen, M, Schwab, U, Eriksson, JG, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, Tuomilehto, J, Uusitupa, M
Cardiovascular diabetology. 2011;:83
Abstract
BACKGROUND Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic effects. Two receptors for adiponectin, ADIPOR1 and ADIPOR2, have been characterized that mediate effects of adiponectin in various tissues. We examined whether genetic variation in ADIPOR2 predicts the development of cardiovascular disease (CVD) and/or Type 2 Diabetes (T2DM) in individuals with impaired glucose tolerance (IGT) participating the Finnish Diabetes Prevention Study (DPS). METHODS CVD morbidity and mortality data were collected during a median follow-up of 10.2 years (range 1-13 years) and conversion from IGT to T2DM was assessed during a median follow-up of 7 years (range 1-11 years). Altogether eight SNPs in the ADIPOR2 locus were genotyped in 484 participants of the DPS. Moreover, the same SNPs were genotyped and the mRNA expression levels of ADIPOR2 were determined in peripheral blood mononuclear cells and subcutaneous adipose tissue samples derived from 56 individuals participating in the Genobin study. RESULTS In the DPS population, four SNPs (rs10848554, rs11061937, rs1058322, rs16928751) were associated with CVD risk, and two remained significant (p = 0.014 for rs11061937 and p = 0.020 for rs1058322) when all four were included in the same multi-SNP model. Furthermore, the individuals homozygous for the rare minor alleles of rs11061946 and rs11061973 had increased risk of converting from IGT to T2DM. Allele-specific differences in the mRNA expression levels for the rs1058322 variant were seen in peripheral blood mononuclear cells derived from participants of the Genobin study. CONCLUSIONS Our results suggest that SNPs in the ADIPOR2 may modify the risk of CVD in individuals with IGT, possibly through alterations in the mRNA expression levels. In addition an independent genetic signal in ADIPOR2 locus may have an impact on the risk of developing T2DM in individuals with IGT. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT00518167.
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TNFRSF1A coding variants in multiple sclerosis.
Goris, A, Fockaert, N, Cosemans, L, Clysters, K, Nagels, G, Boonen, S, Thijs, V, Robberecht, W, Dubois, B
Journal of neuroimmunology. 2011;(1-2):110-2
Abstract
Patients with the autoinflammatory disease Tumour Necrosis Factor receptor-associated periodic syndrome (TRAPS) who suffer from demyelinating disease have been described, and one of the milder TRAPS mutations (R92Q in the TNFRSF1A gene) has been suggested as a risk factor for multiple sclerosis (MS). In a study population of 967 MS patients and 1022 controls, we replicate association [P=5×10⁻⁴, 3% in patients versus 1% in controls, OR=2.26 (95% CI 1.41-3.61)], which appears independent of an established common risk variant in the same gene. No other non-synonymous variants in the same allele frequency range influencing risk of MS were observed.
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Absence of mitochondrial progesterone receptor polymorphisms in women with spontaneous preterm birth.
Manuck, TA, Price, TM, Thom, E, Meis, PJ, Dombrowski, MP, Sibai, B, Spong, CY, Rouse, DJ, Iams, JD, Simhan, HN, et al
Reproductive sciences (Thousand Oaks, Calif.). 2010;(10):913-6
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Abstract
OBJECTIVE The truncated mitochondrial progesterone receptor (PR-M) is homologous to nuclear PRs with the exception of an amino terminus hydrophobic membrane localization sequence, which localizes PR-M to mitochondria. Given the matrilineal inheritance of both spontaneous preterm birth (SPTB) and the mitochondrial genome, we hypothesized that (a) PR-M is polymorphic and (b) PR-M localization sequence polymorphisms could result in variable progesterone-mitochondrial effects and variable responsiveness to progesterone prophylaxis. METHODS Secondary analysis of DNA from women enrolled in a multicenter, prospective, study of 17 alpha-hydroxyprogesterone caproate (17OHPC) versus placebo for the prevention of recurrent SPTB. DNA was extracted from stored saliva. RESULTS The PR-M localization sequence was sequenced on 344 patients. Sequences were compared with the previously published 48 base-pair sequence, and all were identical. CONCLUSIONS We did not detect genetic variation in the mitochondrial localization sequence of the truncated PR-M in a group of women at high risk for SPTB.
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FokI variant of vitamin D receptor gene and factors related to atherosclerosis associated with ossification of the posterior longitudinal ligament of the spine: a multi-hospital case-control study.
Kobashi, G, Ohta, K, Washio, M, Okamoto, K, Sasaki, S, Yokoyama, T, Miyake, Y, Sakamoto, N, Hata, A, Tamashiro, H, et al
Spine. 2008;(16):E553-8
Abstract
STUDY DESIGN A sex- and age-matched case-control study with genotyping of the FokI variant of the vitamin D receptor gene (VDR) was carried out. OBJECTIVES To facilitate the early prediction, prevention, and treatment of ossification of the posterior longitudinal ligament (OPLL) of the spine, we analyzed the FokI variant of VDR and past body mass indexes, histories of past illness, family history, and body pliability along with lifestyle factors. SUMMARY OF BACKGROUND DATA Many possible genetic and environmental risk factors for OPLL have been suggested, including male sex, high body mass index, diabetes mellitus, trauma, hormonal imbalance, and dietary and sleeping habits and genetic variants. METHODS Both a self-administered questionnaire and whole blood samples were obtained from 63 patients with OPLL and 126 sex-, age-, and hospital-matched controls free of backbone diseases were randomly selected from hospital patients. VDR genotyping was carried out using PCR-RFLP methods. After univariate analysis, multivariate and subgroup analyses according to the VDR genotype was applied to clarify the confounding relationship between VDR genotype and other possible risk factors. RESULTS A multivariate analysis revealed that the VDR FF genotype, family history of myocardial infarction, high body mass index at age 40, long working hours, and working with night shift to be independent potent risk factors for OPLL. CONCLUSION The risk of developing OPLL may possibly be reduced gradually and effectively by removing or minimizing the effect of such lifestyle factors one at a time through targeted preventive intervention.