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Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.

ABSTRACT: Iron is essential for body homeostasis, but iron overload may lead to metabolic abnormalities and thus increase the risk for atherosclerosis and many other diseases. Major histocompatibility complex class I-like transmembrane protein (HFE) is involved in body iron metabolism. The gene coding for HFE has 3 well-known polymorphic sites of which H63D (rs1799945, C?>?G) has recently been associated with hypertension in a genome-wide association study (GWAS) study. In the present study, we wanted to clarify whether the genetic variant associates with hypertension in a Finnish cohort consisting of 50-year-old men and women. The study included 399 hypertensive cases and 751 controls from the Tampere adult population cardiovascular risk study (TAMRISK) cohort. Genotyping of polymorphisms was done by polymerase chain reaction using DNAs extracted from buccal swabs. We found that individuals with the mutated form of the H63D polymorphic site (G-allele) had a 1.4-fold risk (P?=?0.037, 95% confidence interval [CI] 1.02-1.89) for hypertension at the age of 50 years compared with the CC genotype carriers. When obese subjects (body mass index?>?30?kg/m²) were analyzed in their own group, the risk for hypertension was even stronger (odds ratio 4.15, P?

SUBMITTER: Maatta KM

PROVIDER: S-EPMC4602945 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.

Määttä Kirsi M KM Nikkari Seppo T ST Kunnas Tarja A TA

Medicine 20150101 4

Iron is essential for body homeostasis, but iron overload may lead to metabolic abnormalities and thus increase the risk for atherosclerosis and many other diseases. Major histocompatibility complex class I-like transmembrane protein (HFE) is involved in body iron metabolism. The gene coding for HFE has 3 well-known polymorphic sites of which H63D (rs1799945, C > G) has recently been associated with hypertension in a genome-wide association study (GWAS) study. In the present study, we wanted to ...[more]

PMID: 25634189

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Project description:BackgroundScreening program participants with iron overload (IO) phenotypes without HFE p.C282Y/p.C282Y are incompletely characterized.MethodsWe studied white participants who had IO phenotypes without p.C282Y/p.C282Y in post-screening clinical examinations (CE). We defined IO phenotypes as a) elevated serum ferritin (SF) and transferrin saturation (TS) at screening and CE, and b) absence of IO treatment, anemia, transfusion >10 units, alcohol intake >30 g/d, hepatitis B or C, and pregnancy. We defined IO-related disease as elevated alanine or aspartate aminotransferase (ALT/AST) or swelling/tenderness of 2nd/3rd metacarpophalangeal (MCP) joints. All participants had HFE p.C282Y and p.H63D genotyping.ResultsThere were 32 men and 26 women (mean age 54±16 y). Median food/supplemental iron intakes were 14.3/0.0 mg/d. Relative risks of HFE genotypes were 12.9 (p.C282Y/p.H63D), 3.0 (p.H63D/p.H63D), 1.9 (p.C282Y/wt), 0.9 (p.H63D/wt), and 0.5 (wt/wt) compared to 42,640 white screening participants without IO phenotypes or p.C282Y/p.C282Y. Regression on SF revealed positive associations: MCV (p = 0.0006; β coefficient = 0.4531); swelling/tenderness of MCP joints (p = 0.0033; β = 0.3455); and p.H63D/wt (p = 0.0015; β = 0.4146). IO-related disease (18 elevated ALT/AST, one swelling/tenderness of MCP joints) occurred in 19 participants (7 men, 12 women). Median MCV was higher in participants with IO-related disease (97 fL vs. 94 fL; p = 0.0007). Logistic regression on IO-related disease revealed a significant association with diabetes (p = 0.0416; odds ratio 18.9 (95% confidence interval 1.0, 341.1)).ConclusionsIn the present 58 screening program participants who had IO phenotypes without HFE p.C282Y/p.C282Y, relative risks of HFE genotypes p.C282Y/p.H63D, p.H63D/p.H63D, and p.C282Y/wt were significantly higher than in 42,640 white screening participants with neither IO phenotypes nor p.C282Y/p.C282Y. SF was significantly associated with MCV, swelling/tenderness of 2nd/3rd MCP joints, and p.H63D/wt. IO-related disease was significantly associated with MCV and diabetes.

Project description:ObjectivePeople 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.DesignThis time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART.MethodsSoluble 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.ResultsOf 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.ConclusionsHigher 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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Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.

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Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.

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