Common Coding Variants of the
            <i>HNF1A</i>
            Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults

Reiner, Alexander P.; Gross, Myron D.; Carlson, Christopher S.; Bielinski, Suzette J.; Lange, Leslie A.; Fornage, Myriam; Jenny, Nancy S.; Walston, Jeremy D.; Tracy, Russell P.; Williams, O. Dale; Jacobs, David R.; Nickerson, Deborah A.

doi:10.1161/circgenetics.108.839506

Cited by 43 publications

(48 citation statements)

References 49 publications

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“…In addition, inflammatory cytokines, such as IL-6 and CRP, could be transcriptionally modulated during inflammation in hepatocytes (41), which might weaken associations of circulating biomarkers and their coding genes. This hypothesis receives some support by our finding that the top SNPs related to CRP level included the transcription factor hepatocyte nuclear factor (HNF1A); SNPs in this gene have been previously related to CRP and fibrinogen levels (see Table E2) (42,43). As a result, genetic effects on circulating levels of systemic inflammatory biomarkers may be more difficult to detect than for pneumoproteins.…”

Section: Discussionmentioning

confidence: 87%

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

Kim

Cho

Hersh

et al. 2012

Am J Respir Crit Care Med

113

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Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-a) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P , 1 3 10 28 ), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P ¼ 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P ¼ 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

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Section: Discussionmentioning

confidence: 87%

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

Kim

Cho

Hersh

et al. 2012

Am J Respir Crit Care Med

113

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“…The protein HNF1α is shown to bind directly to the CRP promoter to activate gene transcription and to promote cytokine-driven CRP gene expression [24]. Given the complex role of HNF1α in modulating the expression of target genes like CRP , common variants at HNF1A locus are suggested to alter the gene and protein function via multiple mechanisms [25]. The missense variants rs1169288 (Ile27Leu) and rs2464196 (Ser486Asn) were previously reported to show association with CRP level and suggested to be functionally relevant [25].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Association with C-Reactive Protein Levels in CLHNS: Evidence for the CRP and HNF1A Loci and their Interaction with Exposure to a Pathogenic Environment

McDade

Kuzawa

et al. 2011

Inflammation

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Recent genome-wide association (GWA) studies have related several genetic loci, including CRP, HNF1A and LEPR, to circulating C-reactive protein (CRP) levels in populations of European ancestry. The genetic effects in other populations and across varying levels of exposure to a pathogenic environment, an important environmental factor associated with CRP, remain to be determined. We tested 2,073,674 SNPs for association with plasma CRP (limited to ≤ 10 mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The strongest evidence of association was observed with variants at CRP (rs876537, P = 1.4 × 10−9) and HNF1A (rs7305618, P = 1.0 × 10−8). Among other previously reported CRP associated loci, the APOE ε4 haplotype was associated with decreased CRP level (P = 7.1 × 10−4), and modest association was observed with LEPR (rs1892534, P = 0.076), with direction of effects consistent with previous studies. The strongest signal at a locus not previously reported mapped to a gene desert region on chromosome 6q16.1 (rs1408282, P = 2.9 × 10−6). Finally, we observed nominal evidence of interaction with exposure to a pathogenic environment for top main effect SNPs at HNF1A (rs7305618, P = 0.031), LEPR (rs1892535, P = 0.030) and 6q16.1 (rs1408282, P = 0.046). Our findings demonstrate convincing evidence that genetic variants in CRP and HNF1A contribute to plasma CRP in Filipino women, and provide the first evidence that exposure to a pathogenic environment may modify the genetic influence at the HNF1A, LEPR and 6q16.1 loci on plasma CRP level.

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“…The gene has similarly been implicated in coronary artery disease (CAD)/myocardial infarction (MI) [30, 36] as well as its risk traits, including dyslipidemic disorders [30, 37], whereby an increased risk for CAD was also observed in T2DM patients harbouring HNF1a mutations [34]. However, these findings have either not been replicable in other studies or partly refuted by other investigators or meta-analysis studies [38–41].…”

Section: Introductionmentioning

confidence: 99%

A New Susceptibility Locus for Myocardial Infarction, Hypertension, Type 2 Diabetes Mellitus, and Dyslipidemia on Chromosome 12q24

et al. 2014

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We examined the role of hepatic nuclear factor-1 alpha (HNF1a) gene polymorphism on coronary artery disease (CAD) traits in 4631 Saudi angiographed individuals (2419 CAD versus 2212 controls) using TaqMan assay on ABI Prism 7900HT sequence detection system. Following adjustment for confounders, the rs2259820_CC (1.19 (1.01–1.42); P = 0.041), rs2464196_TT (1.19 (1.00–1.40); P = 0.045), and rs2259816_T (1.13 (1.01–1.26); P = 0.031) were associated with MI. The rs2259820_T (1.14 (1.03–1.26); P = 0.011) and rs2464196_C (1.12 (1.02–1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01–1.28); P = 0.032), rs7310409_G (1.16 (1.03–1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05–1.49); P = 0.012) were implicated in hypertension. Hypertriglyceridemia was linked to the rs2393791_T (1.14 (1.02–1.27); P = 0.018), rs7310409_G (1.12 (1.01–1.25); P = 0.031), rs1169310_G (1.15 (1.04–1.28); P = 0.010), and rs1169313_CT+TT (1.24 (1.06–1.45); P = 0.008) and high low density lipoprotein-cholesterol levels were associated with rs2259820_T (1.23 (1.07–1.41); P = 0.004), rs2464196_T (1.22 (1.06–1.39); P = 0.004), and rs2259816_T (1.18 (1.02–1.36); P = 0.023). A 7-mer haplotype CATATAC (χ 2 = 7.50; P = 0.0062), constructed from the studied SNPs, was associated with MI, and CATATA implicated in T2DM (χ 2 = 3.94; P = 0.047). Hypertriglyceridemia was linked to TGCGGG (χ 2 = 4.26; P = 0.039), and obesity to ACGGGT (χ 2 = 5.04; P = 0.025). Our results suggest that the HNF1a is a common susceptibility gene for MI, T2DM, hypertension, and dyslipidemia.

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Common Coding Variants of the HNF1A Gene Are Associated With Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults

Cited by 43 publications

References 49 publications

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

Genome-wide Association with C-Reactive Protein Levels in CLHNS: Evidence for the CRP and HNF1A Loci and their Interaction with Exposure to a Pathogenic Environment

A New Susceptibility Locus for Myocardial Infarction, Hypertension, Type 2 Diabetes Mellitus, and Dyslipidemia on Chromosome 12q24

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