%0 Journal Article %J Hypertension %D 2019 %T HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study. %A Selvaraj, Senthil %A Seidelmann, Sara %A Silvestre, Odilson M %A Claggett, Brian %A Ndumele, Chiadi E %A Cheng, Susan %A Yu, Bing %A Fernandes-Silva, Miguel M %A Grove, Megan L %A Eric Boerwinkle %A Shah, Amil M %A Solomon, Scott D %K Cardiovascular Diseases %K Echocardiography %K Female %K Genetic Predisposition to Disease %K Hemochromatosis Protein %K Humans %K Hypertension %K Male %K Middle Aged %K Mutation %K Polymorphism, Genetic %K Risk Assessment %K United States %K Ventricular Remodeling %X

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3-5.1%) and 1.3% (95% CI, 0.0-2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.

%B Hypertension %V 73 %P 68-74 %8 2019 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30571559?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.118.11730 %0 Journal Article %J J Am Coll Cardiol %D 2018 %T Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. %A Seidelmann, Sara B %A Feofanova, Elena %A Yu, Bing %A Franceschini, Nora %A Claggett, Brian %A Kuokkanen, Mikko %A Puolijoki, Hannu %A Ebeling, Tapani %A Perola, Markus %A Salomaa, Veikko %A Shah, Amil %A Coresh, Josef %A Selvin, Elizabeth %A MacRae, Calum A %A Cheng, Susan %A Eric Boerwinkle %A Solomon, Scott D %K Cardiovascular Diseases %K Exome Sequencing %K Female %K Genetic Variation %K Glucose %K Glucose Tolerance Test %K Humans %K Hyperglycemia %K Intestinal Absorption %K Loss of Function Mutation %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Outcome Assessment, Health Care %K Protective Factors %K Risk Assessment %K Sodium-Glucose Transporter 1 %K United States %K White People %X

BACKGROUND: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized.

OBJECTIVES: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences.

METHODS: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed.

RESULTS: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90).

CONCLUSIONS: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

%B J Am Coll Cardiol %V 72 %P 1763-1773 %8 2018 Oct 09 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/30286918?dopt=Abstract %R 10.1016/j.jacc.2018.07.061 %0 Journal Article %J Nat Commun %D 2016 %T An exome array study of the plasma metabolome. %A Rhee, Eugene P %A Yang, Qiong %A Yu, Bing %A Liu, Xuan %A Cheng, Susan %A Deik, Amy %A Pierce, Kerry A %A Bullock, Kevin %A Ho, Jennifer E %A Levy, Daniel %A Florez, Jose C %A Kathiresan, Sek %A Larson, Martin G %A Vasan, Ramachandran S %A Clish, Clary B %A Wang, Thomas J %A Boerwinkle, Eric %A O'Donnell, Christopher J %A Gerszten, Robert E %K Exome %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Male %K Metabolome %K Middle Aged %K Plasma %K Polymorphism, Single Nucleotide %K Ribonucleosides %K Xanthines %X

The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 × 10(-8) in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome.

%B Nat Commun %V 7 %P 12360 %8 2016 Jul 25 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/27453504?dopt=Abstract %R 10.1038/ncomms12360