Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.

TitleGenome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans.
Publication TypeJournal Article
Year of Publication2014
AuthorsDel-Aguila, JL, Beitelshees, AL, Cooper-Dehoff, RM, Chapman, AB, Gums, JG, Bailey, K, Gong, Y, Turner, ST, Johnson, JA, Boerwinkle, E
JournalPharmacogenomics J
Date Published2014 Feb
KeywordsAdipogenesis, African Americans, Antihypertensive Agents, Blood Glucose, Genome-Wide Association Study, Humans, Hydrochlorothiazide, Hypertension, Lipid Metabolism, Nerve Tissue Proteins, Triglycerides

Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r(2)=0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl(-1) increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.

Alternate JournalPharmacogenomics J.
PubMed ID23400010
PubMed Central IDPMC3812324
Grant ListM01 RR00039 / RR / NCRR NIH HHS / United States
HL53335 / HL / NHLBI NIH HHS / United States
M01 RR000082 / RR / NCRR NIH HHS / United States
UL1 RR029890 / RR / NCRR NIH HHS / United States
U01 GM074492 / GM / NIGMS NIH HHS / United States
M01 RR000039 / RR / NCRR NIH HHS / United States
HL74735 / HL / NHLBI NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
R01 HL074735 / HL / NHLBI NIH HHS / United States
UL1 RR024150 / RR / NCRR NIH HHS / United States
M01 RR00082 / RR / NCRR NIH HHS / United States
UL1 RR025008 / RR / NCRR NIH HHS / United States

Similar Publications

Chen F, Zhang Y, Chandrashekar DS, Varambally S, Creighton CJ. Global impact of somatic structural variation on the cancer proteome. Nat Commun. 2023;14(1):5637.
Rhie A, Nurk S, Cechova M, Hoyt SJ, Taylor DJ, Altemose N, et al.. The complete sequence of a human Y chromosome. Nature. 2023;621(7978):344-354.
Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Indramanee S, Seubwai W, et al.. γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus. World J Gastroenterol. 2023;29(28):4416-4432.
Wojcik MH, Reuter CM, Marwaha S, Mahmoud M, Duyzend MH, Barseghyan H, et al.. Beyond the exome: What's next in diagnostic testing for Mendelian conditions. Am J Hum Genet. 2023;110(8):1229-1248.
Schlosser P, Zhang J, Liu H, Surapaneni AL, Rhee EP, Arking DE, et al.. Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage. Genome Biol. 2023;24(1):150.
Chin C-S, Behera S, Khalak A, Sedlazeck FJ, Sudmant PH, Wagner J, et al.. Multiscale analysis of pangenomes enables improved representation of genomic diversity for repetitive and clinically relevant genes. Nat Methods. 2023;20(8):1213-1221.
Zhao N, Teles F, Lu J, Koestler DC, Beck J, Boerwinkle E, et al.. Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study. J Clin Periodontol. 2023;50(9):1140-1153.
Harris RA, McAllister JM, Strauss JF. Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome. Int J Mol Sci. 2023;24(13).
Qian X, Srinivasan T, He J, Chen R. The Role of Ceramide in Inherited Retinal Disease Pathology. Adv Exp Med Biol. 2023;1415:303-307.
Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, et al.. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease. Am J Hum Genet. 2023;110(8):1394-1413.