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

J L Del-Aguila, A L Beitelshees, R M Cooper-Dehoff, A B Chapman, J G Gums, K Bailey, Y Gong, S T Turner, J A Johnson, E Boerwinkle, J L Del-Aguila, A L Beitelshees, R M Cooper-Dehoff, A B Chapman, J G Gums, K Bailey, Y Gong, S T Turner, J A Johnson, E Boerwinkle

Abstract

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.

Figures

Figure 1
Figure 1
Genome-wide association study (GWAS) meta-analysis Manhattan plot showing the association of triglyceride response to hydrochlorothiazide (HCTZ) treatment in African Americans in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and the Genetic Epidemiology of Responses to Antihypertensive (GERA) studies. Two single nucleotide polymorphisms (SNPs) on chromosome 11 showed genome-wide significance (P=5 × 10−8). Eighteen loci showed P-values less than the suggestive threshold (P=1 × 10−5).
Figure 2
Figure 2
Means change in triglycerides adjusted for sex, age, waist circumference, base line insulin, base line triglycerides, and the two principal components depending on rs12279250 genotype (CC, CT, TT) for Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and the Genetic Epidemiology of Responses to Antihypertensive (GERA) studies. Error bars represent s.e.m.

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