We previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in the subjects of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF) < 0.05] in the NKAIN1-SERINC2 region, in order to confirm our previous finding.
A discovery sample (1,409 European-American cases with alcohol dependence and 1,518 European-American controls) and a replication sample (6,438 European-Australian family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 39,903 subjects from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 SNPs in the subjects with European descent and about 450 SNPs in the subjects with African descent with 0
Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall p=1.8×10−4; VT: overall p=1.4×10−4; Collapsing p=6.5×10−5) and European-Australians (Fp: overall p=0.028; Collapsing p=0.025), but not African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in brain that incorporates serine into lipids. Additionally, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (p<0.05). The associations of 5 of these rare variants that lay within SERINC2 exhibited region-wide significance (p<α=0.0006); and 25 associations survived correction for false discovery rate (q<0.05). The associations of 2 rare variants at SERINC2 were replicated in European-Australians (p<0.05).
We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in the subjects of European descent.
SERINC2; alcohol dependence; rare variant constellations; European descent; association
immunosuppressive agents; inosine monophosphate dehydrogenase; mycophenolate mofetil; mycophenolic acid; pharmacogenetics; pharmacogenomics
CYP2C19; CYP2D6; pharmacogenetics; serotonin–norepinephrine reuptake inhibitor; venlafaxine
Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the Transcription Factor 7-Like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.
We identified cases that developed NOD and age, gender, and race/ethnicity-matched controls from the INternational VErapamil SR Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP*hydrochlorothiazide treatment) interactions. Permuted interaction p values were corrected with the PACT test and adjusted for diabetes-related variables.
In INVEST whites, we observed three TCF7L2 SNPs with significant SNP*treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 (synergy index 3.37 [95%CI 1.72–6.59], p=5.0×10−4, PACT =0.03), which was associated with increased NOD risk in hydrochlorothiazide-treated patients (OR 1.53 [1.04–2.25], p=0.03) and decreased NOD risk in non hydrochlorothiazide-treated patients (OR 0.48 [0.27–0.86], p=0.02). The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association.
Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.
pharmacogenetics; TCF7L2; diabetes mellitus; hydrochlorothiazide
Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose due to higher active metabolite levels and risk of adverse events. However, in vitro lymphocyte proliferation assays performed in subjects with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared to wild type (WT) subjects. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA.
We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored for by routine endomyocardial biopsies.
There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared to WT (13.1± 2.8 vs. 21 ± 4.5 U/mL RBC, p<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (p<0.001), and total rejection score was higher (p=0.02) than WT. AZA was discontinued more frequently in HZ (p=0.01) due to rejection. Incidence of leukopenia was similar between groups (40% vs. 43%, p=1.0).
HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.
azathioprine; thiopurine S-methyltransferase; heart transplantation; rejection; toxicity; pharmacogenomics
UDP-glucuronosytransferase-2B10 (UGT2B10) is the primary catalyst of
nicotine glucuronidation. To develop a predictive genetic model of nicotine
metabolism, the conversion of deuterated (D2)-nicotine to
D2-trans-3'-hydroxycotinine were quantified in 188
European Americans, and the contribution of UGT2B10 genotype to
variability in first-pass nicotine glucuronidation assessed, following a
procedure previously applied to nicotine C-oxidation. The proportion of total
nicotine converted to nicotine-glucuronide (D2-nicotine-glucuronide/
+D2-trans-3'-hydroxycotinine)) was the primary
phenotype. The variant, rs61750900T (D67Y) (minor allele frequency (MAF) = 10%),
is confirmed to abolish nicotine glucuronidation activity. Another variant,
rs112561475G (N397D) (MAF = 2%), is significantly associated with enhanced
glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino
acid, indicating that the majority of human UGT2B10 alleles are
derived hypomorphic alleles. CYP2A6 and
UGT2B10 genotype explain 53% of the variance in oral
nicotine glucuronidation in this sample. CYP2A6 and
UGT2B10 genetic variants are also significantly associated
with un-deuterated (D0) nicotine glucuronidation in subjects smoking
ad libitum. We find no evidence for further common
variation markedly influencing hepatic UGT2B10 expression in
UGT2B10; nicotine; cotinine; metabolism; glucuronidation; CYP2A6
CYP2C8; CYP2C8*3; metabolism; pharmacogenetics; pharmacogenomics; pharmGKB
Pharmacogenomic (PG) testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia.
To characterize the groups of patients who accepted or declined PG testing in the IDEAL study.
Clinical and demographic factors and treatment outcomes were compared at all sites that had approved PG testing. Differences between patients who consented to and declined PG testing were analyzed using Student t and chi-square tests.
In total, 109 of 118 sites participated in the PG sub-study, and 1674 of 2949 (57%) patients enrolled at these sites consented to PG testing. More patients treated in academic medical centers than in community centers (60% vs. 52%, P < 0.001) provided consent. More males than females (58% vs. 54%, P = 0.04) consented to PG testing. There was no significant difference in PG participation between patients from different racial groups, including whites and African Americans (58% vs. 54%, P = 0.07). Treatment outcomes were also similar according to PG participation.
In the IDEAL study, patient consent to PG testing did not introduce selection bias. Treatment at an academic center and male gender were associated with higher rates of PG testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined PG testing.
pharmacogenomics; hepatitis C; peginterferon; ribavirin
breast cancer; pathway; pharmacogenomics; tamoxifen
Gemcitabine; deoxycytidine analogs; pancreatic cancer; non-small cell lung cancer; breast cancer; pharmacogenomics
etoposide; pathway; pharmacogenetics; pharmacogenomics; pharmGKB
anticancer; drug response; pathway; pharmacogenomics; platinum
The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.
Participants and methods
We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).
There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10−4) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans.
Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.
adverse drug event; angioedema; angiotensin-converting enzyme; neprilysin
Sympathetic activation inhibits insulin secretion through activation of pancreatic α2A-adrenoreceptors (α2AARs). A common genetic α2AAR variant (rs553668) is associated with impaired insulin secretion. α2AR-agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypothesis that the selective α2AR-agonist dexmedetomidine (DEX) decreases plasma insulin and increases plasma glucose in humans, and that these effects are modified by genetic α2AAR variants.
Healthy, fasting white (n=31) and black (n=33) subjects aged 18-45 years received 3 sequential infusions of placebo (normal saline) at 30 minute intervals followed by 3 infusions of DEX (0.1, 0.15, and 0.15 mcg/kg). Plasma insulin and glucose concentrations were measured at baseline, after placebo, and after DEX. We genotyped ADRA2A rs553668 and rs2484516, which characterize haplotypes 4 and 4b, respectively.
DEX decreased fasting insulin concentrations by 37%, from a median value after placebo of 7.9 (interquartile range, 6.0 to 12.6) μU/mL to 4.9 (3.5 to 7.9) μU/mL (P <0.001). Plasma glucose concentrations increased from 76±6 mg/dL to 79±7 mg/dL; P<0.001). The rs2484516 variant allele was associated with higher baseline insulin concentrations before (P=0.001) and after adjustment for potential confounders (P=0.014), and a greater decrease in insulin after DEX (P=0.016) that was no longer significant after adjustment for baseline concentrations and other confounders (P=0.58).
Low-dose DEX decreased plasma insulin and mildly increased plasma glucose concentrations in healthy fasting subjects. ADRA2A genetic variation may affect baseline insulin concentrations and thus the insulin decrease after DEX.
Adverse drug reactions; allopurinol; rasburicase; uric acid; uricosurics; pharmacodynamics; pharmacogenetics
Membrane transporters control the influx and efflux of endogenous and xenobiotic substrates, including nutrients and drugs, across cellular membranes.
Whole transcriptome sequencing enables simultaneous analysis of overall and allele-specific mRNA expression, and the detection of multiple RNA isoforms.
Here we characterize variation in RNA transcripts emanating from gene loci encoding transporters based on RNAseq data from 10 human brains (including cocaine overdose and normal brain tissues) and 12 normal livers.
mRNA expression was detected in 65% of transporter genes in either tissue, with many genes generating multiple mRNA transcripts. Single-nucleotide polymorphisms within transporters with previous evidence for pharmacogenomics impact were detected. We also identified noncoding RNAs in the vicinity of transporter genes with potential regulatory functions.
The results obtained with RNAseq provide detailed information on transporter mRNA expression at the molecular level, affording new avenues for the study of membrane transport, with relevance to drug efficacy and toxicity.
alternative splicing; gene expression; RNAseq; transporters
As genotyping technology has progressed, genome-wide association studies (GWAS) have matured into efficient and effective tools for mapping genes underlying human phenotypes. Recent studies have demonstrated the utility of the GWAS approach for examining pharmacogenomic traits, including drug metabolism, efficacy, and toxicity. Application of GWAS to pharmacogenomic outcomes presents unique challenges and opportunities. In the current review, we discuss the potential promises and potential caveats of this approach specifically as it relates to pharmacogenomic studies. Concerns with study design, power and sample size, and analysis are reviewed. We further examine the features of successful pharmacogenomic GWAS, and describe consortia efforts that are likely to expand the reach of pharmacogenomic GWAS in the future.
Genome-wide association; GWAS; pharmacogenetic; pharmacogenomic; drug response; drug metabolism; toxicity
Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap.
We resequenced CYP2D6 in 187 CSKT subjects and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT subjects.
We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9 and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates.
These results highlight the importance of conducting pharmacogenomic research in AI/AN populations and demonstrate that extrapolation from other populations is not appropriate. This information could help to optimize drug therapy for the CSKT population.
American Indian; Alaska Native; indigenous populations; Cytochrome P450; CYP2D6; CYP3A4; CYP3A5; CYP2C9; pharmacogenetics; pharmacogenomics
diuretics; hypertension; pathway; pharmacogenetic; pharmacogenomic
Acetylation; acetylator; NAT1; NAT2; metabolism; pharmacokinetics; genotype; pharmacogenetics; drug toxicity
ABCB1; calcineurin; cyclosporine; CYP3A4; CYP3A5; pharmacodynamics; pharmacogenetics; pharmacokinetics; tacrolimus; transplantation
Evaluate the influence of gender and butyrylcholinesterase (BuChE) genotype on incidence of progression to AD, rate of cognitive and functional decline, and response to rivastigmine treatment in mild cognitive impairment (MCI) subjects.
This retrospective exploratory analysis from a 3–4 year, randomized, placebo-controlled study of rivastigmine in MCI subjects included participants who consented to pharmacogenetic testing.
Of 1018 total patients, 490 (253 [52%] female) were successfully genotyped for BuChE. In subjects receiving placebo, the BuChE wt/wt genotype was associated with a statistically significantly higher rate of progression to AD and functional decline in women, compared with men with the BuChE wt/wt genotype. In subjects with a BuChE-K allele receiving placebo, incidence of progression to AD and rate of functional decline were not significantly different by gender, however cognitive decline was significantly faster in men. Statistically significant benefits of rivastigmine treatment on progression to AD, functional decline, ventricular volume expansion, whole brain atrophy and white matter loss were evident in female BuChE wt/wt.
Gender appears to differentially influence the type of decline in MCI subjects according to BuChE genotype, with more rapid progression of cognitive decline in male BuChE-K, and more rapid progression to AD and functional decline in female BuChE wt/wt. Cognitive decline in male BuChE-K and functional decline and progression to AD in female BuChE wt/wt were significantly attenuated by rivastigmine. Rivastigmine treatment also significantly reduced ventricular expansion, whole brain atrophy rate and white matter loss in female BuChE wt/wt, suggesting a possible disease-modifying effect.
Mild cognitive impairment; butyrylcholinesterase; rivastigmine