Home CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women
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CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women

  • Elisabet Söderström ORCID logo EMAIL logo , Jonas Andersson , Stefan Söderberg , Bethany van Guelpen , Torbjörn K. Nilsson and Johan Hultdin ORCID logo
Published/Copyright: October 24, 2022
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Drug Metabolism and Personalized Therapy
From the journal Drug Metabolism and Personalized Therapy Volume 38 Issue 1

Abstract

Objectives

Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H2S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition to MTHFR, been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI.

Methods

This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28 days after MI symptoms.

Results

Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16–8.54] for heterozygotes, and the dominant model 3.22 [1.22–8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26–8.34] and the dominant model 2.63 [1.06–6.50]. The MTHFR C677T polymorphism was not related to MI.

Conclusions

This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men.

Keywords: CTH ; fatal; H2S; MTHFR ; myocardial infarction; non-fatal

Introduction

The CTH gene encodes the enzyme cystathionine gamma-lyase (CSE), which transforms cystathionine derived from methionine into cysteine. The condensation of homocysteine and serine precedes this reaction to form cystathionine. CSE converts cysteine into pyruvate, ammonia, and the physiological signaling molecule hydrogen sulfide (H2S), and it also catalyzes the reaction of cystine to thiocysteine, which decomposes into cysteine and H2S. In addition, H2S is synthesized by cystathionine β-synthase and 3-mercaptopyruvate sulfurtransferase, though CSE is mainly expressed in vascular and nonvascular smooth muscle cells [1]. H2S has been suggested to play a prominent role in regulating endothelial and cardiovascular function [2]. Experimental studies have claimed potent beneficial effects of H2S in limiting cardiac damage during myocardial ischemia and reperfusion, and heart failure [3]. An ongoing trial (GIPS-IV) studies the effect of an H2S-donor on myocardial infarction (MI) [4]. The CTH G1208T rs1021737 polymorphism (previously annotated either as 1364G>T or 1352C>T) was first described in patients with cystathioninuria by Wang et al. [5], who also found increased homocysteine concentrations among homozygotes [6]. The biochemical properties of this polymorphism show that the CSE variants displayed no difference in kinetic properties [7]. However, there are some studies on this enzyme and a cardiovascular outcome.

In a minor study, the CTH G1208T polymorphism did not show any significant different frequency (seven homozygotes, 16.3%) among female coronary artery bypass grafting (CABG) patients compared to controls (five homozygotes, 8.5%) [8]. A study in a Chinese population (103 male and nine female cases) showed a lower risk of sudden cardiac death (SCD) in subjects with the insertion allele of CTH rs113044851 (OR=0.55, p-value=0.0107) in a dominant model [9]. With such small numbers of individuals, the risk of chance significance is high, resulting in “confirmation bias” of published papers. Therefore, the possible role of the CTH gene polymorphism in cardiovascular pathology should be regarded as unsettled, and larger cohorts should be assessed.

The MTHFR C677T polymorphism, the major genetic determinant of plasma homocysteine concentrations, has been extensively studied in relation to the risk of coronary heart disease (CHD); individuals with the MTHFR 677 TT genotype have been suggested to have a higher risk of CHD [10, 11]. In a more recent meta-analysis, MTHFR C677T and the other major MTHFR polymorphism, A1298C, showed no overall associations with MI risk [12]. We are not aware of any studies looking separately at fatal and non-fatal MI cases. Also, relatively few publications have addressed the MTHFR A1298C polymorphism in relation to cardiovascular risk. A prospective study in rheumatoid arthritis patients showed an association with increased risk of cardiovascular events among 1298 CC homozygotes, and the increased risk remained after 10 years of follow-up [13]. Another study including 107 hemodialysis patients and 103 controls found higher mean intima-media thickness (IMT) among patients with 1298CC compared to 1298AA [14].

The aim of this study was to investigate the CTH G1208T, MTHFR C677T, and MTHFR A1298C polymorphisms in relation to future risk of developing a fatal or non-fatal MI in a population-based cohort.

Materials and methods

Study design and population

This study used a population-based methodology with a nested case-referent design. It is originating in the Northern Sweden Health and Disease Study (NSHDS), consisting of the Västerbotten Intervention Project (VIP) [15], the Northern Sweden WHO Monitoring of Trends and Cardiovascular Disease (MONICA), and the local Mammography Screening Project (MSP) [16]. At baseline, participants fill out a health and lifestyle questionnaire and undergo anthropometric and other measurements. Venous blood samples, generally collected in the morning after an overnight fast, were aliquoted into buffy coat, plasma, and erythrocyte fractions, frozen, and stored at −80 °C at Biobanken Norr before analysis. A detailed description of the study population, and a flowchart showing the inclusion of study participants, was previously published [17, 18]. We included MI cases from the MONICA incidence registry that occurred before the 1st of January 2000 (n=7,337), that also had participated in the NSHDS before the MI incident (n=721). A first-ever fatal, and non-fatal MI, according to ICD-10, were included. Identification of cases was made using WHO and MONICA criteria [19]. For fatal cases, possible MI was included [20]. General practitioners’ reports, hospital records, death certificates, and autopsy reports were screened by research nurses performing the case ascertainment. The MI was classified as fatal for patients who died within 28th days from the onset of symptoms. Exclusion criteria for MI cases were previous MI, stroke, or a cancer diagnosis within five years before and one year after MI. In total, 545 MI cases were included from VIP (n=431), MONICA (n=44) and MSP (n=70). Referents matched for age, sex, time and type of survey, and geographical area were selected, two per case, within the NSHDS cohort. Referents were excluded if they had a diagnosis of MI, stroke, cancer, or death before diagnosing the index case.

At participation in the NSHDS survey, the mean age in this cohort was, for men 53.4 (±7.7) and women 58.2 (±7.5) years, respectively. Lag-time from baseline to MI was for men 4.3 (±2.5) and 3.4 (±2.4) years for women. The study complied with the Helsinki declaration and was approved by the Regional Ethics Committee Umeå, Sweden (Dnr 03-320). All participants gave their informed written consent before inclusion in the NSHDS.

Biochemical analyses

Laboratory technicians performed the biochemical analysis in batch, blinded for case and referent status, reducing the risk of systemic analytical bias. The CTH G1208T, rs1021737 polymorphism was analyzed by pyrosequencing. DNA was prepared from frozen buffy coat samples with a chloroform/phenol method. The primers were designed using the Assay Design Software, v. 1.0.6 (http://techsupport.pyrosequencing.com). The reference sequence used in the primer design and to count nucleotides was NM_001902 (GI: 21361333), and the location of the SNP was confirmed by the NCBI SNP database, reference number dbSNP: rs1021737. Whereas the previous papers by Wang et al. [5, 6] designate this SNP as CTH G1364T, the updated SNP database prefers the designation CTH G1208T for rs1021737, which will thus be used in this paper. The primer sequences chosen were: forward primer, 5′-Biotin-TGAGGAGTTGAAGCTATGGCCTAT–3′; reverse primer 5′-AGGCTCATTGTTGGTCCATTTAA–3′; sequencing primer 5′-TCTGGAATACTAGCTGTGA-3′. Sequencing was performed using a PSQ96 SNP Reagent Kit and a PSQ 96MA system (Biotage AB). Results were automatically analyzed using the PSQ 96MA 2.1 software. Analyzing the patient DNA extracts with the Pyrosequencing protocol, three types of pyrograms were consistently obtained, confirming the presence in the studied population of the three expected genotypes, 1208GG, 1208GT, and 1208TT.

Genotyping of the MTHFR C677T rs1801133 and MTHFR A1298C rs1801131 polymorphisms was performed by the TaqMan allelic discrimination method, using Minor Groove Binder (MGB) probes. PCR reactions were performed with TaqMan assays and reagents on GeneAmp PCR system 9700, PCR programs (Assay-on-Demand, ABI), all from Applied Biosystems (Foster City, CA, USA). PCR products were analyzed on the ABI PRISM 7900HT Sequence Detection System, Applied Biosystems.

Plasma folate concentrations were determined in heparinized samples using DPC® Solid Phase No-Boil Dualcount radioassay (Diagnostic Products Corporation, CA, USA) as previously described [18].

Statistical analysis

For statistical analysis, we used IBM SPSS Statistics 26 (IBM Corporation, New York, NY, USA). Missing data were treated as missing. Hardy-Weinberg equilibrium was calculated for the MTHFR C677T, rs1801133, MTHFR A1298C rs1801131, and CTH G1208T rs1021737 based on the χ 2-test. We coded the MTHFR and CTH genotypes in recessive models (wild type and heterozygote mutant vs. homozygote mutant) and dominant models (wild type vs. heterozygote mutant and homozygote mutant).

To evaluate the relationship between the MTHFR C677T, A1298C, and CTH G1208T polymorphisms and the risk of having a first-ever MI after blood sampling, we calculated odds ratios (OR) with 95% confidence intervals (CI). As cases and referents have the same observational time, we used conditional logistic regression analysis (rather than Cox regression) and the conditional maximum likelihood routine designed for matched analysis. Risk analyses were conducted for the variant genotypes, as well as for a dominant model combining heterozygote and homozygote mutant. In addition to univariable analyses, we also adjusted for plasma folate concentrations, categorized into sex-specific quartiles based on the referents. Folate was considered a potential confounder as it is associated with both the exposure and outcome; folate status influences the effect of the MTHFR C677T polymorphism on enzyme function [21] and it was independently associated with the risk of MI in this cohort [18].

Results

Baseline characteristics and genotype frequencies are presented for referents, cases, and stratified for fatal and non-fatal outcomes in Tables 1 and 2, respectively. The genotype distributions were in Hardy-Weinberg equilibrium for all groups.

Table 1:

Baseline characteristics of referents and cases who later developed a first-ever myocardial infarction (All MI), and stratified in non-fatal and fatal MI (death within 28 days), respectively.

Referents Non-fatal MI Fatal MI All MI
n Mean (SD), % n Mean (SD), % n Mean (SD), % Mean (SD), %
Age at survey, years 1,054 54.8 (±7.9) 416 54.3 (±7.8) 129 57.0 (±7.9) 54.9 (±7.9)
Lag-time to MI, years n.a. n.a. 416 3.9 (±2.4) 129 4.3 (±2.8) 4.0 (±2.5)
BMI 897 25.9 (±3.7) 354 27.0 (±3.8) 107 27.1 (±4.4) 27.0 (±3.9)
Diabetes 851 5.5 340 10.6 99 11.1 10.7
Hypertension 886 45.4 351 65.2 106 60.4 64.1
Current smoking 1,020 18.3 395 40.5 122 41.8 40.8

  1. Presented as mean (SD) for continuous and proportion/percents for categorical variables. n.a., non applicable.

Table 2:

Genotype distributions of the CTH and MTHFR polymorphisms among referents and cases with a subsequentfirst-ever myocardial infarction (All MI), non-fatal and fatal MI (death within 28 days).

Polymorphism Referents All MI Non-fatal MI Fatal MI
n n n n
CTH G1208T rs1021737
 GG 506 272 212 60
 GT 313 178 125 53
 TT 42 22 17 5
 pa 0.47 0.29 0.79 0.11
MTHFR C677T rs1801133
 CC 489 265 202 63
 CT 392 205 156 49
 TT 90 44 30 14
 pa 0.37 0.63 0.99 0.35
MTHFR A1298C rs1801131
 AA 403 198 153 45
 AC 440 255 187 68
 CC 127 64 50 14
 pa 0.69 0.19 0.54 0.12

  1. ap-Values for deviations from Hardy-Weinberg equilibrium.

ORs with 95% CI for developing a first-ever MI associated with the polymorphisms as continuous variables and for the dominant models are presented in Table 3. No significant associations with the risk of developing a first-ever MI were seen for the full dataset or in men or women. After adjustment for plasma folate concentrations, the results remained unchanged (Supplementary Table 1). Recessive models for the polymorphisms were also not significant (data not shown). Associations between the polymorphisms and the risk of fatal or non-fatal first-ever MI are presented in Table 4. In women, heterozygotes and the dominant model of the CTH G1208T and MTHFR A1298C polymorphisms were positively associated with the risk of developing an MI with a fatal outcome within 28 days, whereas for the MTHFR C677T, the associations with fatal MI were null. None of the polymorphisms were associated with the risk of non-fatal MI in the full dataset or in men or women separately. In recessive models of the polymorphisms, no associated risk was seen (data not shown).

Table 3:

Risk of a future first-ever myocardial infarction according to CTH and MTHFR genotypes, presented as odds ratios (95% confidence intervals).

n (C/R)a All n (C/R) Men n (C/R) Women
CTH G1208T rs1021737
 GG 272/506 1.0 199/368 1.0 73/138 1.0
 GT 178/313 1.04 (0.81–1.33) 122/218 1.02 (0.76–1.37) 56/95 1.09 (0.68–1.76)
 TT 22/42 0.99 (0.57–1.73) 14/30 0.89 (0.45–1.79) 8/12 1.21 (0.47–3.07)
CTH dominant model 472/861 1.03 (0.81–1.32) 335/616 1.01 (0.76–1.34) 137/245 1.11 (0.70–1.75)
MTHFR C677T rs1801133
 CC 265/489 1.0 185/353 1.0 80/136 1.0
 CT 205/392 0.97 (0.77–1.22) 150/280 1.02 (0.78–1.33) 55/150 0.87 (0.58–1.33)
 TT 44/90 0.90 (0.60–1.35) 31/60 0.94 (0.58–1.52) 13/30 0.84 (0.41–1.69)
677 dominant model 514/971 0.96 (0.77–1.19) 366/693 1.00 (0.77–1.30) 148/278 0.87 (0.58–1.29)
MTHFR A1298C rs1801131
 AA 198/403 1.0 136/277 1.0 62/126 1.0
 AC 255/440 1.19 (0.94–1.50) 189/323 1.22 (0.92–1.62) 66/117 1.10 (0.72–1.70)
 CC 64/127 1.03 (0.72–1.47) 42/92 0.92 (0.59–1.44) 22/35 1.27 (0.69–2.32)
1,298 dominant model 517/970 1.15 (0.92–1.44) 367/692 1.16 (0.88–1.52) 150/278 1.14 (0.76–1.71)

  1. aC, case; R, referent.

Table 4:

Risk of a future first-ever non-fatal or fatal (death within 28 days) myocardial infarction according to CTH and MTHFR genotypes, presented as odds ratios (95% confidence intervals).

First-ever myocardial infarction, non-fatal First-ever myocardial infarction, fatal within 28 days
All Men na Women na All Men na Women na
CTH G1208T rs1021737
 GG 1.0 1.0 149 1.0 63 1.0 1.0 50 1.0 10
 GT 0.98 (0.73–1.31) 1.08 (0.77–1.52) 91 0.75 (0.42–1.32) 34 1.22 (0.75–1.97) 0.85 (0.48–1.52) 31 3.14 (1.16–8.54) 22
 TT 0.96 (0.51–1.82) 1.03 (0.48–2.24) 12 0.78 (0.25–2.45) 5 1.10 (0.36–3.42) 0.51 (0.10–2.62) 2 3.74 (0.65–21.52) 3
CTH dominant model 0.98 (0.74–1.30) 1.08 (0.78–1.50) 252 0.75 (0.43–1.31) 102 1.20 (0.75–1.94) 0.82 (0.47–1.45) 83 3.22 (1.22–8.51) 35
MTHFR C677T rs1801133
 CC 1.0 1.0 144 1.0 58 1.0 1.0 41 1.0 22
 CT 0.95 (0.73–1.23) 0.94 (0.69–1.28) 111 0.97 (0.60–1.55) 45 1.06 (0.66–1.72) 1.33 (0.75–2.36) 39 0.62 (0.25–1.53) 10
 TT 0.81 (0.51–1.30) 0.84 (0.48–1.49) 21 0.76 (0.34–1.72) 9 1.23 (0.56–2.70) 1.26 (0.49–3.26) 10 1.09 (0.26–4.49) 4
677 dominant model 0.92 (0.72–1.18) 0.92 (0.69–1.24) 276 0.92 (0.59–1.45) 112 1.09 (0.70–1.72) 1.32 (0.77–2.26) 90 0.69 (0.30–1.61) 36
MTHFR A1298C rs1801131
 AA 1.0 1.0 103 1.0 50 1.0 1.0 33 1.0 12
 AC 1.07 (0.82–1.40) 1.22 (0.88–1.69) 143 0.77 (0.47–1.28) 44 1.62 (0.99–2.66) 1.20 (0.67–2.16) 46 3.24 (1.26–8.34) 22
 CC 1.08 (0.72–1.61) 0.95 (0.57–1.57) 31 1.35 (0.68–2.67) 19 0.92 (0.42–1.99) 0.85 (0.34–2.14) 11 1.05 (0.24–4.58) 3
1,298 dominant model 1.07 (0.83–1.38) 1.16 (0.85–1.58) 277 0.90 (0.57–1.42) 113 1.48 (0.91–2.39) 1.14 (0.64–2.02) 90 2.63 (1.06–6.50) 37

  1. an, MI cases. Significant odds ratios (p<0.05) are presented in bold.

Discussion

In this first study of fatal MI, our main finding demonstrates that women in the dominant model for the CTH G1208T polymorphism have a potentially higher risk, OR=3.22 (1.22–8.51), of developing a first-ever MI with a fatal outcome within 28 days, compared to female individuals with the wild type. The enzyme CSE, coded by the CTH gene, is mainly expressed in vascular and nonvascular smooth muscle cells [1] and participates in the endogenous synthesis of H2S. CSE, due to its role in H2S generation, might affect the risk of a future MI. Despite that the biochemical properties of the polymorphism CSE variants have shown no difference in kinetic properties [7], differences may still exist in vivo for individuals who are homozygous for the polymorphic variation. A difference in the activity of purified enzyme variants vs. in vivo in homozygous individuals for polymorphic variation is seen, for example, in human catechol O-methyltransferase: homozygosity for a specific allele (SNP V108M) is associated with lower enzyme activity in different human tissues despite similar kinetic properties in the purified polymorphic variants [22]. We, therefore, performed this prospective nested case-referent study, including fatal and non-fatal MI´s.

We are aware of only two previous case-control studies on CTH polymorphisms and cardiovascular disease. The first study included coronary bypass grafting (CABG) patients (n=178), and they found no association with CAD and the CTH G1208T polymorphism. Still, they noted a non-significant higher genotype frequency among women [8]. In our study, the increase in risk was confined to women, providing further support for a possible sex-driven association. In the same CABG patient sample, increased methylation in the CTH gene promoter was observed in CABG cases compared to controls in the total sample (OR=2.16, p=0.039) and for men (OR=2.4, p=0.039) but not in women (OR=0.54, p=0.495, n=43 cases), after adjustment for smoking, age, and gender [23]. The lack of association for women may be due to low power as only four female patients, and five female controls were hypermethylated in that study. The second study on CTH and cardiovascular disease (103 male and nine female cases) showed a lower risk of sudden cardiac death in subjects with the insertion allele of CTH rs113044851 (OR=0.55, p=0.0107) in a dominant model [9].

In CSE knockout mice models, findings suggest that decreased endogenous production of H2S accelerates atherosclerosis [24], and exogenous H2S improves myocardial reconstruction after myocardial infarction, as indicated by experimental animal models [25]. In humans, the ongoing prophylactic study with H2S-donor sodium thiosulfate (STS) in patients presenting with an STEMI will be followed-up around 2023 [4].

MTHFR polymorphisms, especially C677T, are related to elevated homocysteine status, a well-known risk marker for atherosclerotic disease [21]. There are many studies on MTHFR C677T in relation to cardiovascular disease and MI, but the results are conflicting. This is reflected in a recent meta-analysis based on 47 studies [12]. Their conclusion was that C677T had no association with MI. Subgroup analysis showed that the T allele increased the MI risk in subjects of African origin; the TT homozygotes had reduced risk among North Americans, and the C677T polymorphism reduced the risk of MI in elderly subjects. Part of these differences in associations may be due to gene-nutrient interactions, as folate intake varies between populations. We found no association between the CTH and MTHFR polymorphisms and a first-ever MI despite adjusting for folate status.

In the recent meta-analysis [12], A1298C was not associated with MI, based on seven studies, most of them relatively small. This is, to our knowledge, the first study of MTHFR polymorphism in relation to a first MI, stratified for fatal and non-fatal outcomes. We found that the MTHFR A1298C polymorphism was associated with a higher risk of developing a fatal MI among women. This was seen for heterozygotes and in the dominant model. This was not seen for non-fatal MI or for men. This may indicate a more severe MI, as a fatal outcome was defined as death within 28 days after MI, including those dead on arrival at the hospital. This design was possible as blood was donated years before the first MI. For the C677T polymorphism, no association was seen for fatal or non-fatal MI.

Although our finding for A1298C is new, there are previous reports related to cardiovascular disease. In a prospective study in rheumatoid arthritis patients (n=612) [13], there was an association with an increased risk of cardiovascular events (defined as ischemic heart disease, heart failure, cerebrovascular accident, or peripheral arteriopathy) among 1298 CC homozygotes. No stratification for sex was made; however, the study population consisted of 74.5% female patients. The increased risk remained after 5 and 10 years of follow-up. An association with cardiovascular disease is also supported by a study including hemodialysis patients (n=107) and controls (n=103) where they found higher mean intima-media thickness (IMT) among patients with 1298CC compared to 1298AA [14]. However, this study included only 14 female patients.

Strengths and limitations

A limitation in our study is that the minor allele frequencies of both the CTH and the two MTHFR polymorphisms are relatively low in the Swedish population compared to South/Central European populations, reducing the statistical power to detect significant effects. Still, we were able to find associations with fatal MI. The main strength of this study is the population-based study design, and the population was homogenous regarding ethnicity and is representative of the people of Northern Sweden. Another strength is the rigorous case ascertainment, including defining early fatal and non-fatal MI. We studied and included only first-ever infarction, whereas recurrent cases were not included. Also, the blood samples were collected prospectively before MI, allowing the inclusion of subjects in the study who died shortly after the event.

Conclusions

In this prospective study of first-ever fatal and non-fatal MI and the association with CTH and MTHFR polymorphisms, CTH G1208T and MTHFR A1298C were associated with a higher risk of having a fatal MI among women. No differences were seen among all MI patients. Still, after outcome stratification (fatal or non-fatal), the result may indicate that women with the minor alleles are at risk of having a more serious MI leading to death than women with the wild-type alleles.

Corresponding author: Elisabet Söderström, MD, Department of Medical Biosciences, Clinical Chemistry, Norrbotten County Council, Sunderby Hospital, Umeå University, Building 6M 2:nd floor, 901 85 Umeå, Sweden, Phone: +46(0) 920 282714, Fax: +46 920282688, E-mail:

Funding source: Swedish Research Council

Award Identifier / Grant number: VR 2017-00650

Acknowledgments

We want to thank the participants in the Västerbotten Intervention Program, the Mammography screening project, and the Northern Sweden MONICA study. In particular, we acknowledge the case ascertainment made within the MONICA study. We also thank the Department of Biobank Research at Umeå University (https://www.umu.se/en/biobank-research-unit/), the Northern Sweden Health and Disease Cohort, and Västerbotten County Council for delivering data and blood samples and acknowledge the contribution of Biobank Sweden. We also thank laboratory staff at health care centers and VIP-administrators, as well as Åsa Ågren at the Department of Biobank Research, Umeå University. We also appreciate the assistance provided by Eva Samuelsson and the staff at Clinical Chemistry, Laboratory Medicine, Umeå University Hospital.

  1. Research funding: This work was supported by the Västerbotten County Council and Norrbotten County Council. Biobank Sweden was supported by the Swedish Research Council (VR 2017-00650).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Dr. Söderberg reports personal fees and other from Actelion Ltd, outside the submitted work. All the other authors state no conflict of interest.

  4. Informed consent: Informed written consent was obtained from all individuals included in the NSHDS.

  5. Ethical approval: The study adhered to the Helsinki declaration and was approved by the regional ethical board, Umeå, Sweden (Dnr 03-320).

  6. Data availability: Aggregate data are included in the manuscript and its Supporting Information files. Individual data is not publicly available, as it contains potentially identifying patient information. Data are available upon request from the Northern Sweden Health and Disease Study Biobank. To request data, interested researchers must complete a formal application (available at https://www.umu.se/en/biobank-research-unit/research/access-to-samples-and-data/access-to-nsdd/) and submit it to The Biobank Research Unit at Umeå University (contact via ).

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/dmpt-2022-0119).

Received: 2022-03-05
Accepted: 2022-09-10
Published Online: 2022-10-24

© 2022 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  2. Editorial
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https://doi.org/10.1515/dmpt-2022-0119
Keywords for this article
CTH; fatal; H2S; MTHFR; myocardial infarction; non-fatal
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. News in DMPT: Leaders in Pharmacogenetics Section
  4. Reviews
  5. Application of vibrational spectroscopy and nuclear magnetic resonance methods for drugs pharmacokinetics research
  6. A metabolic blueprint of COVID-19 and long-term vaccine efficacy
  7. Concept of Unani Jali (detergents/cleansers) drugs and its scientific validation: scope for new opportunities in dermatological pharmacotherapeutics
  8. Original Articles
  9. Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations
  10. CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women
  11. Evaluation of pharmacogenomic evidence for drugs related to ADME genes in CPIC database
  12. Therapeutic drug monitoring of teriflunomide: do plasma concentrations predict response to leflunomide in patients with rheumatoid arthritis?
  13. The investigation of the complex population-drug-drug interaction between ritonavir-boosted lopinavir and chloroquine or ivermectin using physiologically-based pharmacokinetic modeling
  14. Phytochemical investigation, antioxidant and anticancer activities of various Unani drugs
  15. The efficacy and safety of dry cupping in cervical spondylosis with optimization of cup application time – a randomized clinical trial
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