Lars Retterstøl

A twin study of C-Reactive Protein compared to other risk factors for coronary heart disease

Coronary heart disease (CHD) tends to cluster in families, and several established risk factors for the disease are to some extent inherited. Inflammation plays a key role in the development of atherosclerosis and CHD. A low-grade inflammation may be detected by highly sensitive C-Reactive Protein (CRP) determination, which is strongly associated to CHD. In order to uncover any role of genetics in low-grade inflammation, we measured CRP in healthy monozygotic twins. The within-pair correlation coefficient of CRP was 0.40, suggesting an important genetic contribution to the control of CRP level. CRP correlated significantly to other CHD risk factors like body mass index (BMI), systolic blood pressure, diastolic blood pressure, plasma fibrinogen, serum high-density lipoprotein cholesterol, plasma homocysteine, and serum triglycerides. Of these variables, BMI was most significantly associated to CRP in a linear multiple regression analysis. We conclude that CRP level (reflecting a low-grade inflammation) exhibits a moderate, but significant degree of heritability. The association between CRP and BMI, which has a larger degree of heritability, could partly explain the heritability of serum CRP level.

C-reactive protein predicts death in patients with previous premature myocardial infarction—A 10 year follow-up study

Atherosclerosis is an inflammatory disease. C-reactive protein (CRP), a marker of inflammation, is associated with coronary heart disease (CHD). We measured CRP in a cohort of 247 patients (193 males and 54 females) who had had their first myocardial infarction (MI) at age < or = 55 (males) or < or = 60 (females). The cut-off values of the 25th, 50th and 75th centiles of CRP were 1.20, 2.37 and 4.20 mg/l. After 10 years, a total of 44 patients (17.8%) had died, 36 (81.8%) of cardiac causes. Unadjusted and adjusted (i.e. for age, ejection fraction (EF), serum total cholesterol (TC), fibrinogen, smoking and hypertension) relative risks (RRs) for total and cardiac mortality were generated. CRP was a strong predictor of death of all causes due to its strength as predictor of cardiac death. The RR of cardiac death was doubled with increasing CRP quartiles, and patients in the top quartile had six times as high risk of cardiac death as patients in the lowest quartile. The RRs were moderately attenuated after adjustment, but still significant. We conclude that CRP is a strong predictor of mortality in patients with premature MI. Thus, inflammation appears to be a critical prognostic factor in patients with previous premature MI.

Plasma total homocysteine levels and prognosis in patients with previous premature myocardial infarction: a 10-year follow-up study

Abstract. Retterstol L, Paus B, Bohn M, Bakken A, Erikssen J, Malinow MR, Berg K (University of Oslo; Ullevål University Hospital, Oslo; Akershus University Hospital, Norway; and Oregon Regional Primate Research Center Beaverton, OR, USA). Plasma total homocysteine levels and prognosis in patients with previous premature myocardial infarction: a 10‐year follow‐up study. J Intern Med 2003; 253: 284–292.

Whole blood folate, homocysteine in serum, and risk of first acute myocardial infarction

High level of total homocysteine (tHcy) is a risk factor for coronary artery disease (CAD), but the mechanism is not known. The serum concentration of tHcy, total cholesterol, high density lipoprotein cholesterol (HDL-C), and apolipoprotein A-I (apo A-I) and the concentration of folate in whole blood were measured in 107 patients with first acute myocardial infarction (MI) and 103 controls. The level of whole blood folate was lower and that of tHcy higher in cases than in controls. An increase of 50 nmol/l whole blood folate was associated with an OR for MI of 0.75, and an increase of 5 micromol/l tHcy with an OR for MI of 1.57. Correlations were observed between the levels of whole blood folate and tHcy and between whole blood folate and alcohol intake, and in MI cases, between tHcy, HDL-C, and apo A-I as well as between HDL-C and alcohol intake. The number of cigarette smokers was higher among cases than controls. In smokers, the level of tHcy was higher and that of whole blood folate lower than in non-smokers. After adjustment for smoking, the whole blood folate and tHcy-associated risks of MI became non-significant. We conclude that smoking may affect folate status and tHcy level adversely. The risk of MI in smokers may at least partly be attributed to hyperhomocysteinemia or low folate.

Mutations in the melanocortin 4 receptor (MC4R) gene in obese patients in Norway.

BACKGROUND Mutations in the melanocortin 4 receptor ( MC4R) gene are the most frequent cause of monogenic forms of obesity, but the reported prevalences of mutations in obese individuals diverge, varying from 0.2 to 5.8%. OBJECTIVE The aim of this study was to assess the prevalence of MC4R mutations in obese children and adults residing in Norway. SUBJECTS AND METHODS We sequenced the coding region of MC4R in 1 027 obese patients. Among these, were 644 adults with a BMI >35 kg/m(2) and 383 children with a body weight >97.5 percentile for height. Identified mutations were analyzed by family studies and a bioinformatic approach including comparative sequence analysis and prediction of impact on transmembrane helix and three dimensional structure. RESULTS Nine mutations were identified, of which four were novel and five previously described. The prevalence of MC4R mutations was 1.6% in pediatric and 0.8% in adult patients. All four novel mutations, I69R, M79I, I195S, and M200del were identified among pediatric patients. M79I was found in an ethnic Norwegian patient, while the rest were identified in second generation immigrants. The previously described mutations Y35X/D37V, V95I, T150I, R236C and V253I were identified in one pediatric and five adult patients. None of the adult patients reported childhood onset of obesity. The M200del mutation was found in a homozygous state, while the rest were heterozygous. CONCLUSION MC4R mutations are not a common cause of obesity in Norway and screening of obese patients does not appear to be warranted. The results are consistent with results from previous studies.

A Common Haplotype in NAPEPLD Is Associated With Severe Obesity in a Norwegian Population‐Based Cohort (the HUNT Study)

Obesity has a strong genetic etiology involving numerous identified metabolic pathways and others not yet examined. We investigated the association between severe obesity and genetic variation in selected candidate genes, including three drug‐related genes: cannabinoid receptor 1 (CNR1), N‐acyl phosphatidylethanolamine phospholipase D (NAPEPLD), and gastric lipase (LIPF); and three genes related to inflammation: nicotinamide phosphoribosyltransferase, six‐transmembrane epithelial antigen of the prostate 4 (STEAP4) and interleukin 18 (IL‐18). Subjects were 1,632 individuals with severe obesity (BMI ≥35 kg/m2) and 3,379 controls (BMI 20–24.9 kg/m2) that took part in a Norwegian population based cohort study. Tagging single‐nucleotide polymorphisms (SNPs) of the coding region of these genes were analyzed. SNP‐haplotypes for each gene were constructed in order to analyze allelic, genotypic, and haplotypic association to obesity. A single SNPs rs17605251 in NAPEPLD was nominally associated with BMI ≥35 kg/m2 (P = 0.035). A common haplotype in NAPEPLD was associated with BMI ≥35 kg/m2, after correction for multiple testing. The allele frequency was 56.8% in cases and 60.3% in controls, giving an odds ratio (OR) of 0.87 (95% confidence interval (CI) 0.79, 0.95; P = 0.0016). Homozygosity for this haplotype was protective against obesity (OR 0.79 (CI 0.70–0.91); P = 0.00059). The SNP rs7913071 in LIPF was associated with obesity, but the association lost statistical significance after correction for multiple testing. The CNR1, IL‐18, STEAP4, and nicotinamide phosphoribosyltransferase genes were not associated with obesity. In conclusion a common haplotype in NAPEPLD, an enzyme involved in endocannabinoid synthesis, was protective against obesity.

Adrenoleukodystrophy in Norway: High Rate of De Novo Mutations and Age-Dependent Penetrance

To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients.

Plasma fibrinogen level and long-term prognosis in Norwegian middle-aged patients with previous myocardial infarction. A 10 year follow-up study

Abstract. Retterstol L, Kierulf P, Pedersen JC, Bohn M, Bakken A, Erikssen J, Berg K (Institute of Medical Genetics, University of Oslo and Ullevål University Hospital, Oslo; and Central Hospital of Akershus, Nordbyhagen, Norway). Plasma fibrinogen level and long‐term prognosis in Norwegian middle‐aged patients with previous myocardial infarction. A 10 years follow‐up study. J Intern Med 2001; 249: 511–518.

FTO Genotype and Weight Gain in Obese and Normal Weight Adults From a Norwegian Population Based Cohort (the HUNT Study)

The fat mass and obesity associated gene ( FTO) is associated with bodyweight and obesity. The aim of this study was to investigate if FTO genotype affects weight gain in adulthood. We investigated the weight development over a period of 11 years in a case-control study, consisting of 1,632 cases (BMI≥35 kg/m (2)) and 3,379 normal weight controls (BMI 20-24.9 kg/m (2)) from a Norwegian population based cohort, the HUNT study. Subjects were aged 20-80 at baseline, 25% men and 75% women. FTO genotype was assessed by genotyping of the SNP rs1421085. A strong association between FTO and obesity was found, consistent with an additive gene effect. Cases had an average weight gain of 11.1 kg, whereas controls had an average weight gain of 1.4 kg. Genotype was neither associated with weight gain in obese, nor controls. Cases had an average weight gain of 10.7 kg for individuals with zero risk alleles, 11.3 for one risk allele and 11.1 kg for two risk alleles. Controls had an average weight gain of 1.4 kg, 1.4 and 1.3 for the respective genotypes. In conclusion, FTO was associated with obesity, but not with weight gain in adults during 11 years of follow-up.

A double blind evaluation of cognitive decline in a Norwegian cohort of asymptomatic carriers of Huntington's disease

Previous studies investigating subclinical signs of cognitive decline in presymptomatic carriers of Huntingtons disease (HD) have shown conflicting results. The current study examines cognition in 105 at-risk individuals, using a broad neuropsychological test battery and adopting strict inclusion criteria for attaining a homogeneous sample. Results obtained by analyses of variance and effect size calculations indicate no clinical evidence of significant cognitive decline in asymptomatic HD carriers very far from onset of illness compared to noncarriers. Closeness to disease onset amongst gene carriers influenced cognition negatively whereas cytosine–adenine–guanine (CAG) repeat size did not. The findings call for longitudinal follow-up studies using a combination of clinical instruments and experimental paradigms to pinpoint when subtle cognitive deficits occur and within which of the cognitive domains.