Leifur Franzson

Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density

Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 × 10−12 for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).

Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5).

The Association between Parathyroid Hormone, Vitamin D and Bone Mineral Density in 70-Year-Old Icelandic Women

Abstract: Parathyroid hormone (PTH) may be an important determinant of cortical bone remodeling in the elderly. Vitamin D status is one of the determining factors in this relationship. The aim of this study was to quantify the relationship between serum PTH, vitamin D and bone mineral density (BMD) in elderly women in Reykjavik (64° N), where daily intake of cod liver oil is common and mean calcium intake is high. ln PTH correlated inversely with 25(OH)D (r=−0.26, p<0.01). In multivariate analysis PTH correlated inversely with whole body BMD (mostly cortical bone) (R2= 2.2%, p = 0.04) but not with the lumbar spine BMD, reflecting more cancellous bone. No association was found between 25(OH)D levels and BMD at any site in univariate or multivariate analysis. Osteocalcin, a measure of bone turnover, was negatively associated with BMD and this association remained significant when corrected for PTH levels. In summary, in this fairly vitamin D replete population with high calcium intake, PTH was negatively associated with total body BMD. We infer that suppression of PTH may reduce cortical bone loss, but other factors are likely to contribute to age-related bone remodeling and osteoporosis.

The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities.

Objectives: To examine the effect of raloxifene on bone turnover in elderly women.

A compendium of inborn errors of metabolism mapped onto the human metabolic network

Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases.

Age-Related Decline in Bone Mass Measured by Dual-Energy X-Ray Absorptiometry and Quantitative Ultrasound in a Population-Based Sample of Both Sexes: Identification of Useful Ultrasound Thresholds for Osteoporosis Screening

Quantitative ultrasound (QUS) can be used as a screening tool for low bone mineral density (BMD), but clinical guidelines have not been set. The aim of this population-based, cross-sectional study was to compare age-related changes in bone mass measured by QUS (Lunar, Achilles Plus) and dual-energy X-ray absorptiometry (DXA) in a random sample of 1630 individuals (1041 females, 589 males) 30-85 yr of age. Individuals with DXA T-scores < or =-2.5 at the femoral neck or total hip were identified and receiver operating curves (ROCs) were used to calculate cutoff points for QUS. Sensitivity, specificity, and kappa statistics were calculated. Age-related bone loss was significantly larger with QUS than DXA at all sites in women. For men, the curves were similar for QUS and DXA in the hip. Similar correlations were found between QUS and DXA in different age groups of both sexes (0.36-0.60). For women aged 50-65 yr, a QUS T-score >-1.0 was found to be the most applicable for identifying normal BMD. In the 70-85 yr age group, a T-score <-2.5 for women and a T-score <-0.5 for men seemed reasonable cutoffs for identifying normal BMD (sensitivity: 86-93%; specificity: 28-44%; discordance: 33-73%). Calcaneal QUS cannot be used for the diagnosis of osteoporosis according to WHO criteria, but it can be of use to exclude osteoporosis in 30-40% of our cases.

Factors associated with elevated or blunted PTH response in vitamin D insufficient adults

Objectives.  The purpose of this study was to examine factors associated with high or low parathyroid hormone (PTH) levels in relationship to vitamin D insufficiency.

Discrepancies between creatinine- and cystatin C-based equations: Implications for identification of chronic kidney disease in the general population

Abstract Objective. Early detection and treatment of chronic kidney disease (CKD) is important for slowing the progression of the disease and decreasing the associated risk of cardiovascular disease. This study examined how two creatinine-based and two cystatin C-based equations for calculating estimated glomerular filtration rate (eGFR) perform relative to each other in identifying CKD in a large cohort of community-dwelling individuals. Material and methods. A total of 1630 adults were recruited from the Reykjavik area. Each subjects eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) Study and Cockroft–Gault equations, and two cystatin C-based equations. The prevalence of decreased eGFR obtained by the four equations was compared and the relative performance of the equations examined. Results. The MDRD equation labelled significantly fewer individuals as having CKD (5.3%) relative to the other equations (12.8–19.7%). Agreement between equations was limited, with up to one-third of subjects diagnosed as having CKD by the MDRD equation being classified as normal by other equations. Correlations between creatinine- and cystatin C-based equations varied with age, gender and diuretic use. Conclusions. The MDRD equation results in lower population-wide estimates of CKD relative to the other equations tested. An understanding of the performance of these equations is critical when they are used for estimating the prevalence of CKD in a population-wide setting or for diagnosing the disorder in clinical practice.

Risk factors for bone loss in the hip of 75-year-old women: A 4-year follow-up study

Risk factors for bone loss among the elderly are largely unknown. The objective of the study was to examine longitudinal bone loss in the hip in one-hundred and sixty-two 75-year-old women. Bone mineral density (BMD, g/cm(2)) was measured with dual X-ray absorptiometry (DXA) at baseline and after 4 years. The relationship between changes in BMD during follow-up and the following factors; baseline BMD, baseline weight, weight change, baseline lean and fat body mass (measured with DXA), serum values of biochemical markers and hormones, nutritional and lifestyle factors according to a questionnaire was assessed. The annual mean (SD) change in femoral neck BMD was -0.31% (1.38) in total trochanter -0.35% (1.15) and total hip -0.34% (1.10) and did not differ significantly between measurement sites. Bisphosphonate users had a 2.9%, 1.7% and 1.9% mean adjusted increase in femoral neck, total trochanter and total hip BMD respectively, different from none-users (p<0.05). Subjects with more than three weekly physical activity sessions had less femoral neck bone loss than less active women (p<0.05). The proportion of the variance in BMD changes explained by multivariate models (R(2)) was 12-13%. Women gaining weight had less loss of BMD than those losing weight in the trochanter and the total hip (p<0.001), and in the femoral neck (p=0.055). Elderly women should be advised to maintain their body weight and participate in physical activity. Despite the large number of variables examined in this study, bone loss occurring with increased age is not thoroughly explained.