Multilevel analysis of systolic blood pressure and ACE gene I/D polymorphism in 438 Swedish families – a public health perspective

BACKGROUND: Individuals belonging to the same family share a number of genetic as well as environmental circumstances that may condition a common SBP level. Among the genetic factors, the angiotensin converting enzyme (ACE) gene I/D polymorphism appears as a possible candidate as it might influence both SBP and the pharmacological effect of ACE inhibitors. We aimed to combine genetic epidemiology with public health ideas concerning life-course and multilevel epidemiology in order to understand the role of familial factors regarding individual SBP. METHODS: We applied multilevel regression analysis on 1926 individuals nested within 438 families from South Sweden. Modelling familial SBP variance as a function of age and use of ACE inhibitors we calculates a variance partition coefficient and the proportional change in familial SBP variance attributable to differences in ACE gene I/D polymorphism RESULTS: Our results suggest the existence of genetic or environmental circumstances that produce a considerable familial clustering of SBP, especially among individuals using ACE-inhibitors. However, ACE gene I/D polymorphism seems to play a minor role in this context. In addition, familial factors – genetic, environmental or their interaction – shape SBP among non-users of ACE inhibitors but their effect is expressed later in the life-course. CONCLUSION: Strategies directed to prevent hypertension should be launched in younger rather than in older ages and both prevention of hypertension and its treatment with ACE inhibitors should be focused on families rather than on individuals

Variation in plasma calcium analysis in primary care in Sweden - a multilevel analysis

<p>Abstract</p> <p>Background</p> <p>Primary hyperparathyroidism (pHPT) is a common disease that often remains undetected and causes severe disturbance especially in postmenopausal women. Therefore, national recommendations promoting early pHPT detection by plasma calcium (P-Ca) have been issued in Sweden. In this study we aimed to investigate variation of P-Ca analysis between physicians and health care centres (HCCs) in primary care in county of Skaraborg, Sweden.</p> <p>Methods</p> <p>In this cross sectional study of patients' records during 2005 we analysed records from 154 629 patients attending 457 physicians at 24 HCCs. We used multilevel logistic regression analysis (MLRA) and adjusted for patient, physician and HCC characteristics. Differences were expressed as median odds ratio (MOR).</p> <p>Results</p> <p>There was a substantial variation in number of P-Ca analyses between both HCCs (MOR_HCC1.65 [1.44-2.07]) and physicians (MOR_physician1.95 [1.85-2.08]). The odds for a P-Ca analysis were lower for male patients (OR 0.80 [0.77-0.83]) and increased with the number of diagnoses (OR 25.8 [23.5-28.5]). Sex of the physician had no influence on P-Ca test ordering (OR 0.93 [0.78-1.09]). Physicians under education ordered most P-Ca analyses (OR 1.69 [1.35-2.24]) and locum least (OR 0.73 [0.57-0.94]). More of the variance was attributed to the physician level than the HCC level. Different mix of patients did not explain this variance between physicians. Theoretically, if a patient were able to change both GP and HCC, the odds of a P-Ca analysis would in median increase by 2.45. Including characteristics of the patients, physicians and HCCs in the MLRA model did not explain the variance.</p> <p>Conclusions</p> <p>The physician level was more important than the HCC level for the variation in P-Ca analysis, but further exploration of unidentified contextual factors is crucial for future monitoring of practice variation.</p

Validity of registration of ICD codes and prescriptions in a research database in Swedish primary care: a cross-sectional study in Skaraborg primary care database

<p>Abstract</p> <p>Background</p> <p>In recent years, several primary care databases recording information from computerized medical records have been established and used for quality assessment of medical care and research. However, to be useful for research purposes, the data generated routinely from every day practice require registration of high quality. In this study we aimed to investigate (i) the frequency and validity of ICD code and drug prescription registration in the new Skaraborg primary care database (SPCD) and (ii) to investigate the sources of variation in this registration.</p> <p>Methods</p> <p>SPCD contains anonymous electronic medical records (ProfDoc III) automatically retrieved from all 24 public health care centres (HCC) in Skaraborg, Sweden. The frequencies of ICD code registration for the selected diagnoses diabetes mellitus, hypertension and chronic cardiovascular disease and the relevant drug prescriptions in the time period between May 2002 and October 2003 were analysed. The validity of data registration in the SPCD was assessed in a random sample of 50 medical records from each HCC (n = 1200 records) using the medical record text as gold standard. The variance of ICD code registration was studied with multi-level logistic regression analysis and expressed as median odds ratio (MOR).</p> <p>Results</p> <p>For diabetes mellitus and hypertension ICD codes were registered in 80-90% of cases, while for congestive heart failure and ischemic heart disease ICD codes were registered more seldom (60-70%). Drug prescription registration was overall high (88%). A correlation between the frequency of ICD coded visits and the sensitivity of the ICD code registration was found for hypertension and congestive heart failure but not for diabetes or ischemic heart disease.</p> <p>The frequency of ICD code registration varied from 42 to 90% between HCCs, and the greatest variation was found at the physician level (MOR_PHYSICIAN= 4.2 and MOR_HCC= 2.3).</p> <p>Conclusions</p> <p>Since the frequency of ICD code registration varies between different diagnoses, each diagnosis must be separately validated. Improved frequency and quality of ICD code registration might be achieved by interventions directed towards the physicians where the greatest amount of variation was found.</p

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations