Paul Elliott

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

CONTEXTnPlasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.nnnOBJECTIVEnTo investigate association of genetic loci with CRP levels and risk of coronary heart disease.nnnDESIGN, SETTING, AND PARTICIPANTSnWe first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.nnnMAIN OUTCOME MEASUREnRisk of coronary heart disease.nnnRESULTSnPolymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.nnnCONCLUSIONnThe lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (pu200a=u200a1.1×10-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (pu200a=u200a1.02×10-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.

Trends and inequalities in cardiovascular disease mortality across 7932 English electoral wards, 1982–2006: Bayesian spatial analysis

Background Cardiovascular disease (CVD) mortality has more than halved in England since the 1980s, but there are few data on small-area trends. We estimated CVD mortality by ward in 5-year intervals between 1982 and 2006, and examined trends in relation to starting mortality, region and community deprivation. Methods We analysed CVD death rates using a Bayesian spatial technique for all 7932 English electoral wards in consecutive 5-year intervals between 1982 and 2006, separately for men and women aged 30–64 years and ≥65 years. Results Age-standardized CVD mortality declined in the majority of wards, but increased in 186 wards for women aged ≥65 years. The decline was larger where starting mortality had been higher. When grouped by deprivation quintile, absolute inequality between most- and least-deprived wards narrowed over time in those aged 30–64 years, but increased in older adults; relative inequalities worsened in all four age–sex groups. Wards with high CVD mortality in 2002–06 fell into two groups: those in and around large metropolitan cities in northern England that started with high mortality in 1982–86 and could not ‘catch up’, despite impressive declines, and those that started with average or low mortality in the 1980s but ‘fell behind’ because of small mortality reductions. Conclusions Improving population health and reducing health inequalities should be treated as related policy and measurement goals. Ongoing analysis of mortality by small area is essential to monitor local effects on health and health inequalities of the public health and healthcare systems.

Coronary heart disease in Indian Asians.

The Indian Asian population accounts for a fifth of all global deaths from coronary heart disease (CHD). CHD deaths on the Indian subcontinent have doubled since 1990, and are predicted to rise a further 50% by 2030. Reasons underlying the increased CHD mortality among Indian Asians remain unknown. Although conventional cardiovascular risk factors contribute to CHD in Indian Asians as in other populations, these do not account for their increased risk. Type-2 diabetes, insulin resistance and related metabolic disturbances are more prevalent amongst Indian Asians than Europeans, and have been proposed as major determinants of higher CHD risk among Indian Asians. However, this view is not supported by prospective data. Genome-wide association studies have not identified differences in allele frequencies or effect sizes in known loci to explain the increased CHD risk in Indian Asians. Limited knowledge of mechanisms underlying higher CHD risk amongst Indian Asians presents a major obstacle to reducing the burden of CHD in this population. Systems biology approaches such as genomics, epigenomics, metabolomics and transcriptomics, provide a non-biased approach for discovery of novel biomarkers and disease pathways underlying CHD. Incorporation of these ‘omic’ approaches in prospective Indian Asian cohorts such as the London Life Sciences Population Study (LOLIPOP) provide an exciting opportunity for the identification of new risk factors underlying CHD in this high risk population.

Epigenetic signatures of internal migration in Italy

Background: Observational studies have suggested that the risks of non-communicable diseases in voluntary migrants become similar to those in the host population after one or more generations, supporting the hypothesis that these diseases have a predominantly environmental (rather than inherited) origin. However, no study has been conducted thus far to identify alterations at the molecular level that might mediate these changes in disease risk after migration. Methods: Using genome-wide DNA methylation profiles from more than 1000 Italian participants, we conducted an epigenome-wide association study (EWAS) to identify differences between south-to-north migrants and their origin (southern natives) and host (north-western natives) populations. Results: We identified several differentially methylated CpG loci, in particular when comparing south-to-north migrants with north-western natives. We hypothesise that these alterations may underlie an adaptive response to exposure differentials that exist between origin and host populations. Conclusions: Our study is the first large agnostic investigation of DNA methylation changes linked to migratory processes, and shows the potential of EWAS to investigate their biological effects.