Puneetpal Singh

APOE distribution in world populations with new data from India and the UK.

Background: The APOE gene and its protein product is associated with a number of plasma proteins like very-low density lipoprotein (VLDL), high density lipoprotein (HDL) chylomicrons, chylomicron remnants, and plays a crucial role in lipid metabolism. The APOE gene is polymorphic and common alleles (*E2, *E3 and *E4) have been associated with a number of common and complex diseases in different populations. Due to their crucial role in metabolism and clinical significance, it is imperative that allelic variation in different populations is analysed to evaluate the usage of APOE in an evolutionary and clinical context. Aim: We report allelic variation at the APOE locus in three European and four Indian populations and evaluate global patterns of genetic variation at this locus. The large, intricate and unexpected heterogeneity of this locus in its global perspective may have insightful consequences, which we have explored in this paper. Subject and methods: Apolipoprotein E genotypes were determined in four population groups (Punjabi Sikhs, Punjabi Hindus, Maria Gonds and Koch, total individuals = 497) of India and three regionally sub-divided British populations (Nottinghamshire, East Midlands and West Midlands, total individuals = 621). The extent and distribution of APOE allele frequencies were compared with 292 populations of the world using a variety of multivariate methods. Results: Three alleles, APOE*E2, APOE*E3 and APOE*E4, were observed with contrasting variation, although *E4 was absent in the tribal population of Koch. Higher heterozygosities (>43%) in British populations reflected their greater genetic diversity at this locus. The overall pattern of allelic diversity among these populations is comparable to many European and Indian populations. At a global level, higher frequencies of the *E2 allele were observed in Africa and Oceania (0.099 ± 0.083 and 0.111 ± 0.052, respectively). Similarly, *E4 allele averages were higher in Oceania (0.221 ± 0.149) and Africa (0.209 ± 0.090), while Indian and Asian populations showed the highest frequencies of *E3 allele. The coefficient of gene differentiation was found to be highest in South America (9.6%), although the highest genetic diversity was observed in Oceania (48.7%) and Africa (46.3%). APOE*E2 revealed a statistically significant decreasing cline towards the north in Asia (r = −0.407, d.f. = 70, p < 0.05), which is not compatible with the coronary heart disease statistics in this continent. APOE*E4 showed a significant increasing cline in North European populations. Spatial autocorrelation analysis shows that the variation at this locus is influenced by ‘isolation by distance’ with a strong positive correlation for lower distances up to 1313 km. Conclusion: Overall APOE allelic variation in UK and Indian populations is comparable to previous studies but in tribal populations *E4 allele frequency was very low or absent. At a global level allelic variation shows that geography, isolation by distance, genetic drift and possibly pre-historical selection are responsible for shaping the spectrum of genetic variation at the APOE gene. Overall, APOE is a good anthropogenetic and clinical diagnostic marker. Résumé. Arrière plan: Le gène APOE et la protéine qui en dérive, est associé à de nombreuses protéines plasmatiques telles que les lipoprotéines de très basse densité (VLDL), les lipoprotéines de haute densité (HDL), chylomicrons et restants de chylomicrons et joue un rôle crucial dans le métabolisme des lipides. Le gène APOE est polymorphe et ses allèles communs (*E2, *E3 and *E4) ont été associés à de nombreuses maladies communes et complexes dans diverses populations. Du fait de leur rôle déterminant dans le métabolisme et sa signification clinique, il est impératif que la variation allélique de différentes populations soit analysée et d’évaluer l’usage de l’APOE dans les contextes clinique et évolutif. But: On présente la variation allélique du locus APOE dans trois populations européennes et quatre populations indiennes et on évalue le modèle global de variation génétique à ce locus. L’hétérogénéité forte, complexe et inattendue de ce locus dans sa perspective globale peut revêtir des significations intéressantes, qui soon explorées dans ce travail. Sujets et méthodes: Les génotypes de l’Alipoprotéine E ont été déterminés dans quatre groupes indiens (Sikhs du Panjab, Hindous du Panjab, Maria Gonds et Koch, soit au total 497 individus) et The dans trois subdivisions régionales de la population britannique (Nottinghamshire, East Midlands et West Midlands, doit au total 621 individus). L’étendue et la distribution des fréquences alléliques de APOE ont été comparées avec 292 populations dans le monde, au moyen de diverses méthodes multivariées. Résultats: Trois allèles : APOE*E2, APOE*E3 et APOE*E4, présentent des variations différentes, mais *E4 est absent de la population tribale de Koch. Les plus fortes hétérozygosités (>43%) des populations britanniques reflète leur plus grande diversité génétique à ce locus. Le schéma général de la diversité allélique de ces populations est comparable à de nombreuses populations européennes et indiennes. A un niveau global, des fréquences élevées de l’allèle *E2 ont été observées en Afrique et en Océanie (respectivement 0,099 ± 0,083 et 0,111 ± 0,052 ). De façon similaire, les niveaux de l’allèle *E4 sont plus élevés en Océanie (0,221 ± 0,149) et en Afrique (0,209 ± 0,090), alors que les populations indiennes et asiatiques présentent les plus hautes fréquences de l’allèle *E3. Le coefficient de différenciation génique le plus élevé est en Amérique du Sud (9,6%), malgré que la diversité génétique la plus grande soit observée en Océanie (48.7%) et en Afrique (46.3%). L’APOE*E2 présente un gradient décroissant statistiquement significatif (r = –0,407, d.l. = 70 p < 0,05) en direction du nord en Asie, qui n’est pas compatible avec les statistiques sur les maladies coronariennes de ce continent. APOE*E4 présente un gradient croissant significatif dans les populations nord-européennes. Une analyse d’autocorrélation spatiale montre que la variation à ce locus est influencée par l’isolement par la distance avec une corrélation fortement positive pour les distances inférieures à 1313 km. Conclusion: La variation allélique générale de l’APOE dans les populations du Royaume-Uni et les populations indiennes est comparable aux études antérieures, mais la fréquence de *E4 est très basse ou absente dans les populations tribales. A un niveau global, la variation allélique montre que la géographie, l’isolement par la distance, la dérive génétique et de possibles sélections préhistoriques, sont responsables de la forme du spectre de variation du gène APOE. Enfin, APOE est un bon marqueur anthropogénétique et de diagnostic clinique. Zusammenfassung. Hintergrund: Das APOE-Gen und sein Proteinprodukt sind mit einer Reihe von Plasmaproteinen, wie dem very-low density-Lipoprotein (VLDL), den high density-Lipoprotein (HDL)-Chylomikronen und Chylomikron-Bruchstücken vergesellschaftet, und spielen eine entscheidende Rolle im Lipidstoffwechsel. Das APOE-Gen ist polymorph, und häufige Allele (*E2, *E3 und *E4) sind in verschiedenen Populationen mit einer Reihe von häufigen und komplexen Erkrankungen in Verbindung gebracht worden. Aufgrund ihrer bedeutsamen Rolle im Stoffwechsel und ihrer klinischen Bedeutung ist es sehr wichtig, dass die allelische Variation bei verschiedenen Populationen analysiert wird, um den Verwendung von APOE in einem evolutionären und klinischen Kontext zu beurteilen. Ziel: Wir berichten über die allelische Variation auf dem APOE-Locus bei drei Europäischen und vier Indischen Populationen und untersuchen globale Muster von genetischer Variation auf diesem Locus. Die in globaler Sicht große, verwirrende und unerwartete Heterogenität dieses Locus könnte weitere Einsichten zur Folge haben, die wir in dieser Arbeit näher ausgeführt haben. Probanden und Methoden: Apolipoprotein E-Genotypen wurden bei vier Bevölkerungsgruppen bestimmt (Punjabi Sikhs, Punjabi Hindus, Maria Gonds und Koch, insgesamt 497 Personen) aus Indien und drei regional unterteilten Britischen Populationen (Nottinghamshire, East Midlands und West Midlands, insgesamt 621 Personen). Das Ausmaß und die Verteilung von APOE-Allel-Frequenzen wurden mit 292 Populationen der restlichen Welt unter Verwendung einer Vielzahl multivariater Methoden verglichen. Ergebnisses: Drei Allele, APOE*E2, APOE*E3 und APOE*E4, wurden beobachtet mit jeweils unterschiedlicher Variation, allerdings war *E4 bei der eingeborenen Koch-Population nicht vorhanden. Größere Heterozygositäten (>43%) bei den Britischen Populationen spiegelten die größere genetische Vielfalt auf diesem Locus wider. Das Gesamtmuster der allelischen Diversität bei diesen Populationen ist mit dem vieler anderer Europäischer und Indischer Populationen vergleichbar. Auf globalem Niveau beobachtet man das *E2-Allel häufiger in Afrika und Ozeanien (0,099 ± 0,083 bzw. 0,111 ± 0,052). Desgleichen war das *E4-Allel im Mittel in Ozeanien (0,221 ± 0,149) und Afrika (0,209 ± 0,090) häufiger, während Indische und Asiatische Populationen am häufigsten das *E3-Allel zeigten. Der Koeffizient der Gendifferenzierung war in Südamerika am höchsten (9,6%), wohingegen die größte genetische Diversität in Ozeanien (48,7%) und Afrika (46,3%) beobachtet wurde. APOE*E2 zeigte einen statistisch signifikanten nach Norden abnehmenden Trend in Asien (r = –0,407, d.f. = 70, p < 0,05), der nicht mit den Statistiken betreffend koronare Herzkrankheit auf diesem Kontinent übereinstimmt. APOE*E4 zeigte einen signifikanten zunehmenden Trend bei Nordeuropäischen Völkern. Eine spaziale Autokorrelationsanalyse zeigt, dass die Variation auf diesem Locus durch “Isolation aufgrund von Entfernung” (‘isolation by distance’) beeinflusst wird mit einer starken positiven Korrelation für geringere Entfernungen bis zu 1313 km. Zusammenfassung: Die gesamte all

Role of C-reactive protein in cerebrovascular disease: a critical review

C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.

C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage

Background and Purpose— Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage. Methods— Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist–associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth >12.5 cm3 or relative growth >33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan–Meier analysis was used for survival. Results— EHG occurred in 25.8%, ENW in 19.3%, and mortality was 31.8% at 30 days. Thirty-day mortality was significantly higher in patients with ENW (hazard ratio, 3.21; 95% confidence interval, 2.00–5.17; P<0.0001) and in patients with EHG (hazard ratio, 2.13; 95% confidence interval, 1.42–3.18; P<0.0001, log-rank test). Median CRP was 12 mg/L (interquartile range, 10–17) in the EHG group and 7 mg/L (interquartile range, 4–12.1) in those without EHG (P<0.0001). In multivariable analyses, plasma CRP>10 mg/L independently predicted EHG (odds ratio, 4.71; 95% confidence interval, 2.75–8.06; P<0.0001) and ENW (odds ratio, 2.70; 95% confidence interval, 1.50–4.84; P=0.0009). Conclusions— CRP>10 mg/L is independently predictive of EHG and ENW, both of which are associated with increased mortality. Inflammation may be important in contributing to EHG and warrants further investigation.

Apolipoprotein E polymorphism and its relation to plasma lipids in coronary heart disease.

BACKGROUND The present investigation is aimed at examining the Apolipoprotein E (APOE) genotypic influence on coronary heart disease (CHD) risk in northwest India (Punjab), where this disease is emerging as a major threat to public-health care system. MATERIALS AND METHODS The present study comprised of angiographically diagnosed coronary heart disease patients (n = 193) and controls (n = 150) of Punjab. Genetic polymorphism of APOE gene was investigated by polymerase chain reaction (PCR), and its association with lipid levels was evaluated. RESULTS The allele frequencies of epsilon2, epsilon3, and epsilon4 were 0.054, 0.795, 0.151; and 0.077, 0.856, 0.067 in patients and controls respectively. The bearers of E3/E4 genotype had threefold higher propensity of developing CHD in this population (OR, 3.04; CI, 1.55-6.25; P < 0.001), which exacerbated (OR, 4.18; CI, 2.03-9.27; P < 0.001) after correcting for age, sex, BMI, and lipid-lowering drugs. Lower HDL-C levels and higher LDL-C levels were found to be correlated with E3/E4 genotype (P < 0.01). Other concomitants like body mass index (BMI), total cholesterol (TC), and triglyceride (TG) levels did not show up as genetic determinants in this part of the region. CONCLUSIONS A significant association (P = 0.016) of epsilon4 allele, especially E3/E4 genotype, with CHD was observed, along with HDL-C and LDL-C concentrations, in the population of northwest India.

Is Plasma Fibrinogen Useful in Evaluating Ischemic Stroke Patients?. Why, How, and When

See related article, pages 1687–1691. In this issue of Stroke , del Zoppo et al1 report new data on the association between hyperfibrinogenemia and functional prognosis after ischemic stroke using the placebo data from 2 well-known clinical interventional trials on the use of defibrinogenating agent ancrod in acute ischemic stroke.2,3 Briefly, the authors explore the relationship of fibrinogen with the ischemic stroke outcome showing that patients with lower initial fibrinogen levels (<4.5 g/L) had better functional outcomes even when corrected for age and initial stroke severity.1 They confirmed a relationship between fibrinogen and prognosis independent of other cardiovascular risk factors and stroke severity.4,5 Because patients at risk for the development of fibrinogen-related ischemic complications of atherosclerosis can be easily identified and nonpharmacological treatment (cessation of smoking, diet, exercise) seems to lower raised fibrinogen levels together with several drugs (fibrates, Ω3 fatty acids, ticlopidine, pentoxifylline, defibrotide),6 clinically oriented secondary prevention recommendations7 should consider the role of fibrinogen in ischemic stroke. The clinical use of fibrinogen measurement should be based on (1) evidence regarding the ability of fibrinogen to predict ischemic stroke prognosis beyond that of current prognostic prediction methods or models, and (2) evidence regarding the use of prognosis prediction to treatment of ischemic stroke.6 A large body of well-done studies demonstrates an association between fibrinogen levels and ischemic stroke prognosis.1,4,5,8–18 There are, however, uncertainties in the exact role that fibrinogen plays in the determining ischemic stroke prognosis and the reliability of fibrinogen assessment. Because fibrinogen concentrations remain associated with ischemic stroke prognosis after adjustment for many known prognostic risk factors, including age, stroke severity, and neuroradiological findings, it follows that a prognostic prediction model that adds fibrinogen would provide more accurate assessment of ischemic stroke prognosis. Whether this improved accuracy …

SNP–SNP interactions within APOE gene influence plasma lipids in postmenopausal osteoporosis

Biological revelations have gradually started clearing the complex relationships of bones with lipids. Studies have shown that lipid proWles are related to bone mass, bone fragility and fracture risk [1, 2]. It has been observed that oxidized lipids inhibit mineralization of bone, induce osteoblastic diVerentiation in vascular cells, and hyperlipidemia reduces bone density in mice [3]. To understand the genetic link between lipids and osteoporosis risk, apolipoprotein E gene (APOE) is a potential candidate because of its vital contribution to both lipid and vitamin K metabolism. APOE is located on the chromosome 19q13.2 and has three codominant alleles i.e. APOE2, APOE3 and APOE4. It serves as a ligand for receptor-mediated uptake of lipoprotein particles, which are the main carriers of vitamin K, and availability of vitamin K is an essential step for the carboxylation of glutamic acid residues of osteocalcin, an important bone protein. A study has shown that decrease in bone mineral density (BMD) in hemodialysis patients is correlated with hyperlipidemia, and the risk of fractures in such patients varies according to APOE genotypes [4]. Some preliminary Wndings suggest that APOE contributes to the variation in cholesterol increase with menopause [5], and APOE-E4-negative subjects respond better to hormone replacement therapy (HRT) for lowering lipid levels than APOE-E4-positive subjects [6]. However, in what way, genomic changes within APOE inXuence lipids for the risk of osteoporosis remains unclear. The impact of individual APOE SNP or allelic variant on lipid levels may vary if another nearby SNP is also participating or in linkage disequilibrium with another functional SNP. Studies comprising single SNP would have overlooked coordinated eVects of such SNPs. The present study explored the SNP–SNP interactions of four pertinent APOE SNPs (rs440446, rs769450, rs429358 and rs7412) as the genetic mediators of lipids in postmenopausal osteoporotic women of Punjab Province of Northwest India. Out of 366 randomly selected postmenopausal women who were not using HRT and were aged between 45 and 70 (Mean age 53.2 § 9.2), 154 osteoporotic women (71-lumbar spine and 83-femoral neck cases) were enrolled after veriWcation of the fractures from original radiographs and validation by DEXA (dual energy X-ray absorptiometry) unless they met the exclusion criteria: hyperlipidemia, irregular cycles or premature ovarian failure (menopause < 38 years), women with surgical menopause, any systemic disease or receiving medications known to inXuence calcium metabolism. DEXA veriWed population-based 83 postmenopausal women were enrolled as controls, according to a random-digit invitation from residents of the same geographic suburban and rural areas from Northwest India with three main exclusion criteria: hyperlipidemia, any fracture before or after menopause or any anti-osteoporotic treatment. Detailed information on age, medical history, years since menopause and gynecological history was obtained from these subjects. Height and weight were measured, and BMI (kg/m) was calculated. In the present study, none of the subjects were found to be alcohol users or smokers. Bone mineral density was measured by DEXA using Hologic QRR 4500 (Hologic Inc. Waltham, MA, M. Singh (&) · P. Singh Molecular Genetics Laboratory, Department of Human Biology, Punjabi University, Patiala, Punjab 147002, India e-mail: singh_m12@rediffmail.com

The ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype

The present study investigated genetic variation in the 3’ flanking region of ApoA-I (PstI), the 3’ untranslated region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI) in 435 type 2 diabetes mellitus patients, divided according to the presence or absence of coronary heart disease (CHD). Uncommon allele frequencies (P2, S2, X2) were 17.5%, 32.5%, 16.2% and 29.5%, 17.9%, 13.8% in patients with and without CHD, respectively. Linkage disequilibrium (D’ = 0.31-0.73, p<0.01) was observed in all diallelic pairs except XbaI/PstI and XbaI/SstI in patients having CHD. Haplotype analysis revealed that P1-S2-X1 is a susceptibility haplotype that increases the risk of CHD in diabetes (OR 2.85, CI 1.51-5.61), exacerbating risk (OR 3.57, CI 1.81-7.45) even after adjustment for confounders. The findings in the present study suggest that each unit of P1-S2-X1 in diabetes increases the risk of CHD by a factor of 1.37+0.307 (β ± SE), which is manifest in its multiplicative mode.

Molecular genetic variation in the East Midlands, England: analysis of VNTR, STR and Alu insertion/deletion polymorphisms.

Background: Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) have been used successfully in disease analysis and studies of human evolution and population genetic diversity. However DNA-based comprehensive population genetic studies of the East Midlands, England are limited. Subjects and methods: To enlarge our understanding of genetic variation in the East Midlands, a study was conducted on five regional populations: north-west Derbyshire, north-east Derbyshire, south Derbyshire, Nottinghamshire and Leicestershire. Blood samples were collected from donors whose ancestors had lived in the region for at least three generations. Seven VNTRs (MS1 (D1S7), MS31 (D7S21), MS43A (D12S11) and YNH24 (D2S44), D1S80, APOB, YNZ22 (D17S5)), six STRs (HumTHO1, HumVWA31A, HumF13A01, HumFESFPS, HumCSF1PO, HumTPOX) and six Alu insertion/deletion polymorphisms (TPA25, ACE, PV92, F13B, APO, D1) were analysed in approximately 500 individuals. Allele or bin frequencies were calculated using gene counting and fixed bin methods. The chi-square method and exact tests were used to assess Hardy-Weinberg equilibrium. Genetic distances were calculated using Neis DA method and correspondence analysis was used to assess population affinities. Results: The overall pattern of allele frequencies was similar to many European and UK populations for a number of genetic systems. Overall heterogeneity was observed for five loci: MS43A, MS31, HumF13A01, HumFESFPS and HumTHO1. Twenty-three of 190 pairwise population comparisons were also statistically significant at the 5% level. Average molecular genetic system heterozygosity was 1.5 times higher than observed with conventional blood group systems. GST values for molecular systems were also higher than conventional systems (0.012 vs 0.005) and suggest a low to moderate level of differentiation. Conclusion: The allele frequency spectrum and inter-population comparisons show that there is significant genetic variation in the five contiguous regional populations of the East Midlands. Some of this variation may be due to local geographical barriers, genetic drift and possibly the settlement patterns of Continental European invaders.

Vitamin D receptor (VDR) gene polymorphism influences the risk of osteoporosis in postmenopausal women of Northwest India

SummaryThe influence of VDR gene for the risk of osteoporosis has remained inconclusive. VDR gene polymorphism in relation to BMD in postmenopausal women of Northwest India revealed a susceptibility haplotype AGT. Possession of this haplotype exacerbates the risk of osteoporosis by 2.8 times, which manifests in recessive mode of inheritance.PurposeThe purpose of this study is to understand the influence of coordinated effect of various single nucleotide polymorphisms (SNPs) within vitamin D receptor (VDR) gene for the risk of osteoporosis, which has remained undefined so far.MethodsFour pertinent SNPs of VDR gene, i.e., rs2228570, rs1544410, rs17879735, and rs731236 were examined with polymerase chain reaction–restriction fragment length polymorphism in dual energy X-ray absorptiometry verified 188 osteoporotics, 115 osteopenics, and 147 normal postmenopausal women of Northwest India.ResultsMinor allele ‘T’ of rs2228570 showed significant influence for the risk of osteoporosis (OR 1.60, 95%CI 1.16–2.20, P = 0.004) and also in dominant (OR 2.32, 95%CI 1.47–3.64, P = 0.0006) and additive model (OR 2.41, 95%CI 1.49–3.87, P = 0.0006) after Bonferroni correction. Minor allele (T) of rs2228570 showed an allele dose effect with BMD of L1-L4 (P = 0.009) and FN (P = 0.036). Disease association analysis exposed a susceptibility haplotype AGT which influences the risk of osteopenia (OR 2.04, 95%CI 1.03–4.08, P = 0.036) and osteoporosis (OR 2.90, 95%CI 1.61–5.38, P = 0.00005) after adjusting the effects of age, BMI and years since menopause. This haplotype is significantly associated with BMDs at lumbar spine (P = 0.0001) and femoral neck (P = 0.016).ConclusionIn-depth analysis of this haplotype with other methods of Wald statistics and Akaike information criterion confirmed that carriers of each unit of this haplotype AGT increases the risk of osteoporosis by a factor of 2.80 ± 0.34 (β ± SE) which manifests (P = 0.1 × 10−6) in its recessive mode of inheritance.

Diabetes to cardiovascular disease: is depression the potential missing link?

The etiopathological consequences of diabetes and its imperative sequels have been explored extensively in the scientific arena of cardiovascular diabetology. Innumerable risk covariates and confounders have been delineated for the primary and secondary prevention of diabetes and cardiovascular diseases (CVD). However, an intricate interaction of depression on them has been largely overlooked. Depression influences and participates in each and every step that worsens the diabetic state for developing cardiovascular complications. The dilemma is that it coexists, remains silent and generally not considered as relevant clinical parameter amenable to intervention. In this review, it is highlighted that depression has strong association and linkages with both diabetes and CVD and it should be considered and diagnosed at every stage of the diabetes to CVD continuum. Careful attention to the diagnosis and management of these disease states would contribute in lessening the CVD burden of the society.