Sarabjit S. Mastana

The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease

Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise — both acute and chronic — exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.

The Genetic Heritage of the Earliest Settlers Persists Both in Indian Tribal and Caste Populations

Two tribal groups from southern India--the Chenchus and Koyas--were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools.

Most of the extant mtDNA boundaries in South and Southwest Asia were likely shaped during the initial settlement of Eurasia by anatomically modern humans

BackgroundRecent advances in the understanding of the maternal and paternal heritage of south and southwest Asian populations have highlighted their role in the colonization of Eurasia by anatomically modern humans. Further understanding requires a deeper insight into the topology of the branches of the Indian mtDNA phylogenetic tree, which should be contextualized within the phylogeography of the neighboring regional mtDNA variation. Accordingly, we have analyzed mtDNA control and coding region variation in 796 Indian (including both tribal and caste populations from different parts of India) and 436 Iranian mtDNAs. The results were integrated and analyzed together with published data from South, Southeast Asia and West Eurasia.ResultsFour new Indian-specific haplogroup M sub-clades were defined. These, in combination with two previously described haplogroups, encompass approximately one third of the haplogroup M mtDNAs in India. Their phylogeography and spread among different linguistic phyla and social strata was investigated in detail. Furthermore, the analysis of the Iranian mtDNA pool revealed patterns of limited reciprocal gene flow between Iran and the Indian sub-continent and allowed the identification of different assemblies of shared mtDNA sub-clades.ConclusionsSince the initial peopling of South and West Asia by anatomically modern humans, when this region may well have provided the initial settlers who colonized much of the rest of Eurasia, the gene flow in and out of India of the maternally transmitted mtDNA has been surprisingly limited. Specifically, our analysis of the mtDNA haplogroups, which are shared between Indian and Iranian populations and exhibit coalescence ages corresponding to around the early Upper Paleolithic, indicates that they are present in India largely as Indian-specific sub-lineages. In contrast, other ancient Indian-specific variants of M and R are very rare outside the sub-continent.

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

Human angiotensin-converting enzyme I/D and α-actinin 3 R577X genotypes and muscle functional and contractile properties

The angiotensin‐converting enzyme (ACE) I/D and α‐actinin 3 (ACTN3) R/X polymorphisms have been suggested to influence variations in skeletal muscle function. This study investigated the association between ACE I/D and ACTN3 R/X polymorphisms and muscle strength and contractile properties in young UK Caucasian men. Measurements of the knee extensor muscles were taken from 79 recreationally active but non‐strength‐trained males on two occasions. Isometric knee extensor strength was measured using a conventional strength‐testing chair. Maximal twitches were electrically evoked by percutaneous stimulation to assess time‐to‐peak tension, half‐relaxation time and peak rate of force development. The torque–velocity relationship was measured at four angular velocities (0, 30, 90 and 240 deg s−1) using isokinetic dynamometry, and the relative torque at high velocity was calculated (torque at 240 deg s−1 as a percentage of that at 30 deg s−1). The ACE I/D and ACTN3 R/X polymorphisms were genotyped from whole blood by polymerase chain reaction. Serum ACE activity was assayed from serum using automated spectrophotometry. Physical characteristics were independent of either genotype. Absolute and relative high‐velocity torque were not influenced by ACE or ACTN3 genotypes. Isometric strength and the time course of a maximal twitch were independent of ACE and ACTN3 genotypes. Serum ACE activity was significantly dependent on ACE genotype (P < 0.001), but was not associated with any measure of functional or contractile properties. Knee extensor functional and contractile properties, including high‐velocity strength, were not influenced by ACE and ACTN3 polymorphisms in a cohort of UK Caucasian males. Any influence of these individual polymorphisms on human skeletal muscle does not appear to be of sufficient magnitude to influence function in free‐living UK Caucasian men.

Anthropology of the apolipoprotein E (apo E) gene: low frequency of apo E4 allele in Basques and in tribal (Baiga) populations of India

The distribution of apolipoprotein E (apo E) polymorphism was examined in 11 population groups not previously studied for this system. There is a marked difference in phenotype and gene frequency between the populations of England and Spain. The south European populations of Basques and Spanish non-Basques showed greater similarity to the populations of South Asia. The study clearly indicates that the distribution of apo E alleles does match with regions showing a high mortality rate of coronary heart disease. The data presented also indicate that authochthon groups such as Basques in Europe and tribals in India may throw better light on the role of apolipoproteins in the regulation of lipid levels in disease.

Paraoxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians

BACKGROUND Polymorphisms in paraoxonase 1 (PON1) coding for PON1 enzyme have been studied as genetic markers of coronary artery disease (CAD). PON1 Q192R and PON1 L55M polymorphisms have been analyzed extensively, but data on association and role of these polymorphisms in the etiology of CAD are conflicting. In this study, we tested the genetic association between PON1 Q192R and PON1 L55M polymorphisms and CAD among north Indians. MATERIALS AND METHODS Two hundred eighty-five angiographically proven patients with coronary artery disease and 200 sex-matched and ethnically matched controls were genotyped for 2 PON1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype/ allele frequencies were compared in patients and controls using the chi-square test. RESULTS At PON1-192 locus, there were significant differences between patients and controls (P< 0.05), leading to significant odds ratios for RR genotype (OR= 1.92, CI: 1.19-3.10) and *R allele (OR= 1.30, CI: 1.00-1.70). These odds ratios were higher in the sub-sample of smokers (2.84 and 1.45, respectively). Binary logistic regression analysis also confirmed that *R allele carriers (QR and RR) have a higher risk of CAD (OR= 3.54, CI: 1.67-5.53). PON1-55 locus did not show significant differences between patients and controls, but LL genotype and *L allele were significant risk factors in the nonsmoker group. RL haplotype was also significantly associated with CAD risk (OR= 1.44, CI: 1.08-1.93). CONCLUSIONS PON1-192R allele and RR genotype are significantly associated with CAD patients from the north Indian population (Uttar Pradesh). This association was stronger in smokers, supporting the conclusion that an interaction between PON1 activity and smoking augments CAD risk. Further studies with larger sample size are warranted to confirm these associations in different Indian populations.

Angiotensin-Converting Enzyme Deletion Polymorphism Is Associated with Hypertension in a Sikh Population

The deletion polymorphism, situated in intron 16, of angiotensin-converting enzyme (ACE) gene (17q23) has been observed to be associated with an increased risk for myocardial infarction and left ventricular hypertrophy in Caucasian populations. The homozygous genotype for the deletion allele (DD) has additionally been observed at greater frequencies in hypertensive individuals of African-American and Japanese origin. In a population-based study of a Sikh population, we compared the occurrence of the insertion/deletion polymorphism at the ACE gene in subjects with hypertension to those with normal blood pressure. The ACE deletion allele was observed with a greater frequency in hypertensive subjects than in the normotensive subjects (p < 0.0001). These findings raise the possibility that in some ethnic subgroups, variation in or near the ACE gene may contribute to the development, and severity, of hypertension.

Haptoglobin Subtypes among Four Different Populations

Haptoglobin subtypes were analysed by isoelectric focusing in four populations from Colombia, England, Nigeria, and India. There is a wide range of variation of allele frequencies in these four populations: HP*1S = 15-28%, HP*1F = 5-19%, HP*2FS = 54-79%. With the exception of the English, and the Spanish-speaking population of Colombia, all interpopulation comparisons showed significant heterogeneity. There is an extreme variation for the HP*1F allele in different populations, and a possible geographical cline of the HP*2FS allele increasing from west to east. The data presented here suggest that HP subtypes provide a useful anthropogenetic marker for racial differentiation.

Genetic Variation of Apolipoproteins in North Indians

Genetic variation at three apolipoprotein loci (APOA4, APOH, and APOE) has been examined in nine endogamous populations of Punjab, North India. The overall pattern of allele frequency variation at different loci is compatible with that of European populations, but observed microvariation differentiates the populations according to their position in the Indian caste structure. The most common allele at the APOA4 locus was APOA4*1 with a narrow frequency range (89%-92%). APOH*2 allele frequency was highest in these populations (0.852-0.914). APOE*E4 allele frequency was relatively low (6%-10%) in the North Indian populations compared to its frequency in many European populations. The anthropological usage of these polymorphisms was evaluated using multivariate analyses. Genetic distance analysis and principal correspondence analysis showed that the North Indian populations are closest to Europeans, followed by Chinese and African populations. Overall, this study highlights the usefulness of apolipoproteins as genetic markers for clinical, population, and anthropological studies.