Pharmacogenetics of SLCO1B1: Population genetics and effect on statins

Kohonneiden kolesterolipitoisuuksien alentamisessa käytettävien statiinien hyödyt sydän- ja verisuonisairauksien estossa on vahvasti osoitettu ja niiden käyttö on niin Suomessa kuin muuallakin maailmassa kasvanut voimakkaasti – Suomessa statiininkäyttäjiä on noin 600 000. Statiinilääkitys on pitkäaikaisessakin käytössä melko hyvin siedetty, mutta yleisimpinä haittavaikutuksina voi ilmetä lihasheikkoutta, -kipua ja -kramppeja, jotka voivat edetä jopa henkeä uhkaavaksi lihasvaurioksi. Lihashaittariski suurenee suhteessa statiiniannokseen ja plasman statiinipitoisuuksiin. Statiinien plasmapitoisuuksissa, tehossa ja haittavaikutusten ilmenemisessä on suuria potilaskohtaisia eroja. SLCO1B1-geenin koodaama OATP1B1-kuljetusproteiini kuljettaa monia elimistön omia aineita ja lääkeaineita verenkierrosta solukalvon läpi maksasoluun, mm. statiineja, joiden kolesterolia alentava vaikutus ja poistuminen elimistöstä tapahtuvat pääosin maksassa. Erään SLCO1B1-geenin nukleotidimuutoksen (c.521T>C) tiedetään heikentävän OATP1B1:n kuljetustehoa. Tässä väitöskirjatyössä selvitettiin SLCO1B1-geenin perinnöllistä muuntelua suomalaisilla ja eri väestöissä maailmanlaajuisesti. Lisäksi selvitettiin SLCO1B1:n muunnosten vaikutusta eri statiinien pitoisuuksiin (farmakokinetiikka) ja vaikutuksiin (farmakodynamiikka) sekä kolesteroliaineenvaihduntaan. Näihin tutkimuksiin valittiin SLCO1B1-genotyypin perusteella terveitä vapaaehtoisia koehenkilöitä, joille annettiin eri päivinä kerta-annos kutakin tutkittavaa statiinia: fluvastatiinia, pravastatiinia, simvastatiinia, rosuvastatiinia ja atorvastatiinia. Verinäytteistä määritettiin plasman statiinien ja niiden aineenvaihduntatuotteiden sekä kolesterolin ja sen muodostumista ja imeytymistä kuvaavien merkkiaineiden pitoisuuksia. Toiminnallisesti merkittävien SLCO1B1-geenimuunnosten esiintyvyydessä todettiin suuria eroja eri väestöjen välillä. Suomalaisilla SLCO1B1 c.521TC-genotyypin (geenimuunnos toisessa vastinkromosomissa) esiintyvyys oli noin 32 % ja SLCO1B1 c.521CC-genotyypin (geenimuunnos molemmissa vastinkromosomeissa) esiintyvyys noin 4 %. Globaalisti geenimuunnosten esiintyvyys korreloi maapallon leveyspiirien kanssa siten, että matalaan transportteriaktiivisuuteen johtavat muunnokset olivat yleisimpiä pohjoisessa ja korkeaan aktiivisuuteen johtavat päiväntasaajan lähellä asuvilla väestöillä. SLCO1B1-genotyypillä oli merkittävä vaikutus statiinien plasmapitoisuksiin lukuun ottamatta fluvastatiinia. Simvastatiinihapon plasmapitoisuudet olivat keskimäärin 220 %, atorvastatiinin 140 %, pravastatiinin 90 % ja rosuvastatiinin 70 % suuremmat c.521CC-genotyypin omaavilla koehenkilöillä verrattuna normaalin c.521TT-genotyypin omaaviin. Genotyypillä ei ollut merkittävää vaikutusta minkään statiinin tehoon tässä kerta-annostutkimuksessa, mutta geenimuunnoksen kantajilla perustason kolesterolisynteesinopeus oli suurempi. Tulokset osoittavat, että SLCO1B1 c.521T>C geenimuunnos on varsin yleinen suomalaisilla ja muilla ei-afrikkalaisilla väestöillä. Tämä geenimuunnos voi altistaa erityisesti simvastatiinin, mutta myös atorvastatiinin, pravastatiinin ja rosuvastatiinin, aiheuttamille lihashaitoille suurentamalla niiden plasmapitoisuuksia. SLCO1B1:n geenimuunnoksen testaamista voidaan tulevaisuudessa käyttää apuna valittaessa sopivaa statiinilääkitystä ja -annosta potilaalle, ja näin parantaa sekä statiinihoidon turvallisuutta että tehoa.

Intraspecific variation in brain size and architecture : population divergence and phenotypic plasticity

Brain size and architecture exhibit great evolutionary and ontogenetic variation. Yet, studies on population variation (within a single species) in brain size and architecture, or in brain plasticity induced by ecologically relevant biotic factors have been largely overlooked. Here, I address the following questions: (i) do locally adapted populations differ in brain size and architecture, (ii) can the biotic environment induce brain plasticity, and (iii) do locally adapted populations differ in levels of brain plasticity? In the first two chapters I report large variation in both absolute and relative brain size, as well as in the relative sizes of brain parts, among divergent nine-spined stickleback (Pungitius pungitius) populations. Some traits show habitat-dependent divergence, implying natural selection being responsible for the observed patterns. Namely, marine sticklebacks have relatively larger bulbi olfactorii (chemosensory centre) and telencephala (involved in learning) than pond sticklebacks. Further, I demonstrate the importance of common garden studies in drawing firm evolutionary conclusions. In the following three chapters I show how the social environment and perceived predation risk shapes brain development. In common frog (Rana temporaria) tadpoles, I demonstrate that under the highest per capita predation risk, tadpoles develop smaller brains than in less risky situations, while high tadpole density results in enlarged tectum opticum (visual brain centre). Visual contact with conspecifics induces enlarged tecta optica in nine-spined sticklebacks, whereas when only olfactory cues from conspecifics are available, bulbus olfactorius become enlarged.Perceived predation risk results in smaller hypothalami (complex function) in sticklebacks. Further, group-living has a negative effect on relative brain size in the competition-adapted pond sticklebacks, but not in the predation-adapted marine sticklebacks. Perceived predation risk induces enlargement of bulbus olfactorius in pond sticklebacks, but not in marine sticklebacks who have larger bulbi olfactorii than pond fish regardless of predation. In sum, my studies demonstrate how applying a microevolutionary approach can help us to understand the enormous variation observed in the brains of wild animals a point-of-view which I high-light in the closing review chapter of my thesis.

Trends and Variability of AVHRR-Derived NPP in India

In this paper, we estimate the trends and variability in Advanced Very High Resolution Radiometer (AVHRR)-derived terrestrial net primary productivity (NPP) over India for the period 1982-2006. We find an increasing trend of 3.9% per decade (r = 0.78, R-2 = 0.61) during the analysis period. A multivariate linear regression of NPP with temperature, precipitation, atmospheric CO2 concentration, soil water and surface solar radiation (r = 0.80, R-2 = 0.65) indicates that the increasing trend is partly driven by increasing atmospheric CO2 concentration and the consequent CO2 fertilization of the ecosystems. However, human interventions may have also played a key role in the NPP increase: non-forest NPP growth is largely driven by increases in irrigated area and fertilizer use, while forest NPP is influenced by plantation and forest conservation programs. A similar multivariate regression of interannual NPP anomalies with temperature, precipitation, soil water, solar radiation and CO2 anomalies suggests that the interannual variability in NPP is primarily driven by precipitation and temperature variability. Mean seasonal NPP is largest during post-monsoon and lowest during the pre-monsoon period, thereby indicating the importance of soil moisture for vegetation productivity.

Variation at Diabetes- and Obesity-Associated Loci May Mirror Neutral Patterns of Human Population Diversity and Diabetes Prevalence in India

South Asian populations harbor a high degree of genetic diversity, due in part to demographic history. Two studies on genome-wide variation in Indian populations have shown that most Indian populations show varying degrees of admixture between ancestral north Indian and ancestral south Indian components. As a result of this structure, genetic variation in India appears to follow a geographic cline. Similarly, Indian populations seem to show detectable differences in diabetes and obesity prevalence between different geographic regions of the country. We tested the hypothesis that genetic variation at diabetes-and obesity-associated loci may be potentially related to different genetic ancestries. We genotyped 2977 individuals from 61 populations across India for 18 SNPs in genes implicated in T2D and obesity. We examined patterns of variation in allele frequency across different geographical gradients and considered state of origin and language affiliation. Our results show that most of the 18 SNPs show no significant correlation with latitude, the geographic cline reported in previous studies, or by language family. Exceptions include KCNQ1 with latitude and THADA and JAK1 with language, which suggests that genetic variation at previously ascertained diabetes-associated loci may only partly mirror geographic patterns of genome-wide diversity in Indian populations.

Co-benefits, trade-offs, barriers and policies for greenhouse gas mitigation in the agriculture, forestry and other land use (AFOLU) sector

The agriculture, forestry and other land use (AFOLU) sector is responsible for approximately 25% of anthropogenic GHG emissions mainly from deforestation and agricultural emissions from livestock, soil and nutrient management. Mitigation from the sector is thus extremely important in meeting emission reduction targets. The sector offers a variety of cost-competitive mitigation options with most analyses indicating a decline in emissions largely due to decreasing deforestation rates. Sustainability criteria are needed to guide development and implementation of AFOLU mitigation measures with particular focus on multifunctional systems that allow the delivery of multiple services from land. It is striking that almost all of the positive and negative impacts, opportunities and barriers are context specific, precluding generic statements about which AFOLU mitigation measures have the greatest promise at a global scale. This finding underlines the importance of considering each mitigation strategy on a case-by-case basis, systemic effects when implementing mitigation options on the national scale, and suggests that policies need to be flexible enough to allow such assessments. National and international agricultural and forest (climate) policies have the potential to alter the opportunity costs of specific land uses in ways that increase opportunities or barriers for attaining climate change mitigation goals. Policies governing practices in agriculture and in forest conservation and management need to account for both effective mitigation and adaptation and can help to orient practices in agriculture and in forestry towards global sharing of innovative technologies for the efficient use of land resources. Different policy instruments, especially economic incentives and regulatory approaches, are currently being applied however, for its successful implementation it is critical to understand how land-use decisions are made and how new social, political and economic forces in the future will influence this process.

The Use of Herbicides to Control Hydrilla and the Effects on Young Largemouth Bass Population Characteristics and Aquatic Vegetation in Lake Seminole, Georgia

From 1997 to 2003, we examined the impacts of two aquatic herbicides, fluridone (Sonar; 1-methyl-3-phenyl-5-[3-(trifluromethl) phenyl]-4(1H)-pyridinone), and dipotassium salt of endothall (Aquathol K; 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid), used to control dense hydrilla (Hydrilla verticillata L. f. Royle), on population characteristics of juvenile largemouth bass (Micropterus salmoides Lacepede) in small coves (<10 ha) in Lake Seminole, Georgia. In addition, we estimated areal coverage and species composition of submersed aquatic vegetation (SAV) communities in each cove. Fish and plants were sampled in both control (hydrilla infested)and herbicide treated coves in November and March- April each year. Electrofishing catch-per-effort for both number and weight of age-0 and age-1 fish for the 1997 to 2002 year classes was either the same or higher (p < 0.05) in herbicide treated than in control coves. Age-0 fish were larger (p <0.05) in treated, than in control coves in November, but at age-1 in the following spring, fish were slightly longer (p <0.05) in the control coves. Higher age-0 catches were associated with greater percent reductions in numeric catch between age-0 and age-1 and reduced lengths of fish in November indicating density-dependent effects. Age-0 fish lengths were also negatively correlated to percent cover of both total and native SAV. Total or native SAV coverages were not associated with catch-per-unit effort for number and weight, but nearly all control and herbicide treated coves had total SAV coverage greater than 40%. Applications of both Sonar and Aquathol K reduced total SAV coverage and hydrilla, permitted the establishment of native SAVs, and had either neutral or positive impacts on young largemouth bass in small coves in Lake Seminole. (PDF contains 7 pages.)

Residential Docks and Piers: Inventory of laws, regulations, and policies for the New England region

While the homes threatened by erosion and the developer illegally filling in marshlands are the projects that make the headlines, for many state regulatory programs, it’s the residential docks and piers that take up the most time. When is a dock too long? What about crossing extended property lines? And at what point does a creek have too many docks? There are no easy answers to these questions. At the request of the Georgia Coastal Management Program, the National Oceanic and Atmospheric Administration (NOAA) Coastal Services Center published in April 2003 an inventory of residential dock and pier management information for the southeastern U.S. This inventory builds upon that effort and includes five New England states and one municipality: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and the Town of Falmouth, Massachusetts. Federal laws, state laws and regulations, permitting policies, and contact information are presented in a tabular format that is easy to use. (PDF contains 16 pages)

Residential Docks and Piers: Inventory of laws, regulations, and policies for the Southeastern United States

While the homes threatened by erosion and the developer illegally filling in marshlands are the projects that make the headlines, for many state regulatory programs, it’s the residential docks and piers that take up the most time. When is a dock too long? What about crossing extended property lines? And at what point does a creek have too many docks? There are no easy answers to any of the dock and pier related questions. Each state has to craft the laws and policies that are best for its natural resources and its political and legal environment. At the same time, mistakes in judgment can be costly for the organization, the homeowner, and the natural resources. At the request of the Georgia Coastal Management Program, the National Oceanic and Atmospheric Administration (NOAA) Coastal Services Center compiled an inventory of dock information for four states—Georgia, Florida, North Carolina, and South Carolina. Federal laws, state laws and regulations, permitting policies, and contact information are included in a tabular format that is easy to use. (PDF contaions 18 pages)

Emerging trends and experiences in Asia-Pacific aquaculture: 2003

This document provides an overview of topical issues in Asian aquaculture for 2003, including a review of its status, progress in research and development, major issues and experiences, together with suggestions on actions for addressing opportunities and constraints. The document has been prepared by NACA and FAO to facilitate discussions at the 15th NACA Governing Council meeting, hosted by the Government of Sri Lanka on 21st-25th April 2004. The final version will be widely circulated as the editors hope it will prove a useful document for all involved in aquaculture, and related fishery development in the Asia-Pacific region. Pending feedback on this 2003 document, further reviews may be considered by NACA and FAO as a way of bringing together regularly in one publication relevant and key issues facing development of aquaculture in the Asia-Pacific region. (PDF contains 153 pages)

The STREAM Initiative: support to regional aquatic resources management. Promoting participation, communication, and policies that support the livelihoods of poor aquatic resource users in the Asia-Pacific. Memorandum

Throughout the Asia-Pacific region capture fisheries and certain less intensive forms of aquaculture can and do play a vital role in livelihoods management, food security, and health and nutrition. Knowledge and experience exist that could be more effectively used in policy for poverty alleviation. (PDF contains 89 pages)

A study of measures of population density and of concentration of fishing effort in the fishery for yellowfin tuna, Neothunnus macropterus, in the Eastern Tropical Pacific Ocean, from 1951 to 1956

ENGLISH: This study shows how the catch and effort statistics, from 1951 to 1956, of the fishery for yellowfin tuna, Neothunnus macropterus, in the Eastern Tropical Pacific Ocean, have been used to compute: (i) two indices of average population density; (ii) an index of concentration of effort on areas of greatest density of available yellowfin. These three indices were then used to determine: (i) quarterly and annual variation in each of them; (ii) the relationship between the two indices of density; (iii) the relationship of each of the indices to the number of exploited one-degree rectangles. To remove extreme sampling variation at low levels of effort, the data from all one-degree rectangles subjected to less than five logged days' fishing in a quarter were eliminated, and the computations were repeated for comparison with those of the original data. SPANISH: Este estudio da a conocer cómo las estadísticas sobre la pesca y el esfuerzo de pesca de la pesquería del atún aleta amarilla, Neothunnus macropterus, en el Océano Pacífico Oriental Tropical, durante 1951 a 1956, han servido para computar: (i) dos índices del promedio de la densidad de la población; (ií) un índice de la concentración del esfuerzo en las áreas de mayor densidad de atún aleta amarilla disponible. Estos tres índices han sido luego usados para determinar: (i) la variación trimestral y anual en cada uno de ellos; (ií) la relación entre los dos índices de densidad; (iii) la relación de cada uno de los índices con el número de rectángulos de un grado explotados. Para evitar la extrema variación del muestreo a bajos niveles de esfuerzo, se eliminaron los datos de todos los rectángulos de un grado sujetos a menos de cinco días de actividad pesquera durante un trimestre según los registros de los cuadernos de bitácora, y las computaciones se repitieron para compararlas con las de los datos originales.