THE VARIABILITY OF MULTI-DRUG RESISTANCE ABCB1 GENE IN THE ROMA POPULATION FROM CROATIA

When overexpressed, a large transmembrane P-glycoprotein, the product of the ABCB1 gene, is a notable impediment to brain-targeted therapies (like antiepileptics) and chemotherapies. Some of the genetic biomarkers with evidence of multi-drug resistance in ABCB1 ― rs1045642, rs1128503, and rs3213619 ― were analyzed in 440 subjects, members of three socio-culturally different Roma (Gypsy) groups of Croatia. Minor allele frequencies (MAFs) of rs1045642 and rs1128503 were the highest in the Balkan Roma (63.6% and 69.4%, respectively) when compared to the Baranja (52.3% and 62.5%) and the Međimurje Roma (48.8% and 54.5%) (p=0.0005 and p=0.0011, respectively). rs3213619 was monomorphic in the Međimurje group, while its MAFs in other two Roma groups were very low (<1.9%). The distribution of five detected haplotypes (four in the Međimurje group) significantly differed between the Roma subpopulations (p<0.0001), just like the frequencies of diplotypes (p=0.0008). At a global scale, the positive relationship between genetic and geographic distances between the 21 investigated populations indicates isolation by spatial distance. However, this is not true for the relationship between Roma and other populations due to their population history. The analyzed ABCB1 loci indicate genetic distinctiveness of the Roma population

3000 years of solitude: extreme differentiation in the island isolates of Dalmatia, Croatia

Communities with increased shared ancestry represent invaluable tools for genetic studies of complex traits. '1001 Dalmatians' research program collects biomedical information for genetic epidemiological research from multiple small isolated populations ('metapopulation') in the islands of Dalmatia, Croatia. Random samples of 100 individuals from 10 small island settlements (n<2000 inhabitants) were collected in 2002 and 2003. These island communities were carefully chosen to represent a wide range of distinct and well-documented demographic histories. Here, we analysed their genetic make-up using 26 short tandem repeat (STR) markers, at least 5 cM apart. We found a very high level of differentiation between most of these island communities based on Wright's fixation indexes, even within the same island. The model-based clustering algorithm, implemented in STRUCTURE, defined six clusters with very distinct genetic signatures, four of which corresponded to single villages. The extent of background LD, assessed with eight linked markers on Xq13-21, paralleled the extent of differentiation and was also very high in most of the populations under study. For each population, demographic history was characterised and 12 'demographic history' variables were tentatively defined. Following stepwise regression, the demographic history variable that most significantly predicted the extent of LD was the proportion of locally born grandparents. Strong isolation and endogamy are likely to be the main forces maintaining this highly structured overall population

SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200?500 lM) compared with other mammals (3?120 lM)1. About 70% of daily urate disposal occurs via the kidneys, and in 5?25% of the human population, impaired renal excretion leads to hyperuricemia2. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7?5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter3, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P &lt; 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance