Genome at juncture of early human migration: a systematic analysis of two whole genomes and thirteen exomes from Kuwaiti population subgroup of inferred Saudi Arabian tribe ancestry.

Population of the State of Kuwait is composed of three genetic subgroups of inferred Persian, Saudi Arabian tribe and Bedouin ancestry. The Saudi Arabian tribe subgroup traces its origin to the Najd region of Saudi Arabia. By sequencing two whole genomes and thirteen exomes from this subgroup at high coverage (>40X), we identify 4,950,724 Single Nucleotide Polymorphisms (SNPs), 515,802 indels and 39,762 structural variations. Of the identified variants, 10,098 (8.3%) exomic SNPs, 139,923 (2.9%) non-exomic SNPs, 5,256 (54.3%) exomic indels, and 374,959 (74.08%) non-exomic indels are 'novel'. Up to 8,070 (79.9%) of the reported novel biallelic exomic SNPs are seen in low frequency (minor allele frequency <5%). We observe 5,462 known and 1,004 novel potentially deleterious nonsynonymous SNPs. Allele frequencies of common SNPs from the 15 exomes is significantly correlated with those from genotype data of a larger cohort of 48 individuals (Pearson correlation coefficient, 0.91; p <2.2×10-16). A set of 2,485 SNPs show significantly different allele frequencies when compared to populations from other continents. Two notable variants having risk alleles in high frequencies in this subgroup are: a nonsynonymous deleterious SNP (rs2108622 [19:g.15990431C>T] from CYP4F2 gene [MIM:*604426]) associated with warfarin dosage levels [MIM:#122700] required to elicit normal anticoagulant response; and a 3' UTR SNP (rs6151429 [22:g.51063477T>C]) from ARSA gene [MIM:*607574]) associated with Metachromatic Leukodystrophy [MIM:#250100]. Hemoglobin Riyadh variant (identified for the first time in a Saudi Arabian woman) is observed in the exome data. The mitochondrial haplogroup profiles of the 15 individuals are consistent with the haplogroup diversity seen in Saudi Arabian natives, who are believed to have received substantial gene flow from Africa and eastern provenance. We present the first genome resource imperative for designing future genetic studies in Saudi Arabian tribe subgroup. The full-length genome sequences and the identified variants are available at ftp://dgr.dasmaninstitute.org and http://dgr.dasmaninstitute.org/DGR/gb.html.

Leptin in association with common variants of MC3R mediates hypertension.

BACKGROUND: Recent research illustrates the role of central melanocortin signaling and leptin in the regulation of arterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD: Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS: We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, ß = 4.9). The N-terminus variant (rs3746619 [Thr6→Lys]) is in linkage disequilibrium (r2 = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, ß=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION: An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans.