@article {1340, title = {Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Oct 31}, pages = {8514-9}, abstract = {

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 {\texttimes} 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 {\texttimes} 10(-7)) and rs17501108 (P = 9.9 {\texttimes} 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 7, Corneal Topography, Enzyme-Linked Immunosorbent Assay, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hepatocyte Growth Factor, Humans, Keratoconus, Middle Aged, Nucleic Acid Hybridization, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Tagged Sites}, issn = {1552-5783}, doi = {10.1167/iovs.11-8261}, author = {Burdon, Kathryn P and Macgregor, Stuart and Bykhovskaya, Yelena and Javadiyan, Sharhbanou and Li, Xiaohui and Laurie, Kate J and Muszynska, Dorota and Lindsay, Richard and Lechner, Judith and Haritunians, Talin and Henders, Anjali K and Dash, Durga and Siscovick, David and Anand, Seema and Aldave, Anthony and Coster, Douglas J and Szczotka-Flynn, Loretta and Mills, Richard A and Iyengar, Sudha K and Taylor, Kent D and Phillips, Tony and Montgomery, Grant W and Rotter, Jerome I and Hewitt, Alex W and Sharma, Shiwani and Rabinowitz, Yaron S and Willoughby, Colin and Craig, Jamie E} } @article {1261, title = {A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Mar 15}, pages = {1241-51}, abstract = {

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 {\texttimes} 10(-8) (P = 3.3 {\texttimes} 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 {\texttimes} 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 {\texttimes} 10(-21)) and higher IGF-I (P = 4.9 {\texttimes} 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 {\texttimes} 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 {\texttimes} 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5\% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 {\texttimes} 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

}, keywords = {Aged, Chromosomes, Human, Pair 7, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddq560}, author = {Kaplan, Robert C and Petersen, Ann-Kristin and Chen, Ming-Huei and Teumer, Alexander and Glazer, Nicole L and D{\"o}ring, Angela and Lam, Carolyn S P and Friedrich, Nele and Newman, Anne and M{\"u}ller, Martina and Yang, Qiong and Homuth, Georg and Cappola, Anne and Klopp, Norman and Smith, Holly and Ernst, Florian and Psaty, Bruce M and Wichmann, H-Erich and Sawyer, Douglas B and Biffar, Reiner and Rotter, Jerome I and Gieger, Christian and Sullivan, Lisa S and V{\"o}lzke, Henry and Rice, Kenneth and Spyroglou, Ariadni and Kroemer, Heyo K and Ida Chen, Y-D and Manolopoulou, Jenny and Nauck, Matthias and Strickler, Howard D and Goodarzi, Mark O and Reincke, Martin and Pollak, Michael N and Bidlingmaier, Martin and Vasan, Ramachandran S and Wallaschofski, Henri} }