M. Geoffrey Hayes

Insulin gene mutations as a cause of permanent neonatal diabetes

We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with β cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially β cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of β cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.

Identification of Type 2 Diabetes Genes in Mexican Americans Through Genome-wide Association Studies

OBJECTIVE—The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a Mexican-American population. RESEARCH DESIGN AND METHODS—We genotyped 116,204 single nucleotide polymorphisms (SNPs) in 281 Mexican Americans with type 2 diabetes and 280 random Mexican Americans from Starr County, Texas, using the Affymetrix GeneChip Human Mapping 100K set. Allelic association exact tests were calculated. Our most significant SNPs were compared with results from other type 2 diabetes genome-wide association studies (GWASs). Proportions of African, European, and Asian ancestry were estimated from the HapMap samples using structure for each individual to rule out spurious association due to population substructure. RESULTS—We observed more significant allelic associations than expected genome wide, as empirically assessed by permutation (14 below a P of 1 × 10−4 [8.7 expected]). No significant differences were observed between the proportion of ancestry estimates in the case and random control sets, suggesting that the association results were not likely confounded by substructure. A query of our top ∼1% of SNPs (P < 0.01) revealed SNPs in or near four genes that showed evidence for association (P < 0.05) in multiple other GWAS interrogated: rs979752 and rs10500641 near UBQLNL and OR52H1 on chromosome 11, rs2773080 and rs3922812 in or near RALGPS2 on chromosome 1, and rs1509957 near EGR2 on chromosome 10. CONCLUSIONS—We identified several SNPs with suggestive evidence for replicated association with type 2 diabetes that merit further investigation.

Hrdlicka's aleutian population-replacement hypothesis : A radiometric evaluation

In a 1945 monograph, Hrdlika argued that, at 1,000 BP, PaleoAleut people on Umnak Island were replaced by NeoAleut groups moving west along the island chain. His argument was based on cranial measurements of skeletal remains from Chaluka Midden and mummified remains from Kagamil and Ship Rock burial caves. By the 1980s, researchers had concluded that the transition demonstrated by Hrdlika, from a high oblong to a lowvaulted wide face, was merely one example of a global trend in cranial morphology and therefore population replacement had not occurred. Calibrated accelerator radiocarbon dates on purified bone collagen from 80 individuals indicate that PaleoAleuts were the oldest population in the Aleutians, with a time depth of ca. 4,000 years, that Paleo and NeoAleuts were fully contemporary on Umnak Island after 1,000 BP, and that the former continued to bury their dead as inhumations long after the introduction of NeoAleut mummification practices. These results as well as features of the Aleut dietary, genetic, and material record suggest that the appearance of NeoAleut people represents an influx of closely related people characterized by greater social complexity and that social disparities that may have existed between Paleo and NeoAleuts were largely subsumed in the social and demographic upheaval following Russian contact.In a 1945 monograph, Hrdlika argued that, at 1,000 BP, PaleoAleut people on Umnak Island were replaced by NeoAleut groups moving west along the island chain. His argument was based on cranial measurements of skeletal remains from Chaluka Midden and mummified remains from Kagamil and Ship Rock burial caves. By the 1980s, researchers had concluded that the transition demonstrated by Hrdlika, from a high oblong to a lowvaulted wide face, was merely one example of a global trend in cranial morphology and therefore population replacement had not occurred. Calibrated accelerator radiocarbon dates on purified bone collagen from 80 individuals indicate that PaleoAleuts were the oldest population in the Aleutians, with a time depth of ca. 4,000 years, that Paleo and NeoAleuts were fully contemporary on Umnak Island after 1,000 BP, and that the former continued to bury their dead as inhumations long after the introduction of NeoAleut mummification practices. These results as well as features of the Aleut dietary, g...

Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population.

AbstractVariation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and ≥50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis ≥50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.

A Genome-Wide Screen for Hyposmia Susceptibility Loci

Olfactory dysfunction is an important public health problem in the United States, with approximately 14 million elderly Americans having chronic olfactory impairment. We performed a genome-wide linkage scan for loci influencing susceptibility to hyposmia in the Hutterites, a founder population of European ancestry. Using interviews regarding the olfactory medical history and psychophysical smell testing, we identified 25 individuals with severe hyposmia. Elimination of subjects with confounding conditions yielded 7 hyposmics for analysis. A 52-member pedigree including all affected individuals was constructed from the larger, >1623-member pedigree, and a genome-wide screen for loci influencing the trait of hyposmia using 1123 markers was performed. The most significant evidence for linkage with hyposmia extended over a 45 cM region on chromosome 4q (P = 0.0013). Although this signal meets the criteria for suggestive linkage only and will require replication, these results offer the strongest data to date on the effects of genetic variation on olfactory dysfunction.

Variation in the perilipin gene (PLIN) affects glucose and lipid metabolism in non-Hispanic white women with and without polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetes mellitus (T2DM). Since obesity plays an important role in the etiology of PCOS, we sought to determine if variants in the perilipin gene (PLIN), a gene previously implicated in the development of obesity, were also associated with PCOS. We typed six single nucleotide polymorphisms (haplotype tagging and/or previously associated with obesity or related metabolic traits) in PLIN in 305 unrelated non-Hispanic white women (185 with PCOS and 120 without PCOS). None of the variants was associated with PCOS (P<0.05). However, the variant rs1052700*A was associated with increased risk for glucose intolerance (impaired glucose tolerance or T2DM) in both non-PCOS (OR=1.75 [1.02-3.01], P=0.044) and PCOS subjects (OR=1.67 [1.08-2.59], P=0.022). It was also associated with increased LDL (P=0.007) and total cholesterol levels (P=0.042). These results suggest that genetic variation in PLIN may affect glucose and lipid metabolism in women both with and without PCOS.