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Evidence Of Onset And Progression Genes
In An Animal Model Of Diabetes Mellitus Implicates On Age-Specific
QTL Mapping
Marcelo A. Nobrega and Howard J. Jacob
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Introduction
A commonly overlooked issue pertaining to many
complex diseases is that their onset and later progression may
not represent a linear cascade of events linked simply by a
chronological exacerbation of the pathological features. It
is plausible that distinct mechanisms, and as a corollary, genes,
modulate the initiation of a disease and its later rate of progression.
In such a scenario, the genetic factors that determine the severity
of the final pathological outcome are different than those that
triggered the disease process. The elaboration of this paradigm,
namely that the genetic regulation of complex diseases may be
determined by the action of multiple genes that impact the disease
traits asynchronously, predicts that the detection of genes
involved in this process will be time-limited, such that specific
genetic factors can only be detected at certain disease stages,
making the quest to identify genes regulating complex diseases
akin to hitting a moving target. To test the hypotheses that
distinct genes determine the onset and progression of diabetes,
we used the GK rat, a model that spontaneously develops non-insulin-dependent
diabetes mellitus (NIDDM). We carried out a genome-wide scan
in the F2 progeny of a cross between GK/Mcw and control BN/SsNHsd/Mcw
(BN) rats. Diabetes-related phenotypes were assayed at 3 months
of age, and subsequently assessed longitudinally, at 6, 9, and
12 months of age. This design allowed us to map genomic regions
linked to diabetes at different ages in the same F2 population,
evaluating whether the QTLs linked to diabetes at early ages
are also linked at later stages of the disease.
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Summary
592±19mg/dL at 12 months. A total genome
scan was used to map these traits, at 3, 6, 9, and 12 months
of age. Maximum LOD scores at 3, 6, 9 and 12 months, respectively,
at each chromosome; (n.s<2.8):
Chr1: 8.6, 7.2, 2.8, n.s
Chr4: n.s, n.s, n.s, 10.4
Chr5: 4.9, n.s, 4.6, 2.8
Chr10: 4.7, 7.5, 4.6, n.s.
The quantitative effects of the QTLs at chromosome 1 and 4 were
analyzed longitudinally. Thus, in 3-month old BN homozygotes
(B/B) at chromosomes 1 (B/B-1) and 4 (B/B-4), glycemia was 272±14mg/dL,
not significantly different from 292±17mg/dL, observed
in B/B-1 homozygous for GK (G/G) at chromosome 4 (G/G-4). Moreover,
glycemia was 354±24mg/dL in 3-month old G/G-1 and G/G-4
animals, not different than in G/G-1 and B/B-4 animals (396±28mg/dL).
At 12 months, glycemia in G/G-1 and B/B-4 was 389±27mgldL,
showing no increase in spite of an early onset hyperglycemia.
In contrast, glycemia in B/B-1 and G/G-4 increased to 463±15mg/dL
at 12 months. Therefore, onset of hyperglycemia is regulated
independent of chromosome 4 and progression of hyperglycemia
is regulated primarily by chromosome 4. These different loci
will only be detected if phenotyping is performed at specific
ages.
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