This study investigated associations between single nucleotide polymorphisms (SNP) in the leptin, leptin receptor, and neuropeptide Y (NPY) genes with growth, milk production, and fertility traits. Holstein Friesian heifers from 19 UK dairy farms were recruited at birth, providing an initial population of 509. Animals were monitored until they either reached the end of their second lactation or were culled. Size (weight, height, length, girth) was measured at 1, 6, and 15 mo to assess growth traits. Heifer fertility was assessed by recording age at service, age at conception, age at first calving, and number of services. Cow fertility was assessed by recording days from calving to service and conception, services per conception, percentage of animals in calf at 100 d after calving and the calving interval in each lactation. Milk production was recorded as days in milk, total milk per lactation, 305-d yield, milk per day, and peak yield. Mixed model analyses revealed that leptin SNP were associated with early skeletal growth (height, A1457G; length, A59V), fertility (UASMS1, UASMS2, A1457G, A59V) and milk production (A59V). The leptin receptor SNP (T945M) was only weakly associated with milk per day and days to first service. The NPY SNP (NPY1) was associated with the prevalence of the animal being in calf 100 d after calving and 305-d milk yield in the first lactation. The association of leptin SNP with fertility traits in heifers, in addition to lactating cows, suggests that some effects on fertility are direct and not necessarily mediated via altered tissue mobilization. In accord with this, other work has shown that leptin can affect oocyte quality and early embryo development. These results support the use of leptin SNP to inform marker-assisted selection in dairy cows.

Abstract. Dairy cows mobilise body tissues to support milk production and, because glucose supplies are limited, lipids are used preferentially for energy production. Lipogenic activity is switched off and lipolytic mechanisms in adipose tissue increase through changes in the expression of several key enzymes. This results in a loss of body condition, together with high circulating concentrations of non-esterified fatty acids. Changes in the synthesis, secretion and signalling pathways of somatotrophic hormones (insulin, growth hormone, insulin-like growth factor 1) and adipokines (e.g. leptin) are central to the regulation of these processes. A high reliance on fatty acids as an energy source in the peripartum period causes oxidative damage to mitochondria in metabolically active tissues, including the liver and reproductive tract. The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway. Polymorphisms in TFAM and UCP2, two autosomal mitochondrial genes, have been associated with longevity in dairy cows. Polymorphisms in many other genes that affect lipid metabolism also show some associations with fertility traits. These include DGAT1, SCD1, DECR1, CRH, CBFA2T1, GH, LEP and NPY. Excess lipid accumulation in oocytes and the regenerating endometrium reduces fertility via reductions in embryo survival and increased inflammatory changes, respectively.

Leptin is an important regulator of fetal and placental growth. This study evaluated the association of single nucleotide polymorphisms (SNP) in the leptin gene with perinatal mortality (stillbirths and mortality within 24h of parturition) in 385 Holstein-Friesian heifers on 18 dairy farms in the United Kingdom. The 3 SNP evaluated were exon 2FB, UASMS1, and UASMS2. The mean age at first calving was 27.0+/-0.2 mo. Associations between each SNP and perinatal mortality (calf alive or dead) were tested using a generalized linear model that included herd-year-season, calf sex, age at first calving, and age and pedigree of the dam. The overall level of perinatal mortality in the population was 16.9%, with significant allelic substitution effects for exon 2FB and UASMS1. These 2 SNP were in close linkage disequilibrium with each other (r(2)=0.98) but not with UASMS2 (r(2)=0.10). For exon 2FB, perinatal mortality was similar between heifers carrying the CT and TT alleles (20%), but was higher than in heifers carrying the CC allele (11%). For UASMS1, mortality was 21% with the CC and CT alleles but only 10% with the TT allele. No associations of perinatal mortality with SNP were found in the UASMS2 data set, possibly influenced by the low frequency (2%) of the TT genotype. No significant effects of herd-year-season, age at first calving, or calf sex were found. In conclusion, polymorphisms in the leptin gene were associated with 2-fold differences in perinatal mortality in dairy heifers.

Insulin-like growth factor binding protein-2 (IGFBP2) is a key regulator of IGF activity that has been associated with insulin resistance and obesity. In cows, IGFBP2 mRNA expression is differentially regulated according to nutritional status in different tissues including the liver, reproductive tract, and mammary gland. This study investigated associations between single nucleotide polymorphisms (SNPs) in bovine IGFBP2 with fertility, milk production, and metabolic traits in Holstein-Friesian dairy cows. Fertility was assessed in heifers by measuring age at first service, age at first conception, and age at first calving. During the first and second lactation, the number of postpartum days for commencement of luteal activity (based on milk progesterone profiles), days to first service, days to conception, average milk production per day, 305-day milk yield, total milk yield, and total days in milk were recorded. Blood samples were taken at -1, +1, and +8 weeks relative to first and second calving for assessment of metabolic status (IGF1, insulin, beta-hydroxybutyrate, and glucose). Five novel SNPs were identified in IGFBP2, two of which had significant associations with fertility (age at conception in heifers and commencement of luteal activity) and 305-day milk yield in lactation 1. Trends of association were also observed with the peripartum metabolic status, in particular the glucose, insulin, and beta-hydroxybutyrate concentrations around second calving. These results indicate that IGFBP2 SNPs may influence tissue mobilization in dairy cows and may thus be of interest for marker assisted selection.

The autosomal genes mitochondrial transcription factor A (TFAM) and uncoupling protein 2 (UCP2) are both involved in moderating mitochondrial energy production. This study investigated single nucleotide polymorphisms (SNPs) in TFAM and UCP2 and their associations with growth, fertility, milk production and survival in UK dairy cows. Holstein-Friesian heifers (n = 509) were recruited at birth and monitored until they either reached the end of their second lactation or were culled. Weight, height, length and girth were measured at 1, 6 and 15 months of age to assess growth. Fertility records were obtained for both heifers and cows and production traits (milk per day, peak yield and 305-day yield) were recorded in the first and second lactation. Mixed model and survival analyses revealed that TFAM3 GG homozygotes, representing 49% of the population, were larger than the AG heterozygotes throughout the growing period, had worse fertility, produced less milk in both lactations and were more likely to be culled. TFAM3 AA homozygotes (7% of population) were generally smaller as heifers, had slightly worse fertility and also produced less milk. This suggests a clear advantage for maximizing the heterozygotic population for this SNP. Furthermore, the results for milk per day suggest an overdominant effect, as both homozygotes of TFAM3 had significantly lower yields than the heterozygote. For UCP2, the minority CG heterozygotes (6% of population) were larger as heifers, had a reduced age at first conception and a delayed return to cyclicity after calving, when compared against the majority (94%) GG homozygotes.